Kurzgesagt – In a Nutshell 

Sources – Cancer City


We thank the following experts for their help with this script:


Assistant Professor, Georgia State University, USA


H. Lee Moffitt Cancer Center & Research Institute, USA




– An undead city under siege, soldiers and police ruthlessly shooting down waves of zombies that flood from infected streets, trying to escape and infect more cities. This is what happens when your body fights cancer, more exciting than any movie. How does this battle for survival unfold?


In this video we explain the concept of cancer immunoediting. Simply put, it is a framework for explaining the interactions between the immune system and cancer, and the ways in which the immune system shapes the fate of the cancer. It is explained to happen in three phases: 

1- Elimination, where the immune system destroys transformed, not-yet-cancer cells. 

2- Equilibrium, where a few cells which skipped through the elimination get edited by the immune system

3- Escape, where cancer cells grow progressively, establish the tumor microenvironment and become clinically visible. 


In the rest of the video and in the following we look a bit more in detail at what happens in each stage. 


Though the research has a longer history, the framework was outlined relatively recently in the following landmark paper and summarized in the following figure from the paper:


#Schreiber et al. Cancer Immunoediting: Integrating Immunity’s Roles in Cancer Suppression and Promotion. 2011

https://www.science.org/doi/10.1126/science.1203486

Quote: “We postulate that the cancer immunoediting process, in its most complex embodiment, proceeds sequentially through three distinct phases that we have termed “elimination,” “equilibrium,” and “escape” (Fig. 3) (18, 24–29). However, in some cases tumor cells may directly enter into either the equilibrium or escape phases without passing through an earlier phase. In addition, external factors may influence the directionality of the flow. The latter consideration may help explain the influences of environmental stress, immune system deterioration accompanying aging, and even immunotherapeutic intervention on tumor cell outgrowth in human cancer patients.”

The processes and the involved immune players depicted in the above figure were a summary of the research findings up until that time and more and more evidence in support of the framework accumulated later on. The complexity of both the immune system and cancer have made it challenging to study the interaction between the two. But with new techniques and experiments, more parts of the framework is uncovered and it has been established as an active research field since then. 


For further reading, follow-up paper from the same authors reporting on the updates on the concept with new research after the initial paper: 

#Mittal et al. New insights into cancer immunoediting and its three component phases — elimination, equilibrium and escape. 2014.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4388310/pdf/nihms-580653.pdf


The Elimination Phase


– It all begins with a single corrupted cell. It is no longer able to repair its genetic code, it can’t kill itself anymore and it is beginning to multiply rapidly. At this point things are not great, not terrible – this cell is not yet dangerous but if nothing happens, it soon will be.


Transformation of normal cells to cancer cells is called carcinogenesis. Researchers divide carcinogenesis in three stages: tumor initiation, tumor promotion and tumor progression. What we, throughout this video, basically refer to as ‘cancer cells’ actually have different features in each stage and are referred to with different names. 


Following figure and table summarize these stages and characteristics of each stage respectively. Though it might look like all the different names make it more complicated, the multistage process is actually helpful to understand that cancer is a dynamic and indeed complicated disease. So to clarify the terminology for the rest of the video: The “single corrupted cell” refers to the Initiated cell, as shown in the following figure. The new, autonomous growth of a tissue in the last stage Progression is referred to as Neoplasia. Neoplasms can be benign or malignant (invasive), and essentially the malignant neoplasms are called cancer. Tumor is the general term that can refer to mass of benign or malignant neoplasm.


#James E. Klaunig. An Introduction to Interdisciplinary Toxicology, Chapter 8 - Carcinogenesis. 2020.

https://www.sciencedirect.com/science/article/pii/B9780128136027000089

This multistage process is studied mostly for chemical carcinogenesis, not for inducers like viruses or radiation.

 The first stage, Initiation, involves the production of a stable, heritable mutational change in a normal cell. This is not necessarily sufficient for neoplasm formation. There are several paths for the initiated cell: 


Initiated cells might progress through all three stages of the cancer process following high or repeated exposure to DNA damaging agents. These agents are generally called complete carcinogens. 



– Over a few weeks the corrupted cell keeps making copies of itself. One cell turns into dozens, hundreds, thousands. Because the original was broken, its copies are breaking and mutating even more. They turn into different genetic lineages, clans that are working together and competing. 


This refers to the first phase of the Promotion where the initiated cells attain growth autonomy through which they undergo mainly a quantitative expansion, and they turn into a focal lesion or preneoplastic lesion. External or internal agents can be tumor promoters but those are not necessarily causing mutations or damaging DNA, but can still be carcinogenic. They modify gene expression through which they can increase cell proliferation and/or inhibit apoptosis of the initiated cell. Tumor promotion is dose dependent and reversible.


 

#Weston A, Harris CC. Multistage Carcinogenesis. In: Kufe DW, Pollock RE, Weichselbaum RR, et al., editors. Holland-Frei Cancer Medicine. 2003. 

https://www.ncbi.nlm.nih.gov/books/NBK13982/

Quote: “Tumor promotion comprises the selective clonal expansion of initiated cells. Because the accumulation rate of mutations is proportional to the rate of cell division, or at least the rate at which stem cells are replaced, clonal expansion of initiated cells thus, produces a larger population of cells that are at risk of further genetic changes and malignant conversion.19,28 Tumor promoters are generally nonmutagenic, are not carcinogenic alone, and often (but not always) are able to mediate their biologic effects without metabolic activation. These agents are characterized by their ability to reduce the latency period for tumor formation after exposure of a tissue to a tumor initiator, or to increase the number of tumors formed in that tissue.”



#Laconi, Doratiottoa and Vineis. The microenvironments of multistage carcinogenesis. 2008.

https://www.sciencedirect.com/science/article/abs/pii/S1044579X08000400

Quote: ”In light of these facts, two questions emerge as particularly relevant to the biology of cancer development in these systems:

(i) How do focal proliferative lesions arise?

(ii) How do they evolve towards cancer?

According to classical multistage modelling of carcinogenesis, the first question refers to the process of tumor promotion or selection, while the second encompasses the long phase of tumor progression. Broadly speaking, tumor promotion consists of the selective (clonal) expansion of altered cells to form focal lesions [3]. Within this definition, the process of promotion is mainly a quantitative phenomenon (many cells arising from a single cell), while no qualitative changes are necessarily implied; it is a fact that cell populations in early nodules, papillomas, or polyps are rather homogeneous in size and shape, or in the expression of specific biochemical markers [1]. However, these latter properties are lost during tumor progression, which is typically characterized by increasing levels of tumor cell heterogeneity. This implies that qualitative changes are now dominant [4], generating distinct cellular sub-clones with different phenotypes. Such a background represents the landscape for the full deployment of tumor progression.”

#Mel Greaves & Carlo C. Maley. Clonal evolution in cancer. 2012

https://www.nature.com/articles/nature10762

Quote: “In most cases, transformation and metastases are probably clonal2 because they are derived from single cells; therefore, the identification of the mutations present in all of the cells of a tumour can help to reconstruct the genotype of the founder cell. These founder events limit the genetic and clonal complexity of tumours. We already had a long list of recurring driver mutations (with gain or loss of function) as a result of the fine mapping of chromosomal breaks, candidate gene sequencing and functional screening of bulk samples from tumours. However, the use of genomic screens has demonstrated the scale of cancer-genome complexity. Individual cancers can contain hundreds, or tens of thousands, of mutations and chromosomal alterations2. The great majority of these are assumed to be neutral mutations arising from genetic instability. Chromosomal instability (amplifications, deletions, translocations and other structural changes) is a common feature, but it is not clear whether there is an increased rate of simple base-pair mutations in cancer2,21,23,52. Evolutionarily neutral alterations are thought to register in the screens because they hitchhike on clonal expansions that are driven by selectively advantageous alterations or by drift. In addition, data have confirmed that each cancer in each patient has an individually unique genomic profile. It is possible that cancer cells need only a modest number of phenotypic traits to deal with all of the constraints and evolve into a fully malignant or metastatic tumour25, but the genomics data suggest that this can be achieved by an almost infinite variety of evolutionary trajectories and with multiple different combinations of driver mutations44.”



– Some mutate in a way that makes them weaker, others’ mutations don’t change anything, while a few become more fit and better at survival. Together they now form a tiny, tiny tumor. Not cancer yet, but getting there.


Cancers evolve by a reiterative process of expansion of transformed cells with identical genomes (clonal expansion), genetic diversification due to mutations on this clonal population, and then selection of a certain subpopulation from this new cells with different genomes (clonal selection) and further expansion of these new cells. So cancer cells in a tumor are not all identical and in some way, each cancer multiplies different cancers within overlapping or distinct tissue neighborhoods. Consequently, each cancer is individually unique, even though a small amount of features may be sufficient to have full malignant cancer, there are many pathways through which these traits can arise. 


This genomic variation can arise as a result of accumulation of random, neutral mutations and turn out to be non-functional (passenger mutations), under a selection process that favors mutations with advantageous functions (driver mutations). Most of the mutations are passengers, but a smaller number are functionally relevant drivers. Clonal evolution is an interplay of these changes as well as deleterious mutations, mutations that increase the rate of other genetic changes and changes to the microenvironment that influence the fitness effects of those mutations.


One way to think of this variation could be seen as an effort of the tumor cells searching for solutions to survive the restrictions imposed by the tissue microenvironment they are in. As the tumor gets bigger, the restrictions may limit the growth. While cancer cells can double in ~1–2 days, tumors can do so in ~60–200 days, which implies that most cancer cells die before they can divide.


#Greaves and Maley. Clonal Evolution In Cancer. 2012.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3367003/pdf/nihms377748.pdf

#Black & McGranahan. Genetic and non-genetic clonal diversity in cancer evolution. 2021.

https://www.nature.com/articles/s41568-021-00336-2

– The growing tumor needs a lot of resources. If the cells don’t get food and oxygen, they will die and the problem just solved itself. Unfortunately a few corrupted cells unlocked a new mutation that saves them: The ability to order the growth of new blood vessels. And so your body provides the supply they need to survive. 


Like normal cells, tumor cells require nutrients and oxygen, and need to get rid of CO2 and waste. They do this by forming new blood vessels which is the process called angiogenesis. If they fail at this, they can’t sustain themselves and grow further. 


#Nishida et al. Angiogenesis in cancer. 2006.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1993983/pdf/vhrm0203-213.pdf

Quote: “In a previous study, Muthukkaruppan and colleagues (1982) compared the

behavior of cancer cells infused into different regions of the same organ. One region

was the iris with blood circulation; another was the anterior chamber without circulation. The cancer cells without blood circulation grew to 1–2mm3 in diameter and then stopped, but grew beyond 2mm3 when placed in an area where angiogenesis was possible. In the absence of vascular support, tumors may become necrotic or even apoptotic (Holmgren et al 1995; Parangi et al 1996). Therefore, angiogenesis is an important factor in the progression of cancer.”


During embryogenesis new blood vessels sprout through angiogenesis but in adults angiogenesis is turned on only for a few occasions like wound healing or for menstrual cycle. However, this process remains in an on-state in cancer promoting the expansion of tumor cells. There is not a single effector molecule that turns the blood vessel formation on, rather there are dozens of activator and inhibitor molecules, whose expression tips the balance towards the action of the more heavily expressed molecules and triggers the Angiogenic Switch. In cancer, mutations in the tumor cells (that cause increased proliferation and hypoxia, or lead to production of factors supporting blood vessels formation)  or inflammation caused by tumor cells can trigger the release of molecules that turns this switch on. This switch changes the tumor from dormant to a rapid growth state. 


#Nishida et al. Angiogenesis in cancer. 2006.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1993983/pdf/vhrm0203-213.pdf

Quote: “Angiogenesis is regulated by both activator and inhibitor molecules. The switch to the angiogenic phenotype involves a change in the local equilibrium between positive and negative regulators of angiogenesis. This signaling activates certain genes in the host tissue that make proteins which encourage the growth of blood vessels (Majima et al 2000; Semenza 2002). Cancer cells require access to blood vessels for growth and metastasis.”

Basically, formation of blood vessels is a four step process:

1. Local injury in the basement membrane causes destruction and hypoxia. 

2. Angiogenic factors activate endothelial cells and they migrate to the site. 

3. Endothelial cells proliferate and stabilize. 

4. Angiogenic factors continue to maintain the process.


There are other phenotypes but one way this process can be triggered in cancer is through hypoxia, which means not having enough oxygen to maintain the normal functioning of tissues. In case of cancer, increased distance between the tumor and the capillaries (or inefficiency of new blood vessels) can cause hypoxia. This will trigger Hypoxia-Inducible Factor-1α (HIF-1α) which is a transcription factor that regulates response to oxygen). This in turn induces the expression of Vascular Endothelial Growth Factor (VEGF, a signaling protein that stimulates production of new blood vessels) and its receptor. 

When tumor cells encounter an endothelial cell (EC, the cell type that makes up the inner lining of blood vessels), the VEGF, which is produced by the tumor cell, binds to the receptors on ECs. This activates other proteins that transmit a signal to the EC nucleus which triggers genes that would make the needed proteins for new ECs. For example, VEGF-activated ECs produce enzymes that can break down extracellular matrix which permits the migration of ECs. ECs divide as they migrate to nearby tissues, they organize into tubes that eventually turn into a network of vessels with the help of further molecules like adhesion and stabilization factors.


The following image shows the basic steps initiated by VEGF secretion by tumor cells, activating an endothelial cell to turn into a tip cell. This mechanism is called sprouting angiogenesis.


#Mabeta and Steenkamp. The VEGF/VEGFR Axis Revisited: Implications for Cancer Therapy. 2022

https://doi.org/10.3390/ijms232415585

This is only one of the ways though that new blood vessels form in tumors. The next figure from the following paper summarizes the other mechanisms. 


#Lugano, Ramachandran and Dimberg.Tumor angiogenesis: causes, consequences, challenges and opportunities. 2020.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7190605/pdf/18_2019_Article_3351.pdf

Quote: “Tumor vascularization occurs through several distinct biological processes, which not only vary between tumor type and anatomic location, but also occur simultaneously within the same cancer tissue. These processes are orchestrated by a range of secreted factors and signaling pathways and can involve participation of non-endothelial cells, such as progenitors or cancer stem cells. Anti-angiogenic therapies using either antibodies or tyrosine kinase inhibitors have been approved to treat several types of cancer. However, the benefit of treatment has so far been modest, some patients not responding at all and others acquiring resistance. It is becoming increasingly clear that blocking tumors from accessing the circulation is not an easy task to accomplish. Tumor vessel functionality and gene expression often differ vastly when comparing different cancer subtypes, and vessel phenotype can be markedly heterogeneous within a single tumor. Here, we summarize the current understanding of cellular and molecular mechanisms involved in tumor angiogenesis and discuss challenges and opportunities associated with vascular targeting.”

Tumor vessels are structurally and functionally different from normal blood vessels. The new vessel network may not divide into neatly organized capillaries, vessel sizes may be varied and the blood flow in this chaotic arrangement can be inefficient. The following image from the paper above compares a healthy vessel to a tumor vessel in a tumor in the mouse brain.  

– But as the tumor grows further, it starts causing damage. Neighboring healthy cells begin to starve and die, which attracts attention. In a sense this tiny tumor is like a rogue town.


As they are clumsily building new blood vessels, cancer cells mess up with the healthy tissue structure around or they suffocate themselves due their inefficient vessel network. They create disturbances, in a way similar to a wound. Under normal conditions, a similar external damage calls out for immune cells to restore order. Damaged cells would release alarm molecules (called alarmins or Danger-Associated Molecular Patterns (DAMPs)) on their cell membrane, which would call the immune cells to the site. Similarly, damaged surrounding cells and cancer cells themselves produce these molecules and propagate inflammation 


#Cendrowicz et al. The Role of Macrophages in Cancer Development and Therapy. 2021

https://www.mdpi.com/2072-6694/13/8/1946

Quote: ”The rapid proliferation of cancer cells results in the fast growth of tumor mass and increased demand for nutrients and oxygen. Essential nutrients are delivered to the tumor by a capillary network formed in the process of neoangiogenesis. The formation of new vessels is regulated by the growth factors released by cells in the TME [34]. Due to poor regulation, the structure and function of newly formed vessels are abnormal with increased vessel permeability, which contributes to disease progression [35]. Hypoxic regions of tumor tissue are formed due to the rapid and uncontrolled cell growth and are accompanied by an increased rate of cancer cell death. Tumor-Associated Macrophages (TAMs) infiltrate these hypoxic regions to regain homeostasis through stimulation of new blood vessel formation. The process of neoangiogenesis is modulated by many factors produced by TAMs, including VEGF, matrix metalloproteinases (MMPs), platelet-derived growth factor (PDGF), and angiopoietin-1 (Figure 2) [36,37]. VEGF induces proliferation and maturation of endothelial cells by engaging the VEGF Receptor 2 (VEGFR2) expressed on the endothelial cells (ECs) [37]. VEGF also stimulates the chemotaxis of macrophages and ECs.”


– Imagine a group of rebels in Brooklyn decided that they were no longer part of New York but started a new settlement called Tumor Town, which happens to occupy the same space. The new city wants to grow, so it orders tons of steel beams, cement and drywalls. New buildings follow no logic, are badly planned, ugly and dangerously crooked. They are built right in the middle of streets, on top of playgrounds and on existing infrastructure. The old neighborhood is torn down or overbuilt to make room for new stuff. Many of the former residents are trapped in the middle of it and begin to starve.  This goes on for a while until the smell of death finally attracts attention. Building inspectors and police show up.


Obviously the metaphor simplifies a lot here but there is great merit to it. Cancer is not just an isolated lump of mutated cells, it’s more like an ecosystem, made up of cancer cells, but also non-cancer cell types and various molecules. This whole thing is called the tumor microenvironment (TME) and is indeed a bustling neighborhood with constant traffic in and around it. Besides tumor cells, it includes - but not limited to- immune cells, blood cells, endothelial cells, fat cells and stroma. Stroma is basically the functional cellular structures and the noncellular connective tissue supporting them. We are not going to look into the contributions of each of these cell types in TME in this video, except for the immune cells. But in short, endothelial cells provide nutrients for tumor growth and can make up routes for the cancer cells to invade other tissues through construction of new blood vessels. Pericytes (cells that wrap around the endothelial cells making up capillaries) contribute to vessel formation and might cause resistance to therapies that target the vessel formation in tumors. Adipocytes (fat cells) secrete signaling molecules which cancer cells can take advantage of. 


Matching the construction metaphor, the function of stroma is to structure and remodel the tissue in healthy tissues  - and for the newly moving cancer cells who are in the process of carving some space for themselves, construction is crucial. As summarized in the figure below, various specialized connective tissue cells like fibroblasts, mesenchymal stromal cells (MSC), osteoblasts (bone cells that synthesize new bone matrix), chondrocytes (cell found in joints that synthesize new cartilage matrix), and the extracellular matrix (ECM) are all working in harmony at their designated construction tasks in healthy (Nonmalignant) tissue. 


#Valkenburg, de Groot & Pienta. Targeting the tumour stroma to improve cancer therapy. 2018.

https://www.nature.com/articles/s41571-018-0007-1

As cancer cells copy themselves, they pull out the resources and other types of cells like fibroblasts, endothelial cells (for new blood vessels), extracellular matrix (ECM, e.g.structural proteins like elastin and collagen), all of which collectively known as tumor stroma. With the addition of immune cells to this environment in the later stages, cancer cells slowly build something different than your healthy tissues but with the same types of structural cells. These different cell types can be utilized by cancer cells to grow and even invade further tissues, so the progression is not only determined by autonomous behavior of cancer cells but by their interactions with tumor stroma. Tumor cells can reside in stroma and transform it, they can change the connective tissue nearby, or modify the metabolism of the healthy resident cells so create a more tolerant stroma for further cancer growth. And all this interaction is facilitated through receptors (like integrin) and signaling molecules like growth factors, chemokines and cytokines. Host cells secrete a cascade of molecules in response to tumor stimuli (like inflammation) which can promote signaling cascades helping tumor cells to invade the surrounding basement membrane and extracellular matrix. Some chemokines, for instance, can increase the permeability of endothelial cells of vasculature, making it easier for the cancer cells to pass through the bloodstream. 

Cytokines are small proteins that bind to specific cell surface receptors and regulate immunity, inflammation and hematopoiesis. Chemokines are smaller cytokines that are mostly taking part in cell chemotaxis and trafficking. 


#The Role of Tumor Stroma in Cancer Progression and Prognosis

https://www.jto.org/action/showPdf?pii=S1556-0864%2815%2931920-1

Quote: “The tumor stroma basically consists of (1) the nonmalignant cells of the tumor such as CAFs, specialized mesenchymal cell types distinctive to each tissue environment, innate and adaptive immune cells,13,18 and vasculature with endothelial cells and pericytes19,20 and (2) the extracellular matrix (ECM) consisting of structural proteins (collagen and elastin), specialized proteins (fibrilin, fibronectin, and elastin), and proteoglycans (Table 1).21”

#Friends or foes — bipolar effects of the tumour stroma in cancer

https://www.nature.com/articles/nrc1477

Quote: “Reciprocal interaction between tumor cells and other cell types occurs in different ways, including direct cell-to-cell contact, secreted molecules and cargo vesicles known as exosomes. Cancer cells express various cell surface ligands that can directly interact with membrane receptors present on other cell types in the vicinity (6). One such class of receptors is the integrins. Integrins bind cells to the ECM and respond to shear stress (6, 7). Cancer cells also shed vesicles loaded with nucleic acids, peptides and metabolites that can fuse with other cells. Extracellular vesicles play role in angiogenesis (8) immunosuppression (9), aid in crosstalk of cancer cells with fibroblasts (10) and development of premetastatic niche (11, 12).”  

“However, the most extensively studied mode of cancer cell interactions is through secreted molecules. The major type of secreted signaling molecules are growth factors, cytokines/chemokines, inflammatory mediators, and metabolites. Soluble ligands secreted by cancer cells bind to their cognate cell surface receptors present on stromal cells, or vice-versa, and activate specific signaling pathways.“



#Hussain et al. The Roles of Stroma-Derived Chemokine in Different Stages of Cancer Metastases. 2020. 

https://www.frontiersin.org/articles/10.3389/fimmu.2020.598532/full

– In your body, attracted by the stench of dead cells, your immune system is activated. First responder immune cells invade the tumor: Macrophages and Natural Killer Cells, police forces that go right to work, killing and eating tumor cells. They release chemical signals that let the whole immune system know that there is cancer to be eradicated. Dendritic Cells, the intelligence officers of your immune system, collect samples of dead tumor cells and begin activating your heavy weapons: Helper and Killer T Cells. 


The immune system executes a series of steps to take control of the cancer, which is called the cancer-immune cycle: 

1) Dendritic cells (DCs) acquire the antigens released from the dead cancer cells and move to the nearest draining lymph node (DLN). 

2) DCs present antigens to T cells through MHC- I and MHC-II molecules. 

3) Effector T cells are activated by recognizing this antigen 

4) Antigen-recognizing cancer-specific T cells in the DLN express the cell adhesion molecules and chemokine receptors necessary for migration and infiltration into the tumor, and then leave the DLN and move through the blood toward the tumor tissue. 

5) These T cells then infiltrate into the tumor  

6) They recognize and bind the MHC-I–antigen complex presented by cancer cells through the T cell receptor (TCR). 

7) Through these processes, cancer cells are finally killed. 


When cancer cells die and additional cancer-antigens are released, the cycle repeats and is amplified compared to the previous cycle.


#Chen & Mellman. Oncology Meets Immunology: The Cancer-Immunity Cycle. 2013.

https://www.cell.com/action/showPdf?pii=S1074-7613%2813%2900296-3

To put simply, the elimination phase can be summarized as one cycle of this process. A more detailed explanation can be found in the following paper. 


#Dunn et al. Cancer immunoediting: from immunosurveillance to tumor escape. 2002. 

https://www.nature.com/articles/ni1102-991

Quote: ”In the first phase of elimination (Fig. 2a), once solid tumors reach a certain size, they begin to grow invasively and require an enhanced blood supply that arises as a consequence of the production of stromagenic and angiogenic proteins77 Invasive growth causes minor disruptions within the surrounding tissue that induce inflammatory signals leading to recruitment of cells of the innate immune system (NKT, NK, γδ Τ cells, macrophages and dendritic cells) into the site50,78,79. Structures on the transformed cells (either expressed as a result of the transformation process itself or induced by the ongoing but limited inflammatory response) are recognized by infiltrating lymphocytes such as NKT, NK or γδ T cells, which are then stimulated to produce IFN-γ80–82. 


In the second phase (Fig. 2b), the IFN-γ that was initially produced may induce a limited amount of tumor death by means of antiproliferative83 and apoptotic 84 mechanisms. However, it also induces the production of the chemokines CXCL10 (interferon inducible protein-10, IP-10),  CXCL9 (monokine induced by IFN-γ, MIG) and CXCL11 (interferon-inducible T cell α chemoattractant, ITAC) from the tumor cells themselves as well as from surrounding normal host tissues 85–87. At least some of these chemokines have potent angiostatic capacities and thus block the formation of new blood vessels within the tumor, which leads to even more tumor cell death 88–91. Tumor cell debris formed as either a direct or indirect consequence of IFN-γ production at the tumor is then ingested by local dendritic cells, which home to draining lymph nodes. Chemokines produced during the escalating inflammatory process recruit more NK cells and macrophages to the site. 


“In the third phase (Fig. 2c), the tumor-infiltrating NK cells and macrophages transactivate one another by reciprocal production of IFNγ and IL-12, and kill more of the tumor by mechanisms involving tumor necrosis factor–related apoptosis-inducing ligand, perforin and reactive oxygen and nitrogen intermediates 46,92–95. In the draining lymph node, the newly immigrated dendritic cells induce tumor-specific CD4+ T helper cells expressing IFN-γ (TH1 cells) that in turn facilitate the development of tumor-specific CD8+ T cells 96–99. 


In the fourth phase (Fig. 2d), tumor specific CD4+ and CD8+ T cells home to the tumor site, where the cytolytic T lymphocytes destroy the remaining antigen-bearing tumor cells whose immunogenicities have been enhanced by exposure to locally produced IFN-γ49.”

– We explained these specialized super weapons in another video, but all you really need to know is that they have a library with every bad thing that could come into your body.


Here is the link to our video: 

You Are Immune Against Every Disease

https://www.youtube.com/watch?v=LmpuerlbJu0&t=287s



– While each cancer is unique, there are genetic corruptions that they can’t hide.

Tumor antigens are those presented by MHC class I or II molecules on the surface of tumor cells. They can be derived from the driver mutations in tumor suppressor genes, oncogenes.  and can occur as a receptor on the cell, a protein or a glycoprotein in cytoplasm or bound to membrane or sometimes even secreted extracellularly etc. 


#Coulie et al. Tumour antigens recognized by T lymphocytes: at the core of cancer immunotherapy. 2014

https://pubmed.ncbi.nlm.nih.gov/24457417/

– And your T Cells know what to look for. They are the most deadly cancer killers you have.


#Gonzalez, Hagerling and Werb. Roles of the immune system in cancer: from tumor initiation to metastatic progression. 2018.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6169832/pdf/1267.pdf

Quote: “CD8+ T cells are the most prominent anti-tumor cells. Upon priming and activation by APCs, the CD8+ T cells differentiate into cytotoxic T lymphocytes (CTLs) and, through the exocytosis of perforin- and granzyme-containing granules, exert an efficient anti-tumoral attack, resulting in the direct destruction of target cells (Hanson et al. 2000; Matsushita et al. 2012). Meanwhile, the CD4+ T helper 1 (Th-1)-mediated anti-tumoral response —through secretion of high amounts of proinflammatory cytokines such as IL-2, TNF-α, and IFN-γ—promotes not only T-cell priming and activation and CTL cytotoxicity but also the anti-tumoral activity of macrophages and NK cells and an overall increase in the presentation of tumor antigens (Kalams and Walker 1998; Pardoll and Topalian 1998; Shankaran et al. 2001). The presence of tumor-infiltrating CD8+ T cells and Th-1 cytokines in tumors correlates with a favorable prognosis in terms of overall survival and a disease-free survival in many malignancies (Fridman et al. 2012).”



– T Cells block the growth of new blood vessels, which starves thousands of tumor cells and puts an end to their growth. Imagine the building inspectors, switching off electricity and water and putting up roadblocks to cancer town so no more food and materials can be delivered.


Regulation of angiogenesis in cancer involves different cell types and molecules that have dual roles. Here, we refer to Helper and Killer T Cells secreting a major antiangiogenic chemokine, called interferon gamma (IFN-γ). IFN-γ directly suppresses blood vessel formation by interfering with the generation and migration of endothelial cells (the cells that make up the inner lining of the blood vessels). IFN-γ secretes further signaling molecules that inhibit growth factors and restrict the proliferation of endothelial cells. 


#Lee et al. Combination of anti-angiogenic therapy and immune checkpoint blockade normalizes vascularimmune crosstalk to potentiate cancer immunity. 2020.

https://pubmed.ncbi.nlm.nih.gov/32913278/

Quote: “Adaptive immune cells are also critical players in the orchestration of tumor angiogenesis by directly affecting EC biology and indirectly modulating myeloid cell phenotypes. Among adaptive immune cells, CD8+ CTLs play a critical role in suppressing tumor angiogenesis by secreting IFN-γ74,75. IFN-γ directly inhibits the proliferation and migration of human endothelial cells and secretes IFN-inducible protein 10 (IP-10) and monokine induced by IFN-γ (MIG). These cytokines also react with CXCR3, restraining the proliferation of endothelial cells and tumor vascularization74,76. Furthermore, IFN-γ signaling downregulates VEGF-A but upregulates CXCL9, CXCL10, and CXCL11, which collectively stimulate vascular maturation by enhancing pericyte recruitment along ECs74,77,78. Another important aspect of IFN-γ in tumor angiogenesis is the reprogramming of TAMs from M2- to M1-like TAMs. Hyperactive IFN-γ/STAT1 signaling promotes M1-like TAM reprogramming, leading to vascular remodeling and consequent tumor eradication7,77,79.

In addition to CD8+ CTLs, CD4+ T helper 1 (TH1) cells assist in tumor vessel normalization by producing IFN-γ in the TME. Depletion of CD4+ TH1 cells decreases pericyte coverage and increases malformed tumor vessels in multiple mouse tumor models, whereas activation of CD4+ T cells improves vessel normalization7,80,81. TH1 cells also polarize M2-like TAMs to M1-like TAMs and induce DC maturation in the TME, which suppresses tumor angiogenesis82”

#Lugano, Ramachandran and Dimberg.Tumor angiogenesis: causes, consequences, challenges and opportunities. 2020.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7190605/pdf/18_2019_Article_3351.pdf

Quote: “T cells promote angiogenesis by secretion of pro-angiogenic factors FGF-2 and heparin-binding epidermal-like growth factor (HB-EGF) [276]. However, the most prominent T cell derived factors, such as TNF, TGFβ, and interferons (IFNs), have anti-angiogenic functions [277–279]. The antiangiogenic effects of IFNs are mediated by direct effects on endothelial cells and other cells in the tumor microenvironment. Treatment with IFN-α/β induced necrosis of endothelial cells within tumors and decreased tumor metastases to the liver and spleen [280]. In vitro, TNF and IFNs can block collagen synthesis and extracellular matrix formation and thus inhibit the formation of capillary-like structures [281, 282]. IFN-γ can inhibit neovascularization and induce apoptosis if endothelial cells in murine glioma models [277]. Type-I polarized T cells (Th1) secrete IFNγ and their presence in the tumor microenvironment usually correlates with good clinical outcome [283]. Interferon Induced CXC family chemokines inhibit endothelial cell proliferation, promote Th1 type T cell, NK and DC infiltration, thereby inhibiting tumor growth. CXCL9, CXCL10 and CXCL11 are interferon-inducible angiostatic chemokines that can directly inhibit angiogenesis by binding CXCR3 on endothelial cells [284–286].”


We mainly talk about Helper and Killer T Cells in the video, but there is another type of T Cell, T regulatory cells (T-Regs). T-Regs suppress the immune response, prevent autoimmune response and have been shown to suppress proliferation of Helper and Killer T Cells. So even though they are crucial for peripheral tolerance (suppression of reaction to self antigens), they can also prevent fully clearing out pathogens and limit antitumor immunity. 


T-Regs are found in most tumors and generally associated with poor clinical outcomes.They are recruited from periphery to tumors through various signaling molecules (for example through certain chemokines that are expressed by the tumor cells due to lack of oxygen) and found to be correlated with markers of increased blood vessel formation, such as over expression of vascular endothelial growth factor (VEGF) which is a signal protein stimulating the formation of new blood vessels. T-Regs can also indirectly promote blood vessel formation by suppressing the effector T cells that can inhibit blood vessel formation.



#Freeman et al. Peripheral blood T lymphocytes and lymphocytes infiltrating human cancers express vascular endothelial growth factor: a potential role for T cells in angiogenesis. 1995.

https://pubmed.ncbi.nlm.nih.gov/7545086/

Quote: “The synthesis of VEGF by peripheral T cells and TIL suggests that T cells may play a role in tumor angiogenesis by secreting angiogenic factors directly into the tumor stroma.”


#Facciabene, Motz and Coukos. T-Regulatory Cells: Key Players in Tumor Immune Escape and Angiogenesis. 2012.

https://aacrjournals.org/cancerres/article/72/9/2162/584187/T-Regulatory-Cells-Key-Players-in-Tumor-Immune

Quote: “Tregs can contribute to tumor angiogenesis through both indirect and direct mechanisms. Tregs promote angiogenesis indirectly by suppressing the activities of Th1 effector T cells that release angiostatic cytokines like TNF-a and IFN-g, as well as interferon-induced chemokines such as CXCL9, 10, and 11. Indeed, Tregs have been shown to promote tumor angiogenesis by specifically inhibiting tumor-reactive T cells (52). However, we have also shown that Tregs can make significant contributions to the direct promotion of tumor angiogenesis (ref. 3, Fig. 1). We showed that tumor hypoxia in ovarian cancer leads to the recruitment of Tregs via CCL28 upregulation (3). The forced expression of CCL28 in mouse ovarian carcinoma resulted in striking increase of in vivo tumor growth. CCL28 expression also resulted in robust Treg accumulation, increased VEGF levels, and significantly increased blood vessel development. Of importance, depletion of CD25+ or CCR10+ cells eliminated Treg cells from the tumor microenvironment and significantly suppressed VEGF expression and angiogenesis at these sites (3). ”

The Equilibrium Phase


– Unfortunately, natural selection spoils your victory. By doing its best to destroy the tumor, your immune system accidentally selected the most fit tumor cells. Remember, the tumor consists of different lineages that keep growing and mutating more. Most of these are eradicated. But just a few are more resilient. One cell survives – it stems from the fittest tumor lineage and was just a bit better at surviving the massacre than anyone else. It decides to do it all over again. But better this time.


Although the immune system recognizes and destroys the vulnerable, antigen-bearing cancer cells, constant division generates cancer cells with reduced immunogenicity. 

This state, where the production of cell variants is balanced by the elimination, is called “equilibrium”. In this phase cancer cells continue to divide, accumulating mutations by chance or in response to inflammation. Even though this state might look like dormancy,  these processes eventually enable tumors to impair the immune system (by immune suppressive effects or by loss of target antigen expression). It is at this stage that tumor escape occurs, resulting in overt clinical cancer. 


#Dunn et al. Cancer immunoediting: from immunosurveillance to tumor escape. 2002. 

https://www.nature.com/articles/ni1102-991

Quote: “In the equilibrium process (Fig. 1b), the host immune system and any tumor cell variant that has survived the elimination process enter into a dynamic equilibrium. In this process, lymphocytes and IFN-γ exert potent selection pressure on the tumor cells that is enough to contain, but not fully extinguish, a tumor bed containing many genetically unstable and rapidly mutating tumor cells. During this period of Darwinian selection, many of the original escape variants of the tumor cell are destroyed, but new variants arise carrying different mutations that provide them with increased resistance to immune attack. It is likely that equilibrium is the longest of the three processes and may occur over a period of many years.”

– This tumor cell is much stronger than any of the thousands that were killed. Maybe it is better at hiding, or fighting back. Maybe it grows faster or is better at stealing resources. Maybe it can survive with much less oxygen. And so it all begins again. 


The cancer-immune cycle repeats itself during the equilibrium page. Cancer cells can evade immune response in different ways in different stages of this cycle. There is a plethora of molecules, cells and mechanisms involved as summarized in the following figure. We are referring to these as a whole with the conflict between the Tumor Town and NYC metaphor in general but there is no specific, one-to-one mapping of the mechanisms onto specific metaphors. We wanted to focus on the competition between the tumor and the immune system and each party pushes different players into the game and counter attacks, thereby shaping each other, which happens under evolutionary selection. 


We will revisit various mechanisms in the following sections but the collection of different methods can be grouped under three main mechanisms: 


This simply refers to cells in tumor microenvironment hindering the effects of immune cells

#Beatty & Gladney. Immune Escape Mechanisms as a Guide for Cancer Immunotherapy. 2015

https://aacrjournals.org/clincancerres/article/21/4/687/176103/Immune-Escape-Mechanisms-as-a-Guide-for-Cancer

#Black & McGranahan. Genetic and non-genetic clonal diversity in cancer evolution. 2021.

https://www.nature.com/articles/s41568-021-00336-2

Quote: “Cancer is also an evolutionary process2,3 , and it was the observation of heterogeneity in malignancies that led Nowell to hypothesize that Darwinian clonal evolution underpinned their development2 . Since then, intra-tumour heterogeneity (ITH), describing diversity within individual tumours, has been defined at multiple different levels, including single point mutations, somatic copy number alterations (SCNAs), epigenetic and transcriptomic changes influencing gene expression, the antitumour immune response and other features of the tumour microenvironment.”



– Finally, a tumor cell changes in a way that makes it properly dangerous, cancer. The type that kills people. How? Immune cells have an off switch that deactivates them before they can attack – which in principle is a good idea. The immune system is super dangerous and in many cases it needs to be shut down, like around your central nervous system. But this off switch can be exploited.


The concerted effort of the immune system to keep the response from getting too strong and destroying the healthy cells happens mainly through inhibitory effects of immune cells on one another. Involved mechanisms are collectively called immune checkpoints. 


Although most self reactive T Cells are eliminated in the thymus, this process is incomplete and the immune system developed several peripheral tolerance mechanisms to deal with self reactive T cells, which either manipulate the responding state of T Cells or extrinsically modulate them through other cells. During tumor development, cancer cells evolve mechanisms that mimic peripheral tolerance and are able to prevent the local cytotoxic response of effector T cells, TAMs, NK cells.


#Gonzalez, Hagerling and Werb. Roles of the immune system in cancer: from tumor initiation to metastatic progression. 2018. 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6169832/pdf/1267.pdf

Quote: “During immune homeostasis, a crucial mechanism of peripheral tolerance is the regulation of effector T-cell response via immune checkpoints on CTLs and activated CD4+ T cells to protect tissue from inflammatory damage. The two better described checkpoint molecules CTLA-4 and PD-1 act as negative regulators of T-cell function and have been associated with immune evasion in cancer (Pardoll 2012). The involvement of CTLA-4 signaling in cancer has been described in melanoma (Bouwhuis et al. 2010) and lung (Khaghanzadeh et al. 2010), breast (Erfani et al. 2006), gastric (Hadinia et al. 2007), and colorectal (Hadinia et al. 2007; Dilmec et al. 2008) cancer. Furthermore, the engagement of PD1 with its coreceptor, PDL-1 (expressed by other immune cells, mesenchymal cells, vascular cells, and cancer cells), results in the down-regulation of T-cell activity, which inhibits their anti-tumor activities such as T-cell migration, proliferation, secretion of cytotoxic mediators, and restriction of cell killing (Topalian et al. 2015).”



– The mutated tumor cell finds a way to switch the immune system off by targeting inhibitor receptors on anti cancer cells. Inhibitor receptors stop immune cells from, well, killing. This cell is the now powerful founder of a new lineage of cancer cells and mass produces thousands of new copies that  once again change and mutate further. Building yet another Tumor Town.



Immune checkpoints are activated when receptors on T cells recognize and bind to partner proteins on tumor cells, which are called immune checkpoint proteins. Binding of checkpoint and partner proteins to each other sends an “off” signal to the T cells. This prevents the immune system from killing tumor cells.


#Gonzalez, Hagerling and Werb. Roles of the immune system in cancer: from tumor initiation to metastatic progression. 2018.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6169832/pdf/1267.pdf

Quote: “Tumor cells evade the immune attack using two main strategies: avoiding the immune recognition and instigating an immunosuppressive TME. In the first, cancer cells may lose the expression of tumor antigens on the cell surface, thus avoiding the recognition by cytotoxic T cells. For example, 40% of non-small cell lung cancers hold a loss of heterozygosity in human leukocyte antigens (HLAs), which leads to immune escape by presenting fewer antigens (McGranahan et al. 2017). Notably, HLA loss has been associated with resistance to T-cell transfer therapy in metastatic colorectal cancer (Tran et al. 2016) and poor outcome response to checkpoint blockade immunotherapy in melanoma and lung cancer patients (Chowell et al. 2018). In this sense, mutations and deletions may result in down-regulation of the antigen-presenting machinery and likely confer resistance to T-cell effector.”


The Escape Phase


– The new cancer cells have become immune to the immune system and everything is different this time. Tumor Town has been rebuilt, more ugly and strange than before, but now the cancer city council has forged all sorts of permits. As building inspectors come to shut down construction, they get confused. Stunned they wander off, unable to order the destruction of the sprawling buildings. 


#Teng et al. From mice to humans: developments in cancer immunoediting. 2015.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4588291/pdf/JCI80004.pdf

Quote: “Escape. When tumors circumvent immune recognition and/ or destruction, they progress from the equilibrium to the escape phase, where they become clinically apparent. Tumors escape due to changes in their response to immunoselection pressures and/or

to increased tumor-induced immunosuppression or immune system deterioration. The mechanisms of tumor cell escape can be classified into three categories, as shown in Figure 1. Over the past two decades, these pathways have been the subjects of intense investigation, with the aim of developing new cancer immunotherapies (reviewed extensively in refs. 1, 3, 5).”

– Police try to enter the illegal city to arrest the builders and execute inhabitants – but this time Tumor Town has erected its own roadblocks that keep the law from entering. Confused officers stand around helplessly.


There are several mechanisms that cancer can evade the immune system and so far we mainly concentrated on loss of antigenicity (cancer cells hiding) and loss of immunogenicity (immune cells losing the capacity to kill tumor cells). There is a third group of methods where the cancer cells actively suppress the immune response, and the tumor microenvironment has a big part in that. 


Main immunosuppressive cells in tumor microenvironment are: 

– Macrophages: they differentiate into M2-type that promote tumor formation, and generate IL-10 instead of IL12 to inhibit the Killer T cell response. They also produce high levels of vascular endothelial growth factor (VEGF).  

– Myeloid-derived suppressor cells (MDSCs) are a group of heterogeneous cells that can strongly inhibit the T Cell response and induce Regulatory T Cells. MDSCs inhibit the immune response by generating arginase, inducible nitric oxide synthase (iNOS), and TGF-β. TGF-β inhibits Killer T cells and Natural Killer Cells by reducing the expression of cytotoxic factors such as perforin and granzyme. . 

– Regulatory T Cells inhibit Killer T cell response and promote tumor progression. 


Metabolism of the TME can also act as immunosuppressant. The concentration of metabolites such as glucose, lactate, and glutamine in the TME affects the function and activity of tumor-infiltrating immune cells. Cancer cells deplete glucose in the TME which hinders T cells, NK cells, macrophages, and DCs that use glucose for anti-cancer activity. Lactate produced by the glycolysis of cancer cells or immune cells also inhibits immune cell function. It inhibits the function of T Cells, but not Regulatory T cells (which are inhibitory for T Cells), contributing to an immunosuppressive environment. Since cytotoxic cells such as Killer T cells and NK cells are sensitive to amino acid restrictions, their function is suppressed when amino acids are depleted. 



– As Tumor Town slowly envelops the former Brooklyn and more and more civilians die, T Cell swat teams arrive to end this travesty. But things got worse – new lineages of Tumor Town officials have started to forge court documents that order police to shoot at the Swat teams.  


Macrophages can flip to a pro-tumor state in the later stages and downregulate Killer T Cell activity. 


#Kim & Cho. The Evasion Mechanisms of Cancer Immunity and Drug Intervention in the Tumor Microenvironment. 2022

https://www.readcube.com/articles/10.3389/fphar.2022.868695

Quote: “The Tumor Microenvironment induces macrophages to differentiate into M2-type tumor associated macrophages that promote tumor formation, and tumor-associated macrophages generate IL-10 instead of IL12 to inhibit the CD8+ T cell response. Tumor-associated macrophages directly inhibit immune checkpoint inhibitor responses by removing anti-PD-1 antibodies from PD-1+ CD8+ T cells in an FcγR-dependent manner”



– What the cancer cells are doing at this point is to actively shut down immune defenses by sending corrupt signals. 


Cancer cells can express surface molecules that can bind to receptors on T- Cells which downregulates the activity or even activates cell death. These receptors are normally in place to regulate immune response and self tolerance, but cancer cells take advantage of these receptors to evade immune response. 


#Kim & Cho. The Evasion Mechanisms of Cancer Immunity and Drug Intervention in the Tumor Microenvironment. 2022

https://www.readcube.com/articles/10.3389/fphar.2022.868695

Quote: “The CD8+ T cells that infiltrate a tumor can simultaneously express several additional co-inhibitory receptors in addition to PD-1, including B and T lymphocyte attenuator (BTLA), lymphocyte activation gene 3 protein (LAG-3), T-cell immunoglobulin domain, mucin domain-3 (TIM3), T-cell immunoglobulin, and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT). Other co-inhibitory receptors are expressed simultaneously, and T cells become exhausted T cells (Tex) that are unresponsive to immune checkpoint inhibitors.”



– The now malignant tumor is no longer a pushover and has begun creating the Cancer Microenvironment. A sort of borderland that is hard to cross. All avenues of attack have been shut down and uncontrollable growth is the consequence.


It is not possible to give a certain time point as when exactly the Tumor Microenvironment (TME) is set. Cancer cells and stroma continuously evolve together, therefore tumor microenvironment is started from the earlier stages onwards. Here, we refer to a more established TME architecture that is very difficult to eradicate and very likely to metasize. 


#Emon et al. Biophysics of Tumor Microenvironment and Cancer Metastasis - A

Mini Review. 2018. 

https://www.sciencedirect.com/science/article/pii/S2001037018300291?via%3Dihub

Quote: (Figure Caption) “Fig. 1. Chronological development of pro-metastatic stromal architecture and the major factors involved. Segment 1 (top right): At the early stages of cancer, epithelial cancer cells secrete various growth factors that facilitates fibroblast activation, differentiation, downregulates ECM degradation by reducing MMPs and hence increase stiffness. In response, stromal fibroblasts regulate factors such as IGF, KGF etc. that promote cell growth and inhibit apoptosis. Segment 2 (bottom right): Upon activation, fibroblasts manifests myofibroblast (or, CAF) signatures and produce activin/TGFβ, IGF that stimulate EMT; HGF that increases cell growth; FGF-2 that increases angiogenesis and so on. In addition, CAFs continue to remodel and reinforce ECM by depositing collagen I, II, V, IX, increasing crosslinking, upregulating LOX and thus stromal stiffness gradually goes up. Due to excessive cellular proliferation and tumor growth, a region at the core becomes hypoxic and cancer cells increase secretion of VEGF and CTGF that are known to support angiogenesis and infiltration respectively. Segment 3 (bottom left): As carcinoma cells go through EMT, they produce CSF-1 which activates macrophages that in turn produce EGF, IL-33 etc. that promotes metastasis. At some regions of the invasive front, the stromal cells align thick collagen bundles radially that can be used as an escape route by the metastatic cells. Eventually, aggressive cancer cells degrade stiff ECM by upregulating MMPs, ADAMs etc., evade stroma, infiltrate lymph nodes and blood vessels and go through metastasis. Segment 4 (top left): Migrating cancer cells anchor at distant sites and starts the process all over to develop secondary tumors. [51, 58, 66–71]. 281B. Emon et al. / Computational and Structural Biotechnology Journal 16 (2018) 279–287”



– This is a dangerous tumor. Cells that are strong and able to fight, push your immune system back and expand further. 


As summarized in the following figure, tumor turned many immune parameters to its advantage at this stage and pushed it to a point of no return. 


#Dunn et al. Cancer immunoediting: from immunosurveillance to tumor escape. 2002. 

https://www.nature.com/articles/ni1102-991

Quote: “In the escape process (Fig. 1c), surviving tumor variants that have acquired insensitivity to immunologic detection and/or elimination through genetic or epigenetic changes begin to expand in an uncontrolled manner. This results in clinically observable malignant disease that, if left unchecked, results in the death of the host.”


Following review paper provides a full account of immune cells and their roles in tumor microenvironment. 


#Gonzalez, Hagerling and Werb. Roles of the immune system in cancer: from tumor initiation to metastatic progression. 2018. 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6169832/pdf/1267.pdf

– If more mutations happen, then some of the cancer cells will begin to explore the world and expand into other tissues, to build new towns. 


As more mutations accumulate, the tumor turns malignant, meaning that it can metastasize to further tissues. 


#Weston A, Harris CC. Multistage Carcinogenesis. In: Kufe DW, Pollock RE, Weichselbaum RR, et al., editors. Holland-Frei Cancer Medicine. 2003. https://www.ncbi.nlm.nih.gov/books/NBK13982/

Quote: “Malignant conversion is the transformation of a preneoplastic cell into one that expresses the malignant phenotype. This process requires further genetic changes. The total dose of a tumor promoter is less significant than frequently repeated administrations, and if the tumor promoter is discontinued before malignant conversion has occurred, premalignant or benign lesions may regress. Tumor promotion contributes to the process of carcinogenesis by the expansion of a population of initiated cells that will then be at risk for malignant conversion. Conversion of a fraction of these cells to malignancy will be accelerated in proportion to the rate of cell division and the quantity of dividing cells in the benign tumor or preneoplastic lesion. In part, these further genetic changes may result from infidelity of DNA synthesis.31 The relatively low probability of malignant conversion can be increased substantially by the exposure of preneoplastic cells to DNA-damaging agents,16 and this process may be mediated through the activation of protooncogenes and inactivation of tumor suppressor genes.”

Quote: “(Figure Caption) Multistage chemical carcinogenesis can be conceptually divided into four stages: tumor initiation, tumor promotion, malignant conversion, and tumor progression. The activation of protooncogenes and inactivation of tumor suppressor genes are mutational events that result from covalent damage to DNA caused by chemical exposures. The accumulation of mutations, and not necessarily the order in which they occur, constitutes multistage carcinogenesis.98”

– In recent years immunotherapy has made enormous progress – it is a relatively new therapy in which your own immune cells are modified to kill cancer better than any medicine can do. It's like giving your building inspectors machine guns and flamethrowers. 


#National Cancer Institute. CAR T Cells: Engineering Patients’ Immune Cells to Treat Their Cancers. 2022. 

https://www.cancer.gov/about-cancer/treatment/research/car-t-cells

Quote: “Currently available CAR T-cell therapies are customized for each individual patient. They are made by collecting T cells from the patient and re-engineering them in the laboratory to produce proteins on their surface called chimeric antigen receptors, or CARs. The CARs recognize and bind to specific proteins, or antigens, on the surface of cancer cells.”


#Albinger, Hartmann & Ullrich. Current status and perspective of CAR-T and CAR-NK cell therapy trials in Germany. 2021

https://www.nature.com/articles/s41434-021-00246-w

Quote: “Chimeric antigen receptor (CAR)-T cell therapies are on the verge of becoming powerful immunotherapeutic tools for combating hematological diseases confronted with pressing medical needs. Lately, CAR-NK cell therapies have also come into focus as novel therapeutic options to address hurdles related to CAR-T cell therapies, such as therapy-induced side effects. Currently, more than 500 CAR-T and 17 CAR-NK cell trials are being conducted worldwide including the four CAR-T cell products Kymriah, Yescarta, Tecartus and Breyanzi, which are already available on the market.”