Research

Unlike hematologic malignancies, solid tumors physically block the infiltration of immune cells due to a dense extracellular matrix (ECM) and high interstitial fluid pressure. Furthermore, the hypoxic and acidic microenvironment, along with immunosuppressive cells such as TAMs, Tregs, and MDSCs, neutralizes the activity of even those immune cells that manage to penetrate, limiting the efficacy of simply injecting potent immune cells. Therefore, our laboratory aims to remodel the immunosuppressive 'Cold Tumor' into an immune-friendly 'Hot Tumor' using cytokines or cell-based therapies. Through this remodeling, we strive to ensure that therapeutic agents and immune cells can reach the deep core of the tumor and exert sustained antitumor effects. 

One of the major cell type utilized by our laboratory is the Mesenchymal Stromal Cell (MSC). MSCs offer the advantage of being an abundant source, as they can be readily obtained from various tissues, including bone marrow, skin, and adipose tissue. When administered via peritumoral injection, MSCs exhibit strong tumor tropism, enabling the localized expression of therapeutic agents specifically within the tumor site. Furthermore, we have engineered these MSCs to overexpress NQO1, providing them with resistance against reactive oxygen species (ROS)-induced stress within the tumor microenvironment. This modification ensures higher persistence and enhanced survival of the cells upon delivery. 

Our laboratory possesses diverse engineering platforms to develop cellular therapuetics with enhanced antitumor efficacy. We employ strategies to secrete cytokines or chemokines, which augment the activity and antitumor functions of immune cells within the tumor microenvironment (TME) or recruit non-infiltrating immune cells into the tumor core. Additionally, we have developed a platform that expresses Chimeric Antigen Receptors (CAR) on the cell surface, allowing for direct interaction with immune cells to reactivate those that have been neutralized or failed to recognize cancer cells. Furthermore, we are developing a next-generation delivery system utilizing Extracellular Vesicles (EV) to transport mRNA and Cas9, aiming to genetically remodel immune cells for improved therapeutic outcomes. 

Our laboratory is validating the therapeutic efficacy of MSCs and other cell therapeutics within the tumor microenvironment (TME) using various mouse models. We have confirmed that when MSCs are administered via peritumoral injection into tumor-bearing mice, the cytokines or therapeutic agents expressed by the MSCs are delivered in a tumor-specific manner, ensuring minimal leakage to other organs. Furthermore, we have verified that these agents not only alter the phenotype of immune cells within the TME but also enhance their antitumor functions, leading to successful TME remodeling. Most notably, we have demonstrated a potent synergistic effect within the tumor when MSCs are combined with Immune Checkpoint Blockade (ICB) or Adoptive Cell Therapy (ACT). 

Our laboratory’s core experimental competencies are categorized into four primary areas. First, we leverage the tumor tropism of MSCs to ensure tumor-specific expression of therapeutic agents, while incorporating an On/Off Switch system to further enhance safety (Tumor-Specific Delivery & Expression System). Second, we conduct comprehensive TME & TIL Analysis using mouse models to evaluate shifts in immune cell populations and phenotypes, extending our analysis from RNA and protein expression to full -omics levels. Third, we develop optimized Chimeric Antigen Receptors (CARs) for MSCs and other cell-based therapies to augment antitumor immunity or implement target protein degradation systems. Lastly, we focus on combination therapies involving MSCs and CAR-T cells, aiming to enhance CAR-T infiltration into solid tumors and ensure the sustained maintenance of their antitumor functions.