Regenerative stem cell–like memory (T_SCM) CD8⁺ T cells persist longer and produce stronger effector functions. We found that MEK1/2 inhibition (MEKi) induces T_SCM that have naive phenotype with self-renewability, enhanced multipotency and proliferative capacity. This is achieved by delaying cell division and enhancing mitochondrial biogenesis and fatty acid oxidation, without affecting T cell receptor-mediated activation. DNA methylation profiling revealed that MEKi-induced T_SCM cells exhibited plasticity and loci-specific profiles similar to bona fide T_SCM isolated from healthy donors, with intermediate characteristics compared to naive and central memory T cells. Ex vivo, antigenic rechallenge of MEKi-treated CD8⁺ T cells showed stronger recall responses. This strategy generated T cells with higher efficacy for adoptive cell therapy. Moreover, MEKi treatment of tumor-bearing mice also showed strong immune-mediated antitumor effects. In conclusion, we show that MEKi leads to CD8⁺ T cell reprogramming into T_SCM that acts as a reservoir for effector T cells with potent therapeutic characteristics. Read more...

PD-1 blockade in unprimed or suboptimally primed CD8 cells induces resistance through the induction of PD-1⁺CD38^hi CD8⁺ cells that is reversed by optimal priming. PD-1⁺CD38^hi CD8⁺ cells serve as a predictive and therapeutic biomarker for anti-PD-1 treatment. Sequencing of anti-PD-1 and vaccine is crucial for successful therapy. Read more..

Major Finding: MEK inhibition caused naïve CD8⁺ T cells to adopt a stem cell–like memory T-cell (T_SCM) phenotype.

Impact: This provides a mechanism for T-cell differentiation and a strategy to enhance ACT and other immunotherapies.

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In the past, studies have shown that inhibition of MEK (MEKi) increases antitumor immunity and leads to the accumulation of activated CD8⁺ T cells in the TME. While this strategy is known to synergize with checkpoint inhibitors and adoptive cell transfer, little is known regarding exactly how MEKi affects T cell function, differentiation, or memory generation. In a study recently published in Nature Immunology, Verma et al. investigated the effects of MEKi on T cells and how it contributes to antitumor immunity.

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WASHINGTON (November 23, 2020) — Immune-system T cells have been reprogrammed into regenerative stem cell-like memory (TSCM) cells that are long-lived, highly active “super immune cells” with strong antitumor activity, according to new research from Georgetown Lombardi Comprehensive Cancer Center. Read more...

Immune-system T cells have been reprogrammed into regenerative stem cell-like memory (TSCM) cells that are long-lived, highly active "super immune cells" with strong antitumor activity, according to new research from Georgetown Lombardi Comprehensive Cancer Center. Read more...

Summary: Immune-system T cells have been reprogrammed into regenerative stem cell-like memory (TSCM) cells that are long-lived, highly active 'super immune cells' with strong antitumor activity, according to new research. Read more...

Checkpoint blockade of the PD-1 axis (PD-1 or PD-L1) can be effective in inducing antitumor immunity, although many patients still relapse or fail to derive clinical benefit at all. Combinations of anti-PD-1 treatment with vaccines against tumor-associated antigens or with other immunomodulatory agents are actively being explored, and optimal timing and sequencing have yet to be established. In clinical trials combining a vaccine with anti-PD-1, anti-PD-1 treatments often begin earlier for logistical reasons. Recently, Verma et al. investigated whether the sequencing of anti-PD-1 and vaccine treatments might influence therapeutic outcomes; their results were published in Nature Immunology. Read more...

New research has uncovered a mechanism thought to explain why some cancers don't respond to a widely used form of immunotherapy called "checkpoint inhibitors" or anti-PD-1. In addition, the scientists say they have found a way to fix the problem, paving a way to expand the number of patients who may benefit from the treatment. Read more...

Powerful immunotherapy treatments have been developed over the past decade that have truly helped make miracles for some cancer patients and their loved ones. These drugs help use the body’s own immune system to turn on the cancer and fight it from within. But it may work only 15% of the time. Now Georgetown University-led research has uncovered a mechanism thought to explain why some cancers don’t respond to a common form of immunotherapy called “checkpoint inhibitors” or anti-PD-1. Moreover, the researchers believe they may have a solution to helping more cancer patients benefit from immunotherapy. Read more...

WASHINGTON (August 2, 2019) — New research has uncovered a mechanism thought to explain why some cancers don’t respond to a widely used form of immunotherapy called “checkpoint inhibitors” or anti-PD-1. In addition, the scientists say they have found a way to fix the problem, paving a way to expand the number of patients who may benefit from the treatment. Read more...