Chinese scientists have revealed key kinases that regulate T-cell failure.

Endogenetic or metastasis of cytotoxic T-cells is the basic medium of anti-tumor immunity, and continuous antigen exposure can gradually turn T-cells into a state of failure.
understanding how to prevent T-cell failure and thus expand its function is one of the most pressing issues in immuno-oncology today.
hematologic subcellular kinase 1 (HPK1) is an immunosuppressive regulated kinase, but also a negative regulatory factor of T-cell receptor (TCR), which destroys the stability of the TCR signal complex.
previous studies have shown that HPK1 kinases inhibit the immune function of multiple cells, and that inactivation of their domain is sufficient to trigger anti-tumor immune response effects.
studies have shown that HPK1 is an extremely important candidate for cancer immunotherapy.
August 28, 2020, The Liao Xuebin Task Force of Tsinghua University, in collaboration with the Wei Lei Task Force of Sun Yat-sen University, revealed THAT1 mediated T-cell dysfunction, and is a drug target for T-cell immunotherapy. Mediates T Cell Dysfunction and Isa Druggable Target for T Cell-Based Immunotherapies were published on Cancer Cell.
In previous studies, researchers have confirmed a strong positive correlation between inhibitory PDCD1 (coding PD-1) subjects and MAP4K1 (coded HPK1) in tumor-indaching T cells of 25 different types of cancer.
by further detecting the correlation between MAP4K1 and other inhibitory ligenes in tumor-invasive T-cells, MAP4K1 was positively related to T-cell failure signals (CD3E, TIGIT, PDCD1, CTLA4, HAVCR2, and LAG3) in different cancer patients, and HPK1 expression in inhibited and HPK1 proteins in tumor specimens was also found to be increased.
these results confirm that HPK1 is positively correborated with tumor-immersive T-cell depletion, suggesting that HPK1 may be the key kinase that regulates T-cell depletion and inhibits anti-tumor immune response.
further studies have found that MAP4K1's missing CD8 plus tumor-soaked lymphocytes (TILs) not only reduce failure, but also have strong anti-tumor activity, HPK1-Blimp1 axis can drive CD8-plus until exhaustion, knocking out MAP4K1 CAR-T cells significantly increased toxicity to tumor cells.
, HPK1 degradation mediated by genetic knock-off, pharmacological inhibition, or protein hydrolysis targeted chimline (PROTAC) improved the efficacy of CAR-T cell immunotherapy in various preclinical mouse models of blood and solid tumors.
these strategies are more effective than genetically removing PD-1 in CAR-T cells.
improving T-cell failure and enhancing the function of effects are effective strategies to improve immunotherapy.
, the development of HPK1 inhibitors or the degradation of HPK1 through PROTACs may be a new frontier in cancer immunotherapy research.
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