Cancer Cell: More powerful! Liao Xuebin/Wei Li collaboration reveals that HPK1 can be a target for T-cell immunotherapy.

Improving T-cell failure and enhancing the function of the effects is a promising strategy for improving immunotherapy.
HPK1 is a promising candidate for cancer immunotherapy.
, however, the functional significance of HPK1 in T-cell-based immunotherapy and the molecular mechanism of HPK1 inhibiting T-cell function have not been well established.
a research paper entitled "Hematopoietic Progenitor Kinase1 (HPK1) Mediates T Cell Dysfunction and Isa Druggable Target for Cell-Based Immunotherapies" published online by Liao Xuebin of Tsinghua University and Wei Lei of Sun Yat-sen University, which showed that the HPK1-NF-B-Blimp1 axis mediates T-cell dysfunction.
expression (coded HPK1) of MAP4K1 was associated with an increase in T-cell failure and poor survival in some cancer-type patients.
in MAP4K1KO mice, tumors grew more slowly than in wild mice, and the failure of immersive T-cells decreased, with higher activity and proliferation.
further demonstrated that genetic depletion, pharmacological inhibition, or protein hydrolysis of HPK1 mediated by proTAC can improve the effectiveness of CAR-T cell-based immunotherapy in various preclinical mouse models of blood and solid tumors.
strategies are more effective than genetically eliminating PD-1 in CAR-T cells.
, the study demonstrated that HPK1 is a median for T-cell dysfunction and an attractive drug-adjustable target for improving the response to immunotherapy.
cytotoxic T cells, which are endogenic or over-transferred, are important media for anti-tumor immunity.
continuous antigen exposure leads to the gradual differentiation of T-cells into a state of failure, characterized by hierarchical loss of effector function and proliferation capacity, as well as significant transcription, apparent genetic and metabolic changes.
understanding how to prevent T-cell failure and thus expand its effect child function is one of the most pressing issues in immuno-oncology.
cancer immunotherapy, such as checkpoint block therapy, based on the regeneration of failed T-cells, has provided therapeutic benefits.
this, many patients have not yet achieved a lasting response, and it has been suggested that the possible cause of the failure of this treatment is that the failed T-cells are in a stable, pre-genetic state, thus limiting their regeneration.
In addition, T cells in a variety of transcription factors (TFs) have been shown to regulate tumor micro-environments (TME), including NFAT, Eomes, T-bet, Blimp-1, BATF, FoxO1, VHL, c-Maf, TOX, NR4A1 and TCF1, but attempts to promote T cell function by regulating TF can be complex.
, a more promising strategy for developing more effective immunotherapy may involve manipulating drug-adjustable targets that regulate T-cell failure or dysfunction.
HPK1 is an immunosuppressive regulated kinase that has a limited expression spectrum in the hema production chamber.
previous studies have determined that HPK1 is a negative signal regulator for T-cells (TCR): cytoptonal HPK1 is collected into the mass membrane after TCR activation, while the active HPK1 phosphorylated bridging protein SLP76 activates SLP76.
as a stop point for the negative regulator protein 14-3-3, which ultimately destabilizing the TCR signal complex.
A recent study analyzed the immune function of a variety of cells, including CD4 T cells, CD8 T cells, and degenerative cells (DC), and determined that inactivation of its kinase domain is sufficient to trigger an anti-tumor immune response.
these studies suggest that HPK1 is a promising candidate for cancer immunotherapy.
, however, the functional significance of HPK1 in T-cell-based immunotherapy and the molecular mechanism of HPK1 inhibiting T-cell function have not been well established.
, the study found the functional significance of HPK1 in T-cell-based immunotherapy, and the study strongly supported HPK1 as a treatable target for immunotherapy.
specifically, the study showed that the HPK1-NF-B-Blimp1 axis mediates T-cell dysfunction.
expression (coded HPK1) of MAP4K1 was associated with an increase in T-cell failure and poor survival in some cancer-type patients.
in MAP4K1KO mice, tumors grew more slowly than in wild mice, and the failure of immersive T-cells decreased, with higher activity and proliferation.
further demonstrated that genetic depletion, pharmacological inhibition, or protein hydrolysis of HPK1 mediated by proTAC can improve the effectiveness of CAR-T cell-based immunotherapy in various preclinical mouse models of blood and solid tumors.
strategies are more effective than genetically eliminating PD-1 in CAR-T cells.
, the study demonstrated that HPK1 is a median for T-cell dysfunction and an attractive drug-adjustable target for improving the response to immunotherapy.
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