High expression of MAP4K1 (which encodes HPK1) correlates with increased T cell exhaustion and with worse patient survival in several cancer types. In MAP4K1KO mice, tumors grow slower than in wild-type mice and infiltrating T cells are less exhausted and more active and proliferative.

HPK1, also known as MAP4K1, is a hematopoietic cell-restricted member of the Ste20 family of serine/threonine kinases that functions as a negative regulator of activation signals generated by the TCR (Kiefer et al., 1996; Hu et al., 1996; Liou et al., 2000).

2024年4月24日 · To enhance the success of tumor immunotherapy in clinical trials, it is important to develop protein degraders, allosteric inhibitors, and antibody-drug conjugates based on the crystal structure of HPK1, and to explore combination therapy approaches.

2020年10月12日 · Here, we show that the HPK1-NFκB-Blimp1 axis mediates T cell dysfunction. High expression of MAP4K1 (which encodes HPK1) correlates with increased T cell exhaustion and with worse patient survival in several cancer types.

In this report, we identified a novel, potent, and selective HPK1 small molecule kinase inhibitor, compound K (CompK). A series of studies were conducted to investigate the mechanism of action of CompK, aiming to understand its potential application in cancer immunotherapy.

2022年6月13日 · Loss of HPK1 kinase function increases cytokine secretion and enhances T cell signaling, virus clearance, and tumor growth inhibition. Therefore, HPK1 is considered a promising target for tumor immunotherapy. Several HPK1 inhibitors have been reported to regulate T cell function.

2022年12月21日 · Hematopoietic progenitor kinase 1 (HPK1) is a negative regulator of T-cell activation, and targeting HPK1 is considered a promising strategy for improving responses to antitumor immune therapies.

HPK1 is an immunosuppressive regulatory kinase with a restricted expression profile in the hematopoietic compartment (Shui et al., 2007; Wang et al., 2012). Previous studies have es-tablished that HPK1 is a negative T cell receptor (TCR) signaling regulator (Shui et al., 2007): cytosolic HPK1 is recruited to the

An oral, potent, highly selective small molecule HPK1 inhibitor demonstrates in vivo tumor growth inhibition as a single agent and in combination with anti-PD1 in syngeneic models.

We identify kinase-dependent roles for HPK1 in CD8 T cells that restrict their anti-viral and anti-tumor responses by using HPK1 kinase-dead (HPK1.kd) knockin mice. Loss of HPK1 kinase function enhanced T cell receptor signaling and cytokine secretion in a T-cell-intrinsic manner.