| First Author | Si J | Year | 2020 |
| Journal | Cancer Cell | Volume | 38 |
| Issue | 4 | Pages | 551-566.e11 |
| PubMed ID | 32860752 | Mgi Jnum | J:296679 |
| Mgi Id | MGI:6467645 | Doi | 10.1016/j.ccell.2020.08.001 |
| Citation | Si J, et al. (2020) Hematopoietic Progenitor Kinase1 (HPK1) Mediates T Cell Dysfunction and Is a Druggable Target for T Cell-Based Immunotherapies. Cancer Cell 38(4):551-566.e11 |
| abstractText | Ameliorating T cell exhaustion and enhancing effector function are promising strategies for the improvement of immunotherapies. Here, we show that the HPK1-NFkappaB-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 MAP4K1(KO) mice, tumors grow slower than in wild-type mice and infiltrating T cells are less exhausted and more active and proliferative. We further show that genetic depletion, pharmacological inhibition, or proteolysis targeting chimera (PROTAC)-mediated degradation of HPK1 improves the efficacy of CAR-T cell-based immunotherapies in diverse preclinical mouse models of hematological and solid tumors. These strategies are more effective than genetically depleting PD-1 in CAR-T cells. Thus, we demonstrate that HPK1 is a mediator of T cell dysfunction and an attractive druggable target to improve immune therapy responses. |
