Q1 · MEDICINE
Article
Author: Si, Jingwen ; Zou, Bin ; Long, Fei ; Sun, Shuhao ; Chen, Ligong ; Du, Xinru ; Li, Yaopeng ; Liao, Xuebin ; Sun, Yan ; Yin, Wen ; Dimitrov, Dimiter S ; Chi, Wenna ; Pang, Bo ; An, Dongjie ; Min, Junxia ; Gao, Yan ; Gao, Guangxun ; Liu, Xing ; Shi, Xiangjun ; Lin, Xingyu ; Liu, Tian ; Wei, Lai
Ameliorating T cell exhaustion and enhancing effector function are promising strategies for the improvement of immunotherapies. 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 MAP4K1KO 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.