HPK1 inhibitor enhanced tumor response to anti-PD-1 immunotherapy in Non-Hodgkin lymphoma

Abstract

Anti-PD-1 immunotherapy has been widely applied in patients with some types of lymphomas. The classical Hodgkin's lymphoma is highly sensitive to immunotherapy but Non-Hodgkin's lymphoma (NHL) is not good response. Therefore, it is valuable to optimize PD-1 blockade treatment in NHL patients. Studies indicated that HPK1 suppressed T cells and reduced the anti-tumor immunity. Therefore, HPK1 inhibitor may restore and elicit antitumor immune responses and is a promising candidate drug target for cancer immunotherapy. We initially explored the Gene Expression Profile Interactive Analysis (GEPIA) databases and it predicted that HPK1 expression increased in DLBCL and was associated with NLRP3. We investigated whether the HPK1 inhibitor could enhance tumor response to anti-PD-1 immunotherapy in NHL and the association between HPK1 and NLRP3. Employing shHPK1 and inhibitor, our study demonstrated that HPK1 inhibitor increased the anti-PD-1 mediated T cell cytotoxicity on BJAB and WSU-DLCL2 co-cultured with peripheral blood mononuclear cells (PBMCs). HPK1 inhibitor increased PD-1, PD-L1, Bax, p53 and NK-kB but decreased NLRP3. These indicated that HPK1 inhibitor was associated with apoptosis and NLRP3 inflammasome pathway in anti-PD-1 mediated T cell cytotoxicity. Our data also demonstrated that HPK1 inhibitor enhanced the efficiency of anti-PD-1 immunotherapy on NHL in in vivo zebrafish xenograft models. In summary, this study provided the evidence that HPK1 inhibitor enhanced tumor response to anti-PD-1 immunotherapy for NHL by promoting apoptosis and blocking NLRP3 pathway. This provides a potential therapeutic option for NHL with combination HPK1 inhibitor and anti-PD-1 immunotherapy.