Lin Yang: Department of Pharmacy, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuma Road 420#, Fuzhou, Fujian, China. apera@163.com.
Qiuling Zhao: Department of Pharmacy, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuma Road 420#, Fuzhou, Fujian, China.
Ting Chen: Department of Pharmacy, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuma Road 420#, Fuzhou, Fujian, China.
Wenbin Liu: Department of Pharmacy, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuma Road 420#, Fuzhou, Fujian, China.
Xiuliang Qiu: Department of Pharmacy, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuma Road 420#, Fuzhou, Fujian, China.
Jincan Chen: State Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fujian College, University of Chinese Academy of Sciences, Fuzhou, Fujian, China.
Shengqiang Huang: Department of Pharmacy, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuma Road 420#, Fuzhou, Fujian, China.
Ruyi Huang: Department of Pharmacy, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuma Road 420#, Fuzhou, Fujian, China.
Liangliang Dong: Department of Pharmacy, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuma Road 420#, Fuzhou, Fujian, China.
Anti-PD-1 immunotherapy has been widely applied in patients with some types of lymphoma. Classical Hodgkin's lymphoma (cHL) is highly sensitive to immunotherapy, but non-Hodgkin's lymphoma (NHL) does not show a good response. Studies have indicated that haematopoietic progenitor kinase 1 (HPK1) suppresses T cells and reduces antitumour immunity. Therefore, HPK1 inhibitors may restore and elicit antitumour immune responses and are promising candidate drug targets for cancer immunotherapy. We first explored the Gene Expression Profile Interactive Analysis (GEPIA) database and predicted that HPK1 expression was increased in diffuse large B-cell lymphoma (DLBCL) and associated with Nod-like receptor protein 3 (NLRP3) expression. We investigated whether an HPK1 inhibitor could enhance the tumour response to anti-PD-1 immunotherapy in NHL and the association between HPK1 and NLRP3 expression. Employing shHPK1 and an inhibitor, we demonstrated that the HPK1 inhibitor increased anti-PD-1-mediated T-cell cytotoxicity in BJAB and WSU-DLCL2 cells cocultured with peripheral blood mononuclear cells (PBMCs). HPK1 inhibitor treatment increased PD-1, PD-L1, Bax, p53 and NK-kB expression but decreased NLRP3 expression, indicating that the HPK1 inhibitor promoted apoptosis and blocked the NLRP3 inflammasome pathway to affect anti-PD-1-mediated T-cell cytotoxicity. Moreover, the HPK1 inhibitor enhanced the efficiency of anti-PD-1 immunotherapy in vivo in a zebrafish xenograft model of NHL. In summary, this study provides evidence that an HPK1 inhibitor enhanced the tumour response to anti-PD-1 immunotherapy in NHL by promoting apoptosis and blocking the NLRP3 pathway. These findings provide a potential therapeutic option for NHL combining HPK1 inhibitor treatment and anti-PD-1 immunotherapy.
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Grants
2020J011117/Natural Science Foundation of Fujian Province
2019Y9040/Joint Funds for the innovation of science and Technology
2022CXA027/Fujian Provincial Health Technology Project
