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An HPK1 inhibitor enhanced the tumour response to anti-PD-1 immunotherapy in non-Hodgkin’s lymphoma

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Abstract

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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Data availability

Anonymized data are available upon request to the corresponding author.

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Funding

This study was supported by Fujian Provincial Health Technology Project (Grant No. 2022CXA027), the Natural Science Foundation of Fujian Province (Grant No. 2020J011117), the Joint Funds for the Innovation of Science and Technology, Fujian Province (Grant No. 2019Y9040).

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Authors and Affiliations

  1. Department of Pharmacy, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuma Road 420#, Fuzhou, Fujian, China

    Lin Yang, Qiuling Zhao, Ting Chen, Wenbin Liu, **uliang Qiu, Shengqiang Huang, Ruyi Huang & Liangliang Dong

  2. 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

    **can Chen

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  1. Lin Yang
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  2. Qiuling Zhao
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Contributions

LY designed the study and wrote the main manuscript. QLZ and TC performed methodology and statistical analysis while WBL and XLQ wrote the original draft. JCC performed methodology. SQH performed the visualization and validation. RYH, LLD performed the modification.

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Correspondence to Lin Yang.

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10238_2023_1068_MOESM1_ESM.tif

Fig. S1 GEPIA dataset predicted the gene expression profile of HPK1. (A) The gene expression profile across all tumor samples and paired normal tissues. (B) The Box Plots the expression of HPK1 in DLBCL and control samples. (C) The overall survival profile of HPK1 level expression in DLBCL and control samples. (D) Correlation analysis for HPK1 and NLRP3 in DLBCL tumor datasets.

10238_2023_1068_MOESM2_ESM.tif

Fig. S2 The CD8(+) T cell number was measured by flow cytometry in BJAB(A) and WSU-DLCL2(B) cells co-cultured with PBMCs and with anti-PD-1 treatment.

10238_2023_1068_MOESM3_ESM.tif

Fig. S3 An HPK1 inhibitor enhanced anti-PD-1 mediated T cell cytotoxicity and apoptosis in WSU-DLCL2 cells. (A) The effect of shHPK1 or GNE-1858 treatment on the proliferation of WSU-DLCL2 cells cocultured with PBMCs after 24 h, 48 h, and 72 h of anti-PD-1 treatment was detected by CCK8 assay. (B) The effect of shHPK1 or GNE-1858 treatment on the proliferation of WSU-DLCL2 cells cocultured with PBMCs after 24 h, 48 h, and 72 h of anti-PD-1 treatment was detected by soft agar colony-formation assay. (C) The effect of shHPK1 or HPK1 inhibitor GNE-1858 treatment on the survival of WSU-DLCL2 cells co-cultured with PBMCs after 3d, 7d and 10d anti-PD-1 treatment was detected with a counter. (D) The effect of shHPK1 or HPK1 inhibitor GNE-1858 treatment on the apoptotic rate of WSU-DLCL2 cells cocultured with PBMCs 72 h of anti-PD-1 treatment was detected by flow cytometry.

10238_2023_1068_MOESM4_ESM.tif

Fig. S4 HPK1 inhibitor treatment affected apoptosis (Bax, p53) and the inflammasome (NLRP3) pathway in WSU-DLCL2 cells.Western blotting was performed to detect the indicated protein levels upon treatment with shHPK1 (A) or an HPK1 inhibitor (B) in WSU-DLCL2 cells cocultured with PBMCs treated with anti-PD-1, and the results were quantified. Gels/blots cropped from different gels are grouped.

Supplementary file5 (DOC 45 KB)

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Yang, L., Zhao, Q., Chen, T. et al. An HPK1 inhibitor enhanced the tumour response to anti-PD-1 immunotherapy in non-Hodgkin’s lymphoma. Clin Exp Med 23, 3767–3780 (2023). https://doi.org/10.1007/s10238-023-01068-3

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