HPK1 inhibitor reinvigorates exhausted tumor-infiltrating CD8+ T cells and synergizes with anti-PD-1 inhibitor in endometrial cancer and ovarian cancer 3530

Abstract Description HPK1 (Hematopoietic Progenitor Kinase 1) is a negative intracellular immune checkpoint that interferes with the priming and activation of T cells. In recent years, several HPK1 inhibitors have been discovered as novel immune-oncology drugs with promising potential to improve anti-tumor immune responses. However, there has been no study showing the potential application of HPK1 in gynecologic malignancies. Therefore, we investigated the expression and role of HPK1 in tumor-infiltrating CD8 T cells (CD8 TILs) and how the selective small molecule kinase inhibitor, FB849, affected the reinvigoration of exhausted CD8 TILs in gynecologic cancers. We isolated TILs from patients with newly diagnosed endometrial (n = 53) and ovarian cancer (n = 46). The HPK1 signaling pathway of CD8 TILs were explored using flow cytometry. TILs were in vitro stimulated with anti-CD3 in the presence of FB849 and/or anti-PD-1, and their proliferation was assessed. We observed that HPK1 marked severely exhausted PD-1+CD8 TILs, and high HPK1 expressers had more exhausted PD-1+CD8 TILs compared to low HPK1 expressers. In addition, FB849 could successfully restore the effector function of exhausted CD8 TILs, and further enhanced anti-PD-1-mediated reinvigoration of CD8 TILs in endometrial cancer. Overall, the results of our present study provide a rationale for clinical trials investigating the anti-tumor efficacy of FB849±anti-PD-1 tailored to the respective properties of gynecologic malignancies. Funding Sources This research was supported by the National Research Foundation of Korea (NRF-2021R1A2C1093502 to Junsik Park), and the grant from 1ST Biotherapeutics, Inc., Republic of Korea. Topic Categories Tumor Immunology: Checkpoints, Prevention, and Treatment (TIPT)