Targeting PD-1 and CD85j can restore intratumoral CD4+GzmB+T-cell functions to combat MHC-II-expressing tumors

• DOI: 10.1136/jitc-2024-010890
• Publication Date: 2025-04-01T21:20:01Z
• Authors: Boyu Wang; Xu Wang; Tianlai Wang; Kelin Meng; Taiyan Yu; Yu Xi; Shaojie Hu; Hui Xiong; Rirong Qu; Zhiwei Yuan; Xue Wang; Chenxi Zeng; Wenbin Zou; Yitao Tian; Yixin Cai; Shengling Fu; Xiangning Fu; Lequn Li
• Keywords: Granzyme

Background A subset of CD4 + T cells with cytotoxic activity has been identified, and these exert their effects by expressing perforin granzymes. Despite the progress made in characterizing various diseases, status non-small cell lung cancer (NSCLC) underlying mechanisms involved promoting intratumoral T-cell activation remain unclear. Methods We used flow cytometry to examine phenotypic functional properties GzmB peripheral blood tumor tissues patients NSCLC. Loss-of-function analyses RNA sequencing were identify interleukin (IL)-15 on restoration function vitro. patient-derived explant model an animal verify immune checkpoint inhibitors activation. Results In NSCLC, impaired cytolytic tumor-infiltrated granzyme B (GzmB)-expressing was restored IL-15 through AKT-FOXO1-T-bet axis. Moreover, stimulation increased solute carrier family 7 member 5 (SLC7A5) expression Protein Kinase (AKT)-dependent manner, inhibition SLC7A5 abrogated effect cells. Additionally, we showed that molecules programmed death-1 (PD-1) CD85j mutually exclusively expressed dual targeting PD-1 enhanced effector activating AKT pathway. Notably, major histocompatibility complex (MHC)-II determine effectiveness T-cell-mediated antitumor immunity response immunotherapy. Conclusions Our study demonstrated tumor-infiltrating fail eliminate tumors. Dual blockade alongside restores drives transformation microenvironment combat MHC-II-expressing