Immunotherapy alongside IL-15 promote intratumoral cytotoxic CD4+T cell activation against MHC-II-expressing tumors

By killing tumor cells, cytotoxic CD8+ T cells are the major effectors in antitumor immunity. A subset of CD4+ T cells also possesses cytotoxic activity by expressing perforin and granzymes and is associated with immunotherapy efficacy. Despite the progress made in characterizing cytotoxic CD4+ T cells in various diseases, the status of cytotoxic CD4+ T cells in non-small cell lung cancer (NSCLC) and the driving mechanisms and forces involved in reviving intratumoral cytotoxic CD4+ T cells remain unclear. Here, we showed that CD4+GzmB+ T cells obtained from patients with NSCLC expressed increased levels of SLC7A5 compared with their counterparts. Upregulation of SLC7A5 was essential for the differentiation of CD4+GzmB+ T cells from naïve CD4+ T cells stimulated with TCR and IL-2. Both T-bet and Eomes are required for the differentiation of CD4+GzmB+ T cells. Interestingly, IL-15 can further increase SLC7A5 expression in differentiated CD4+GzmB+ T cells. Moreover, through activation of the AKT-FOXO1-T-bet axis, IL-15 increased the effector function of intratumoral CD4+GzmB+ T cells. In addition to IL-15, owing to the unique expression profile of PD-1 and CD85j in tumor-infiltrating CD4+GzmB+ T cells, using patient-derived lung cancer explants, we showed that simultaneous blockade of PD-1 and CD85j promoted the effector function of CD4+GzmB+ T cells by activating the AKT pathway. Importantly, using a mouse model of lung cancer, we demonstrated that intrinsic MHC II expression in cancer cells determines the significance of CD4+GzmB+ T-cell-mediated antitumor immunity in response to immunotherapy.