IL-7-primed bystander CD8 tumor-infiltrating lymphocytes optimize the antitumor efficacy of T cell engager immunotherapy

Bispecific T cell engagers (TCEs) show promising clinical efficacy in blood tumors, but their application to solid tumors remains challenging. Here, we show that Fc-fused IL-7 (rhIL-7-hyFc) changes the intratumoral CD8 T cell landscape, enhancing the efficacy of TCE immunotherapy. rhIL-7-hyFc induces a dramatic increase in CD8 tumor-infiltrating lymphocytes (TILs) in various solid tumors, but the majority of these cells are PD-1-negative tumor non-responsive bystander T cells. However, they are non-exhausted and central memory-phenotype CD8 T cells with high T cell receptor (TCR)-recall capacity that can be triggered by tumor antigen-specific TCEs to acquire tumoricidal activity. Single-cell transcriptome analysis reveals that rhIL-7-hyFc-induced bystander CD8 TILs transform into cycling transitional T cells by TCE redirection with decreased memory markers and increased cytotoxic molecules. Notably, TCE treatment has no major effect on tumor-reactive CD8 TILs. Our results suggest that rhIL-7-hyFc treatment promotes the antitumor efficacy of TCE immunotherapy by increasing TCE-sensitive bystander CD8 TILs in solid tumors. [Display omitted] •IL-7-Fc treatment increases PD-1-negative bystander CD8 TILs within solid tumors•IL-7-Fc-induced bystander CD8 TILs display a non-exhausted central memory phenotype•TCE redirects IL-7-Fc-induced bystander CD8 TILs to acquire tumoricidal activity•IL-7-Fc optimizes the antitumor effects of TCEs by reshaping CD8 TIL populations Though promising in cancer immunotherapy, bispecific T cell engagers (TCEs) face challenges in treating solid tumors. Lee et al. demonstrate that IL-7-Fc treatment enhances the antitumor efficacy of TCE immunotherapy in solid tumors by increasing TCE-sensitive CD8 tumor-infiltrating lymphocytes, suggesting a strategy for optimizing TCE immunotherapy with IL-7-Fc.