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

• Published in: Cell reports. Medicine Vol. 5; no. 5; p. 101567
• Main Authors: Lee, Kun-Joo, Choi, Donghoon, Tae, Nara, Song, Ha Won, Kang, Yeon-Woo, Lee, Minji, Moon, Dain, Oh, Youngsik, Park, Sujeong, Kim, Ji-Hae, Jeong, Siheon, Yang, Jaehyuk, Park, Uni, Hong, Da Hee, Byun, Mi-Sun, Park, Su-Hyung, Sohn, Joohyuk, Park, Yunji, Im, Sun-Kyoung, Choi, Sun Shim, Kim, Dae Hee, Lee, Seung-Woo
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 21.05.2024; Elsevier
• Subjects: Animals; bispecific T cell engager; bystander CD8 T cell; Bystander Effect - immunology; cancer immunotherapy; CD8-Positive T-Lymphocytes - immunology; Cell Line, Tumor; combination therapy; Humans; Immunotherapy - methods; interleukin-7; Interleukin-7 - immunology; Interleukin-7 - metabolism; Lymphocytes, Tumor-Infiltrating - drug effects; Lymphocytes, Tumor-Infiltrating - immunology; Mice; Neoplasms - immunology; Neoplasms - therapy; Receptors, Antigen, T-Cell - immunology; Receptors, Antigen, T-Cell - metabolism; solid tumors; tumor microenvironment; tumor-infiltrating lymphocytes; cancer immunotherapy; combination therapy; tumor-infiltrating lymphocytes; tumor microenvironment; interleukin-7; solid tumors; bispecific T cell engager; bystander CD8 T cell
• ISSN: 2666-3791; 2666-3791
• DOI: 10.1016/j.xcrm.2024.101567

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.