Tumor-specific CD8+ Tc9 Cells Activate Host CD4+ T Cells to Control Antigen-Lost Tumors

Abstract Cancer immunotherapies relying on targeted destruction of cancer cells by potent antitumor T cells have achieved unprecedented success in recent years. As a main form of cancer immunotherapies, adoptive T cell therapy (ACT) has shown a durable response in certain cancer patients. However, this response is often short-lived and tumor relapse occurs due to the outgrowth of antigen-lost-variant (ALV) tumors and poor antitumor immune response. Here, We reported that adoptively transfer of murine tumor-specific CD8+ Tc9 but not Tc1/CTL cells achieved long-term control of tumor growth in vivo. Here, we demonstrated that murine tumor-specific Tc9 cells not only killed antigen-expressing primary tumors but also controlled the outgrowth of antigen-lost relapsed tumors by recruiting and activating host effector CD4+ T cells that recognized relapsed tumors. Tc9 cells secreted IL-24 and recruited CCR7-expressing conventional type-2 dendritic cells (cDC2) into tumor-draining lymph nodes to prime host CD4+ T cell response against relapsed tumors. Depleting host CD4+ T cells or deficiency in CCR7 expression impaired Tc9 cell ability to control the outgrowth of relapsed tumor. We also observed that intratumoral IL24 expression was positively correlated with gene signatures of cDC2 and CD4+ T cells in human cancers and expression of IL24 and cDC2 and CD4+ T cell gene signatures were associated with patient’s overall survival. Thus, this study uncovers a novel mechanism underlying activation of tumor-specific CD4+ T cells in vivo. Citation Format: Liuling Xiao, Qing Yi. Tumor-specific CD8+ Tc9 cells activate host CD4+ T cells to control antigen-lost tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3606.