Adoptively transferred tumor-specific IL-9-producing cytotoxic CD8⁺ T cells activate host CD4⁺ T cells to control tumors with antigen loss

Host effector CD4⁺ T cells emerge as critical mediators for tumor regression but whether they can be activated by adoptively transferred CD8⁺ T cells remains unknown. We previously reported that adoptive transfer of interleukin 9 (IL-9)-producing cytotoxic CD8⁺ T (Tc9) cells achieved long-term control of tumor growth. Here, we demonstrate that murine tumor-specific Tc9 cells control the outgrowth of antigen-loss relapsed tumors by recruiting and activating host effector CD4⁺ T cells. Tc9 cells secreted IL-24 and recruited CCR7-expressing conventional type 2 dendritic cells (cDC2 cells) into tumor-draining lymph nodes to prime host CD4⁺ T cells against relapsed tumors. Host CD4⁺ T cell or cDC2 deficiency impaired the ability of Tc9 cells to control relapsed tumor outgrowth. Additionally, intratumoral IL24 expression correlates with cDC2 and CD4⁺ T cell gene signatures in human cancers and their expression is associated with better patient survival. This study reports a mechanism for activation of tumor-specific CD4⁺ T cells in vivo.