Tumor-specific CD8+ Tc9 cells activate host CD4+ T cells to control antigen-lost tumors

Host effector CD4+ T cells are emerging as an important contributor for tumor regression but whether they can be activated by adoptively transferred CD8+ T cells remains unknown. We reported that adoptive transfer of murine tumor-specific CD8+ Tc9 but not Tc1-CTL cells achieved long-term control of tumor growth in vivo. Here, we demonstrate that murine tumor-specific Tc9 cells not only kill antigen expressing primary tumors but also control the outgrowth of antigen-lost relapsed tumors by recruiting and activating host effector CD4+ T cells that recognize relapsed tumors. Tc9 cells secreted interleukin (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 cDC2 impaired Tc9 cells ability to control the outgrowth of relapsed tumor. We also observed that intratumoral IL24 expression was positively correlated with gene signatures of cDC2 and effector CD4+ T cells in human cancers and expression of IL24, cDC2 and CD4+ T cell gene signatures were positively associated with patients overall survival. This study thus uncovers a novel mechanism underlying the activation of tumor-specific CD4+ T cells in vivo.