Intratumoral immune triads are required for immunotherapy-mediated elimination of solid tumors

Tumor-specific CD8 + T cells are frequently dysfunctional and unable to halt tumor growth. We investigated whether tumor-specific CD4 + T cells can be enlisted to overcome CD8 + T cell dysfunction within tumors. We find that the spatial positioning and interactions of CD8 + and CD4 + T cells, but not their numbers, dictate antitumor responses in the context of adoptive T cell therapy as well as immune checkpoint blockade (ICB): CD4 + T cells must engage with CD8 + T cells on the same dendritic cell during the effector phase, forming a threecell-type cluster (triad) to license CD8 + T cell cytotoxicity and cancer cell elimination. When intratumoral triad formation is disrupted, tumors progress despite equal numbers of tumor-specific CD8 + and CD4 + T cells. In patients with pleural mesothelioma treated with ICB, triads are associated with clinical responses. Thus, CD4 + T cells and triads are required for CD8 + T cell cytotoxicity during the effector phase and tumor elimination.