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 anti-tumor 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 three-cell-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.