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