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

• DOI: 10.1016/j.ccell.2024.05.025
• Publication Date: 2024-06-20T14:48:23Z
• Authors: Gabriel Espinosa-...; Edison Chiu; Aurora Scrivo; Paul Zumbo; Asim Dave; Doron Betel; Sung Wook Kang; Hee-Jin Jang; Matthew D. Hellmann; Bryan M. Burt; Hyun-Sung Lee; Andrea Schietinger
• Keywords: Solid tumor; Tumor immunology

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.