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. 2024 Jul 8;42(7):1202-1216.e8.
doi: 10.1016/j.ccell.2024.05.025. Epub 2024 Jun 20.

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

Gabriel Espinosa-Carrasco  1 , Edison Chiu  2 , Aurora Scrivo  3 , Paul Zumbo  4 , Asim Dave  2 , Doron Betel  5 , Sung Wook Kang  6 , Hee-Jin Jang  6 , Matthew D Hellmann  7 , Bryan M Burt  8 , Hyun-Sung Lee  6 , Andrea Schietinger  9
Affiliations

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

Gabriel Espinosa-Carrasco et al. Cancer Cell. .

Abstract

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.

Keywords: CD4 T cell; CD8 T cell; Cancer; adoptive T cell transfer; cancer immunotherapy; dendritic cell; immune checkpoint blockade; triad; tumor; tumor antigen.

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Conflict of interest statement

Declaration of interests M.D.H. is currently an employee and shareholder at AstraZeneca. M.D.H. current address: Early Clinical Development, Oncology R&D, AstraZeneca, New York, NY, USA. B.M.B. received funding from AstaZeneca for the clinical trial related to this project, clinical trial funding from Momatero-Gene, clinical trial funding from Novartis.

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