Tumor-specific cytolytic CD4 T cells mediate immunity against human cancer.

Abstract

CD4 T cells have been implicated in cancer immunity for their helper functions. Moreover, their direct cytotoxic potential has been shown in some patients with cancer. Here, by mining single-cell RNA-seq datasets, we identified CD4 T cell clusters displaying cytotoxic phenotypes in different human cancers, resembling CD8 T cell profiles. Using the peptide-MHCII-multimer technology, we confirmed ex vivo the presence of cytolytic tumor-specific CD4 T cells. We performed an integrated phenotypic and functional characterization of these cells, down to the single-cell level, through a high-throughput nanobiochip consisting of massive arrays of picowells and machine learning. We demonstrated a direct, contact-, and granzyme-dependent cytotoxic activity against tumors, with delayed kinetics compared to classical cytotoxic lymphocytes. Last, we found that this cytotoxic activity was in part dependent on SLAMF7. Agonistic engagement of SLAMF7 enhanced cytotoxicity of tumor-specific CD4 T cells, suggesting that targeting these cells might prove synergistic with other cancer immunotherapies.

• Authors: Amélie Cachot, Mariia Bilous, Yen-Cheng Liu, Xiaokang Li, Margaux Saillard, Mara Cenerenti, Georg Alexander Rockinger, Tania Wyss, Philippe Guillaume, Julien Schmidt, Raphaël Genolet, Giuseppe Ercolano, Maria Pia Protti, Walter Reith, Kalliopi Ioannidou, Laurence de Leval, Joseph A Trapani, George Coukos, Alexandre Harari, Daniel E Speiser, Alexander Mathis, David Gfeller, Hatice Altug, Pedro Romero, Camilla Jandus
• Journal: Science advances (Sci Adv) Vol. 7 Issue 9 (02 2021) ISSN: 2375-2548 [Electronic] United States
• PMID: 33637530 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).

Topics

• CD4-Positive T-Lymphocytes
• CD8-Positive T-Lymphocytes
• Cytotoxicity, Immunologic
• Humans
• Immunotherapy
• Neoplasms
• T-Lymphocytes, Cytotoxic