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

Cachot, A; Bilous, M; Liu, YC; Li, X; Saillard, M; Cenerenti, M; Rockinger, GA; Wyss, T; Guillaume, P; Schmidt, J; Genolet, R; Ercolano, G; Protti, MP; Reith, W; Ioannidou, K; de Leval, L; Trapani, JA; Coukos, G; Harari, A; Speiser, DE; Mathis, A; Gfeller, D; Altug, H; Romero, P; Jandus, C

Author(s): Cachot, A; Bilous, M; Liu, YC; Li, X; Saillard, M; Cenerenti, M; Rockinger, GA; Wyss, T; Guillaume, P; Schmidt, J; Genolet, R; Ercolano, G; Protti, MP; Reith, W; Ioannidou, K; de Leval, L; Trapani, JA; Coukos, G; Harari, A; Speiser, DE; Mathis, A; Gfeller, D; Altug, H; Romero, P; Jandus, C;
Details: Publication Year 2021-02-26,Volume 7,Issue #9,Page eabe3348
Journal Title: Science Advances
Publication Type: Research article
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.
Keywords: *CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Cytotoxicity, Immunologic; Humans; Immunotherapy; *Neoplasms; T-Lymphocytes, Cytotoxic
Department(s): Laboratory Research
PubMed ID: 33637530
Publisher's Version: https://doi.org/10.1126/sciadv.abe3348
Open Access at Publisher's Site: https://doi.org/10.1126/sciadv.abe3348
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2025-06-20 03:31:51

Last Modified: 2025-06-20 03:33:48