CD4+ T cell-induced inflammatory cell death controls immune-evasive tumours

• Published in: Nature (London) 2023-06, Vol.618 (7967), p.1033-1040
• Main Authors: Kruse, Bastian, Buzzai, Anthony C., Shridhar, Naveen, Braun, Andreas D., Gellert, Susan, Knauth, Kristin, Pozniak, Joanna, Peters, Johannes, Dittmann, Paulina, Mengoni, Miriam, van der Sluis, Tetje Cornelia, Höhn, Simon, Antoranz, Asier, Krone, Anna, Fu, Yan, Yu, Di, Essand, Magnus, Geffers, Robert, Mougiakakos, Dimitrios, Kahlfuß, Sascha, Kashkar, Hamid, Gaffal, Evelyn, Bosisio, Francesca M., Bechter, Oliver, Rambow, Florian, Marine, Jean-Christophe, Kastenmüller, Wolfgang, Müller, Andreas J., Tüting, Thomas
• Format: Article
• Language: English
• Subjects: 13/1; 13/109; 13/21; 13/31; 13/51; 14/19; 14/69; 38/23; 38/91; 631/250/2503; 631/250/251; 631/67/580/1884; 64/110; 64/60; 82/80; 96/44; Antigen-presenting cells; Antigen-Presenting Cells - immunology; Antigens; Apoptosis; Cancer; Cancer immunotherapy; CD11c antigen; CD11c Antigen - immunology; CD4 antigen; CD4-Positive T-Lymphocytes - cytology; CD4-Positive T-Lymphocytes - immunology; CD8 antigen; CD8-Positive T-Lymphocytes - immunology; Cell death; Cell Death - immunology; CRISPR; Cytolytic activity; Dendritic cells; Effector cells; Experiments; Histocompatibility Antigens Class II - immunology; Humanities and Social Sciences; Humans; Immunity, Innate; Immunotherapy; Immunotherapy - methods; Inflammation; Inflammation - immunology; Interferon; Interferons - immunology; Killer Cells, Natural - immunology; Lymphocytes; Lymphocytes T; Major histocompatibility complex; Major Histocompatibility Complex - immunology; Melanoma; Metastasis; multidisciplinary; Myeloid cells; Myeloid Cells - immunology; Natural killer cells; Neoplasms - immunology; Neoplasms - pathology; Neoplasms - therapy; Nitric-oxide synthase; Peptides; Phenotypes; Science; Science (multidisciplinary); Stimulators; Th1 Cells - cytology; Th1 Cells - immunology; Tumor Microenvironment - immunology; Tumors
• ISSN: 0028-0836; 1476-4687; 1476-4687
• DOI: 10.1038/s41586-023-06199-x

Most clinically applied cancer immunotherapies rely on the ability of CD8 + cytolytic T cells to directly recognize and kill tumour cells 1 – 3 . These strategies are limited by the emergence of major histocompatibility complex (MHC)-deficient tumour cells and the formation of an immunosuppressive tumour microenvironment 4 – 6 . The ability of CD4 + effector cells to contribute to antitumour immunity independently of CD8 + T cells is increasingly recognized, but strategies to unleash their full potential remain to be identified 7 – 10 . Here, we describe a mechanism whereby a small number of CD4 + T cells is sufficient to eradicate MHC-deficient tumours that escape direct CD8 + T cell targeting. The CD4 + effector T cells preferentially cluster at tumour invasive margins where they interact with MHC-II + CD11c + antigen-presenting cells. We show that T helper type 1 cell-directed CD4 + T cells and innate immune stimulation reprogramme the tumour-associated myeloid cell network towards interferon-activated antigen-presenting and iNOS-expressing tumouricidal effector phenotypes. Together, CD4 + T cells and tumouricidal myeloid cells orchestrate the induction of remote inflammatory cell death that indirectly eradicates interferon-unresponsive and MHC-deficient tumours. These results warrant the clinical exploitation of this ability of CD4 + T cells and innate immune stimulators in a strategy to complement the direct cytolytic activity of CD8 + T cells and natural killer cells and advance cancer immunotherapies. This article describes a mechanism through which CD4 + T cells can eradicate MHC-deficient tumours that escape direct CD8 + T cell targeting and thereby complement the activity of CD8 + T cells and natural killer cells to advance cancer immunotherapies.