1. CD4 + T cell-induced inflammatory cell death controls immune-evasive tumours.
- Author
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Kruse B, Buzzai AC, Shridhar N, Braun AD, Gellert S, Knauth K, Pozniak J, Peters J, Dittmann P, Mengoni M, van der Sluis TC, Höhn S, Antoranz A, Krone A, Fu Y, Yu D, Essand M, Geffers R, Mougiakakos D, Kahlfuß S, Kashkar H, Gaffal E, Bosisio FM, Bechter O, Rambow F, Marine JC, Kastenmüller W, Müller AJ, and Tüting T
- Subjects
- Humans, Antigen-Presenting Cells immunology, CD11c Antigen immunology, CD8-Positive T-Lymphocytes immunology, Histocompatibility Antigens Class II immunology, Immunity, Innate, Interferons immunology, Major Histocompatibility Complex immunology, Killer Cells, Natural immunology, Myeloid Cells immunology, Th1 Cells cytology, Th1 Cells immunology, CD4-Positive T-Lymphocytes cytology, CD4-Positive T-Lymphocytes immunology, Cell Death immunology, Inflammation immunology, Neoplasms immunology, Neoplasms pathology, Neoplasms therapy, Tumor Microenvironment immunology, Immunotherapy methods
- Abstract
Most clinically applied cancer immunotherapies rely on the ability of CD8
+ cytolytic T cells to directly recognize and kill tumour cells1-3 . These strategies are limited by the emergence of major histocompatibility complex (MHC)-deficient tumour cells and the formation of an immunosuppressive tumour microenvironment4-6 . 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 identified7-10 . 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., (© 2023. The Author(s).)- Published
- 2023
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