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

Bastian Kruse, Anthony C. Buzzai, Naveen Shridhar, Andreas D. Braun, Susan Gellert, Kristin Knauth, Joanna Pozniak, Johannes Peters, Paulina Dittmann, Miriam Mengoni, Tetje Cornelia Sluis, Simon Höhn, Asier Antoranz, Anna Krone, Yan Fu, Di Yu, Magnus Essand, Robert Geffers, Dimitrios Mougiakakos, Sascha Kahlfuß, Hamid Kashkar, Evelyn Gaffal, Francesca M. Bosisio, Oliver Bechter, Florian Rambow, Jean-Christophe Marine, Wolfgang Kastenmüller, Andreas J. Müller () and Thomas Tüting ()
Additional contact information
Bastian Kruse: University Hospital and Health Campus Immunology Infectiology and Inflammation (GC-I3), Otto-von-Guericke University
Anthony C. Buzzai: University Hospital and Health Campus Immunology Infectiology and Inflammation (GC-I3), Otto-von-Guericke University
Naveen Shridhar: University Hospital and Health Campus Immunology Infectiology and Inflammation (GC-I3), Otto-von-Guericke University
Andreas D. Braun: University Hospital and Health Campus Immunology Infectiology and Inflammation (GC-I3), Otto-von-Guericke University
Susan Gellert: University Hospital and Health Campus Immunology Infectiology and Inflammation (GC-I3), Otto-von-Guericke University
Kristin Knauth: University Hospital and Health Campus Immunology Infectiology and Inflammation (GC-I3), Otto-von-Guericke University
Joanna Pozniak: Center for Cancer Biology, VIB
Johannes Peters: University Hospital and Health Campus Immunology Infectiology and Inflammation (GC-I3), Otto-von-Guericke University
Paulina Dittmann: University Hospital and Health Campus Immunology Infectiology and Inflammation (GC-I3), Otto-von-Guericke University
Miriam Mengoni: University Hospital and Health Campus Immunology Infectiology and Inflammation (GC-I3), Otto-von-Guericke University
Tetje Cornelia Sluis: University Hospital and Health Campus Immunology Infectiology and Inflammation (GC-I3), Otto-von-Guericke University
Simon Höhn: University Hospital and Health Campus Immunology Infectiology and Inflammation (GC-I3), Otto-von-Guericke University
Asier Antoranz: KU Leuven
Anna Krone: Otto-von-Guericke University
Yan Fu: Otto-von-Guericke University
Di Yu: Uppsala University
Magnus Essand: Uppsala University
Robert Geffers: Helmholtz Centre for Infection Research
Dimitrios Mougiakakos: Otto-von-Guericke University
Sascha Kahlfuß: Otto-von-Guericke University
Hamid Kashkar: University of Cologne
Evelyn Gaffal: University Hospital and Health Campus Immunology Infectiology and Inflammation (GC-I3), Otto-von-Guericke University
Francesca M. Bosisio: UZ Leuven
Oliver Bechter: UZ Leuven
Florian Rambow: University Hospital Essen
Jean-Christophe Marine: Center for Cancer Biology, VIB
Wolfgang Kastenmüller: Institute for Systems Immunology
Andreas J. Müller: Otto-von-Guericke University
Thomas Tüting: University Hospital and Health Campus Immunology Infectiology and Inflammation (GC-I3), Otto-von-Guericke University

Nature, 2023, vol. 618, issue 7967, 1033-1040

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41586-023-06199-x

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