Year: 2023
Type: article
Abstract: 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.
Source: Nature
Authors: Bastian Kruse, Anthony C. Buzzai, Naveen Shridhar, Andreas D. Braun, Susan Gellert, Kristin Knauth, Joanna Pozniak, Johannes Peters, Paulina Dittmann, Miriam Mengoni, Tetje Cornelia van der 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, Thomas Tüting
Institutions: University Hospital Magdeburg, Otto-von-Guericke-Universität Magdeburg, VIB-KU Leuven Center for Cancer Biology, KU Leuven, Uppsala University, Helmholtz Centre for Infection Research, University of Cologne, Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases, Universitair Ziekenhuis Leuven, Essen University Hospital, University of Duisburg-Essen, University of Würzburg
Language: English
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $11,690
OpenAlex ID: W4380628263