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 van der Sluis, Simon Höhn, Asier Antoranz, Anna Krone, Yan Fu, Di Yu, Magnus Essand, Robert Geffers, Dimitrios Mougiakakos, Sascha KahlfußHamid Kashkar, Evelyn Gaffal, Francesca M. Bosisio, Oliver Bechter, Florian Rambow, Jean Christophe Marine, Wolfgang Kastenmüller, Andreas J. Müller*, Thomas Tüting*

*Corresponding author for this work
55 Citations (Scopus)

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.

Original languageEnglish
JournalNature
Volume618
Issue number7967
Pages (from-to)1033-1040
Number of pages8
ISSN0028-0836
DOIs
Publication statusPublished - 29.06.2023
Externally publishedYes

DFG Research Classification Scheme

  • 205-14 Haematology, Oncology
  • 205-22 Clinical Immunology and Allergology

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