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CD4 T cell immunity against cutaneous melanoma encompasses multifaceted MHC II-dependent responses.

Science immunology

Authors: Emma G Bawden, Teagan Wagner, Jan Schröder, Maike Effern, Daniel Hinze, Lewis Newland, Grace H Attrill, Ariane R Lee, Sven Engel, David Freestone, Marcela de Lima Moreira, Elise Gressier, Nathan McBain, Annabell Bachem, Ashraful Haque, Ruining Dong, Angela L Ferguson, Jarem J Edwards, Peter M Ferguson, Richard A Scolyer, James S Wilmott, Christopher M Jewell, Andrew G Brooks, David E Gyorki, Umaimainthan Palendira, Sammy Bedoui, Jason Waithman, Katharina Hochheiser, Michael Hölzel, Thomas Gebhardt

Whereas CD4 T cells conventionally mediate antitumor immunity by providing help to CD8 T cells, recent clinical studies have implied an important role for cytotoxic CD4 T cells in cancer immunity. Using an orthotopic melanoma model, we provide a detailed account of antitumoral CD4 T cell responses and their regulation by major histocompatibility complex class II (MHC II) in the skin. Intravital imaging revealed prominent interactions of CD4 T cells with tumor debris-laden MHC II host antigen-presenting cells that accumulated around tumor cell nests, although direct recognition of MHC II melanoma cells alone could also promote CD4 T cell control. CD4 T cells stably suppressed or eradicated tumors even in the absence of other lymphocytes by using tumor necrosis factor-α and Fas ligand (FasL) but not perforin-mediated cytotoxicity. Interferon-γ was critical for protection, acting both directly on melanoma cells and via induction of nitric oxide synthase in myeloid cells. Our results illustrate multifaceted and context-specific aspects of MHC II-dependent CD4 T cell immunity against cutaneous melanoma, emphasizing modulation of this axis as a potential avenue for immunotherapies.

PMID: 38241401

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