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

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 a...

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Published in:Science immunology Vol. 9; no. 91; p. eadi9517
Main Authors: Bawden, Emma G, Wagner, Teagan, Schröder, Jan, Effern, Maike, Hinze, Daniel, Newland, Lewis, Attrill, Grace H, Lee, Ariane R, Engel, Sven, Freestone, David, de Lima Moreira, Marcela, Gressier, Elise, McBain, Nathan, Bachem, Annabell, Haque, Ashraful, Dong, Ruining, Ferguson, Angela L, Edwards, Jarem J, Ferguson, Peter M, Scolyer, Richard A, Wilmott, James S, Jewell, Christopher M, Brooks, Andrew G, Gyorki, David E, Palendira, Umaimainthan, Bedoui, Sammy, Waithman, Jason, Hochheiser, Katharina, Hölzel, Michael, Gebhardt, Thomas
Format: Journal Article
Language:English
Published: United States 19.01.2024
Subjects:
CD4-Positive T-Lymphocytes
CD8-Positive T-Lymphocytes
Histocompatibility Antigens Class II
HLA Antigens
Humans
Melanoma
Skin Neoplasms
ISSN:2470-9468, 2470-9468
Online Access:Get more information
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Summary: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.
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ISSN:2470-9468
2470-9468
DOI:10.1126/sciimmunol.adi9517