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 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. Editor's summary: CD4⁺ T cells have been primarily appreciated for their helper functions in antitumor immune responses, but the extent to which they directly contribute to tumor killing remains unclear. Using a mouse model of cutaneous melanoma, Bawden et al. characterized the effector functions of CD4⁺ T cells in generating protective antitumor immunity. Melanoma-specific CD4⁺ T cells infiltrated tumors, adopted diverse effector states, and could provide tumor protection independent of other lymphocytes. Whereas MHC II expression by melanoma cells was sufficient to activate protective CD4⁺ T cell–mediated immunity, host antigen-presenting cells could also drive protection. CD4⁺ T cells provided protection through multiple partially redundant cytotoxicity pathways, including TNF and Fas ligand, but also by activating IFN-γ–dependent nitric oxide production in myeloid cells. Together, these results demonstrate that tumor-infiltrating CD4⁺ T cells are equipped to contribute to tumor control through multiple helper and effector modes. —Claire Olingy [ABSTRACT FROM AUTHOR]