Tumour‐specific CD4 T cells eradicate melanoma via indirect recognition of tumour‐derived antigen

The importance of CD4 T cells in tumour immunity has been increasingly recognised, with recent reports describing robust CD4 T cell‐dependent tumour control in mice whose immune‐regulatory mechanisms have been disturbed by irradiation, chemotherapy, immunomodulatory therapy and/or constitutive immunodeficiency. Tumour control in such models has been attributed in large part to direct Major Histocompatibility Complex (MHC) class II‐dependent CD4 T cell killing of tumour cells. To test whether CD4 T cells can eradicate tumours without directly killing tumour cells, we developed an animal model in which tumour‐derived antigen could be presented to T‐cell receptor (TCR)‐transgenic CD4 T cells by host but not tumour MHC class II molecules. In I‐E + mice bearing I‐E null tumours, naive I‐E‐restricted CD4 T cells proliferated locally in tumour‐draining lymph nodes after recognising tumour‐derived antigen on migratory dendritic cells. In lymphopaenic but not immunosufficient hosts, CD4 T cells differentiated into polarised T helper type 1 (Th1) cells expressing interferon gamma (IFNγ), tumor necrosis factor alpha (TNFα) and interleukin (IL)‐2 but little IL‐17, and cleared established tumours. Tumour clearance was enhanced by higher TCR affinity for tumour antigen‐MHC class II and was critically dependent on IFNγ, as demonstrated by early tumour escape in animals treated with an IFNγ blocking antibody. Thus, CD4 T cells and IFNγ can control tumour growth without direct T‐cell killing of tumour cells, and without requiring additional adaptive immune cells such as CD8 T cells and B cells. Our results support a role for effective CD4 T cell‐dependent tumour immunity against MHC class II‐negative tumours.