The immune system can recognise and control cancer cells in a process termed cancer immunosurveillance. There is increasing evidence that CD4+ T cells play an important role in melanoma immunosurveillance but considerable debate surrounds the underlying anti-tumoral mechanisms. This project thus sought to unravel the role of CD4+ T cell responses to melanoma using a transplantable orthotopic murine melanoma model in conjunction with newly generated genetically modified melanoma cell lines. Remarkably, adoptive transfer of naïve or activated antigen-specific CD4+ T cells was highly protective against the development of melanoma. In addition to a classical “helper” function, CD4+ T cells acted as peripheral anti-tumoral effector cells whereby they migrated into the skin, differentiated into Th1 cells and mediated local suppression of tumor development.
We found that CD4+ T cells can directly bind to melanoma cells via MHC-II and have the capacity to mediate killing via several cytotoxic pathways. However, we found that MHC-II expression was dispensable for control mediated by CD4+ T cells, highlighting an important role for indirect display of MHC-II-restricted epitopes by antigen-presenting cells within the tumor microenvironment. The cross-talk between melanoma-specific CD4+ T cells, antigen-presenting cells and melanoma cells in the tumor microenvironment was visualised using two-photon microscopy. In summary, this study demonstrates the important role of CD4+ T cells in melanoma immunosurveillance and provides important insights into underlying antitumoral mechanisms.