G·A·B·B·A

Cancer-associated inflammation mobilizes a variety of leukocyte populations that can inhibit or enhance tumour cell growth in situ. These subsets include gammadelta T cells, which can infiltrate tumours and typically provide large amounts of anti-tumour cytokines, such as interferon-gamma (IFN-gamma. By contrast, we report that in a well-established transplantable (ID8) model of peritoneal/ ovarian cancer, gammadelta T cells promote tumour cell growth. gammadelta T cells accumulated in the ascites in response to tumour challenge, and could be visualized within solid tumour foci. Functional characterization of tumour-associated gammadelta T cells revealed preferential production of interleukin-17A (IL-17), rather than IFN-gamma. Consistent with this, both TCRdelta-deficient and IL-17-deficient mice displayed reduced ID8 tumour growth when compared to wild-type mice. IL-17 production by gammadelta T cells in the tumour environment was essentially restricted to a highly proliferative CD27- subset that expressed Vgamma6 instead of the more common Vgamma1 and Vgamma4 TCR chains. These Vgamma6+ T cells displayed higher levels of the receptor for the IL-17-promoting cytokine, IL-7, that accumulated during ID8 tumour growth. The preferential expansion of IL-17-secreting Vgamma6+ T cells associated with the selective mobilization of unconventional small peritoneal macrophages (SPM) that, in comparison with large peritoneal macrophages (LPM), were enriched for IL-17RA and in pro-tumour and pro-angiogenic molecular mediators which were upregulated by IL-17. Importantly, SPM were uniquely and directly capable of promoting ovarian cancer cell proliferation. Collectively, this thesis proposes an IL-17-dependent lymphoid/ myeloid cross-talk involving gammadelta T cells and SPM that promotes tumour cell growth and thus counteracts cancer immunosurveillance.