Associação Portuguesa de Investigação em Cancro
IMM researchers identify new immune mechanism that promotes ovarian cancer growth
IMM researchers identify new immune mechanism that promotes ovarian cancer growth
A team of researchers from Instituto de Medicina Molecular (IMM) has uncovered an unexpected cellular cross-talk behind ovarian cancer growth that can be exploited as a novel therapeutic target for future immuno-oncology strategies. The work reveals that gamma delta (γδ) T lymphocytes, which are normally seen as anti-tumour, can, surprisingly, promote tumour growth in ovarian cancer. The research, led by Prof. Bruno Silva-Santos, has now been published in PNAS (Proceedings of the Natural Academy of Sciences of the USA).
The new study by PhD student Margarida Rei in the Silva-Santos lab, in collaboration with colleagues from Queen Mary University of London (UK), gives support to this alternative role of γδ T lymphocytes, as the researchers describe a cellular cross-talk, mediated by the pro-inflammatory protein IL-17 (IL-17), between these lymphocytes and small peritoneal macrophages (SPM), that stimulates ovarian cancer proliferation.
The key molecule, IL-17, is preferentially produced by a specific population of γδ T lymphocytes which expand as the tumor grows, and this associates with the recruitment of SPM macrophages, which in turn express pro-tumor and pro-angiogenic mediators (induced by IL-17 itself) capable of directly promoting ovarian cancer cell growth in the peritoneal cavity.
This research opens new avenues for the application, in cancer immunotherapy, of anti-IL-17 antibodies that are already being clinically evaluated in autoimmune and inflammatory diseases such as psoriasis or multiple sclerosis.
Authors and Affiliations:
Margarida Rei, Natacha Gonçalves-Sousa e Bruno Silva-Santos (IMM, Lisboa); Hagen Kulbe e Daniel Pennington (Queen Mary University of London).
Abstract:
Cancer-associated inflammation mobilizes a variety of leukocyte populations that can inhibit or enhance tumour cell growth in situ. These subsets include gd T cells, which can infiltrate tumours and typically provide large amounts of anti-tumour cytokines, such as interferon-g (IFN-g). By contrast, we report here that in a well-established transplantable (ID8) model of peritoneal/ovarian cancer, gd T cells promote tumour cell growth. gd T cells accumulated in the peritoneal cavity in response to tumour challenge, and could be visualized within solid tumour foci. Functional characterization of tumour-associated gd T cells revealed preferential production of interleukin-17A (IL-17), rather than IFN-g. Consistent with this, both TCRd-deficient and IL-17-deficient mice displayed reduced ID8 tumour growth when compared to wild-type animals. IL-17 production by gd T cells in the tumour environment was essentially restricted to a highly proliferative CD27(-) subset that expressed Vg6 instead of the more common Vg1 and Vg4 TCR chains. The preferential expansion of IL-17-secreting CD27(-) Vg6(+) gd 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 for 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 work identifies an IL-17-dependent lymphoid/myeloid cross-talk involving gd T cells and SPM that promotes tumour cell growth and thus counteracts cancer immunosurveillance.
Journal: PNAS - Proceedings of the Natural Academy of Sciences of the USA
