Abstract 2693: Inflammatory signalling in the colon tumour microenvironment enhances stromal cell mediated suppression of anti-tumour immune responses

The colon tumour microenvironment (TME) comprises many cell types including endothelial cells, stromal cells and immune cells. Recent evidence suggests that high tumour stromal cell density correlates with a poor prognosis for colon cancer patients. The majority of these stromal cells are of mesenchymal origin (MSCs) and are known contributors to tumour angiogenesis and invasiveness. Little is known about the role of their immunosuppressive potential in the colon TME. We investigated the molecular regulation of the induced immunosuppressive, tumour-promoting phenotype of tumour-associated MSCs, and the effect of inflammation on this process. Balb/c bone marrow derived MSCs were treated with conditioned medium from untreated CT26 tumour cells (MSC^TCM) or TNF-α treated CT26 cells (MSC^TNF-TCM). Cell surface analysis of MSCs after 72h revealed an increased expression of TCR ligands MHC-I, MHC-II and PD-L1 compared to MSC^Control. This was further potentiated by TNF-α induced tumour cell inflammation. MSC^TCM co-cultured with syngeneic activated T cells displayed an enhanced ability to suppress CD8+ T cell proliferation, which was further potentiated by inflammatory activation of CT26 (MSC^TNF-TCM). This effect was dependent on induced PD-L1 expression on MSCs as PD-1 blockade restored CD8+ T cell proliferation, activation and granzyme B secretion. In an immunocompetent Balb/c syngeneic model, we assessed tumour growth and anti-tumour immune responses following sub-cutaneous injection of CT26 cells alone or co-injection with MSC^Control/MSC^TNF-TCM. Co-injection of MSC^Control significantly promoted tumour growth, and this was further potentiated by the co-injection of MSC^TNF-TCM. This effect was associated with significantly reduced tumour infiltration of CD8 Granzyme B secreting T cells. We showed that this stromal cell mediated tumour promotion could be reversed by administration of a PD-1 blocking antibody, via restoration of granzyme B secreting CD8+ T cells. We show for the first time that stromal cells in the inflammatory TME directly modulate anti-tumour immune responses via PD-L1. This data could lead to better stratification of patients for immunotherapeutic regimens resulting in more targeted and durable responses to overcome stromal mediated tumour immunosuppression in colon cancer.

Citation Format: Grace O'Malley, Kevin Lynch, Serika Naicker, Paul Lohan, Athina Rigalou, Thomas Ritter, Laurence J. Egan, Aideen E. Ryan. Inflammatory signalling in the colon tumour microenvironment enhances stromal cell mediated suppression of anti-tumour immune responses [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2693. doi:10.1158/1538-7445.AM2017-2693