Despite the reported clinical benefits of checkpoint blockade in some cancers, a large proportion of patients fail to respond, and insights from preclinical and clinical studies have indicated that therapy failure may stem from cues emanating from the tumor microenvironment. Strikingly, resistance to PD-1 immunotherapy in patients with metastatic melanoma has been associated with the presence of a transcriptional signature which includes genes connected to wound healing and angiogenesis, suggesting that targeting stromal elements of the tumor microenvironment has the potential to extend the therapeutic window of immunotherapies. The development of strategic therapeutics, however, is likely to depend on the identification of the cellular and molecular mechanisms governing stromal-imposed immune paralysis. In an effort to gain a better understanding on how stromal elements can modulate antitumor immune responses, we have conducted a comprehensive transcriptomic and functional analysis of stromal cells from murine tumors, which enabled the identification of a discrete population of mesenchymal cells bearing striking similarities to fibroblastic reticular cells of lymphoid organs, including expression of podoplanin and high fibrogenic potential. Our data revealed that within tumors, the reticular matrix laid by myofibroblasts promotes the compartmentalization of tumor-infiltrating leukocytes in peritumoral areas and the establishment of a dynamic interplay between T cells and stroma. Functionally, these interactions prompt stromal secretion of nitric oxide that hinders proliferation of lymphocytes, supporting that tumor fibroblasts contribute to immunosuppression by creating and restraining lymphocytes in non-permissive domains of the tumor microenvironment. Accordingly, displacement of T cells from peritumoral areas through the targeting of stroma-deposited collagen fibers augments natural antitumor immune responses and delays tumor progression in immune-competent mice, but not in lymphopenic mice. Collectively, these data shed light on the mechanisms of stroma-mediated immunomodulation in tumors, highlighting a population of lymphoid-like mesenchymal cells with fibrogenic and immunosuppressive potential. Perhaps more importantly, our study suggests that modulating the extracellular matrix has profound consequences on the spatial and functional fate of tumor-infiltrating lymphocytes, supporting that targeting tumor fibrotic responses may represent a valuable approach to complement current immunotherapies and extend their clinical benefits.
Citation Format: Viviana Cremasco, Angelo Grauel, Michael Wu, Jillian Astarita, Matthew Woodruff, Zohreh Amoozgar, Lotte Spel, Flavian Brown, Michael Carroll, Kenzie MacIsaac, Glenn Dranoff, Shannon Turley. Microenvironmental regulation of antitumor immune responses: A lesson from fibroblastic cells [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr IA23.
- ©2016 American Association for Cancer Research.