Tumors are associated with a microenvironment that can influence responses to immunotherapy. Advanced stages of cancer often involve multiple tumors in different locations in the body. We have demonstrated that the tumor microenvironment can vary with anatomical site, and that normal tissue surrounding the site of tumor implantation can contribute to sculpting the subsequent tumor microenvironment. Furthermore, we demonstrate that tumor responses to immunotherapy, consisting of three agonist antibodies, vary with anatomical site. We also investigated whether tumors and their disparate microenvironment can interact with each other at a distance, in a multiple tumor setting, through a form of cross-talk, to affect their responses to immunotherapy. Our study investigated the cross-talk between two tumors with disparate microenvironments in a mouse model. We demonstrated that immunosuppressive visceral tumors could influence distant subcutaneous (SC) tumors, normally responsive to immunotherapy, to render them resistant. We observed distinct modifications in the SC tumor microenvironment following cross-talk with kidney tumors, which exhibit a type-2 macrophage-related immunosuppressive microenvironment. Indeed, when a concomitant kidney tumor was present in the mouse, the SC tumors were highly infiltrated with M2 macrophages and had a reduced T cell and NK cell effector immune profile. Finally, blocking the M2-associated chemokine CCL2 or depleting macrophages, significantly improved the effect of immunotherapy on SC tumors in the presence of concomitant kidney tumors. This work presents a novel finding describing the potential negative influence that a tumor, with a strong immunosuppressive microenvironment, can exert on distant tumors that would normally be responsive to treatment. This report may lead to a new outlook in the selection and prioritization of treatment of multiple tumors in advanced metastatic cancer, which will consider the anatomical location and corresponding microenvironment of individual tumors.
Citation Format: Christel Devaud, Jennifer A. Westwood, Liza John, Carmen S.M. Yong, Paul A. Beavis, Linda A. Snyder, Reto A. Schwendener, Darcy K. Phillip, Michael H. Kershaw. Cross-talk between tumors can affect responses to therapy. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr A105.
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