Abstract A048: Targeting the tumor microenvironment to enhance immunotherapy against cancer

Immunotherapies that harness the immune system against cancer are an attractive proposition for cancer treatment. While there have been some promising successes, only a small fraction of patients obtain clinical benefit. It has become clear that the immunosuppressive tumor microenvironment (TME) is a major obstacle for immunotherapies, because the TME suppresses immune responses, leading to reduced efficacy. We previously demonstrated that the site of tumor growth is a major determinant in sculpting the organ-specific TME, and thus predisposes treatment efficacy (1). In this project, we hypothesize that the TME of visceral tumors is more immunosuppressive than those of the tumors growing elsewhere. We investigated in murine models the difference in the TME in breast cancer growing orthotopically and the same breast cancer growing in the common metastatic sites, such as the lungs. Our findings showed that the breast cancer growing in the lungs was resistant to immunotherapies such as anti-PD1 and anti-CTLA-4, whereas the breast cancer growing orthotopically could be completely eradicated even when the cancer burden was greater. Through an institutional prospective community-based rapid autopsy program (CASCADE), we obtained genetically matched metastases and surrounding tissues from several sites in the same breast cancer patients and investigated the TME from these tumors using novel technologies such as RNAseq and multiplex immunohistochemistry. Strikingly, the TMEs from the same organs in different patients have similar immune gene expression profiles and in contrast, TMEs from the same patient differ greatly in different organs. Together, our research demonstrates an organ-specific difference between TMEs that leads to different responses to therapies. We anticipate that further study of how cancer cells sculpt the TME at different sites will greatly enhance our understanding of the TME and provide promising targets to enhance current immunotherapies, especially for patients who do not respond to existing therapies. Reference: 1. Devaud C., et al. Molecular Therapy 2014;22:18-27. Citation Format: Clare Y. Slaney, Amanda J. Oliver, Michael H. Kershaw. Targeting the tumor microenvironment to enhance immunotherapy against cancer [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A048.