LAUSR

The immune system and the tissue microenvironment shape tumor evolution by providing selection for cancer cells with certain phenotypes. Immunotherapy is one of the most promising current cancer therapies and one of the very few that has the potential to cure even advanced metastatic disease. However, in breast cancer its success thus far has been limited to a subset of triple-negative tumors. This could be due to the testing of a limited set of immune-regulatory agents, but also a consequence of heterogeneity among tumors for mechanisms by which they escape immune surveillance. We hypothesized that the in situ to invasive carcinoma transition is a critical step for immune escape in breast cancer, since in DCIS (ductal carcinoma in situ) cancer cells are still physically separated from the stroma by the basement membrane and myoepithelial cell layer, and tumor-infiltrating leukocytes are rarely detected in direct contact with cancer cells. In contrast, in invasive tumors cancer cells and leukocytes are mixed, providing a strong selection for cancer cells that can overcome a potential immune attack. To begin dissecting mechanisms of immune escape during breast tumor evolution, we analyzed the composition of leukocytes in normal breast tissues, DCIS, and invasive ductal carcinomas (IDC) by a combination of technologies including FACS, RNA-seq, multicolor immunofluorescence, and immune-FISH. Based on these analyses, we found that invasive tumors have a less active immune environment due to a combination of upregulation of immune-suppressive mechanisms by both the cancer cells and various other cell types composing the microenvironment. Our results will improve our understanding of immune escape in breast cancer and aid the design of more effective immunotherapies for both advanced and early-stage disease. Citation Format: Kornelia Polyak. Breast tumor evolution: The role of the microenvironment [abstract]. In: Proceedings of the AACR Special Conference: Advances in Breast Cancer Research; 2017 Oct 7-10; Hollywood, CA. Philadelphia (PA): AACR; Mol Cancer Res 2018;16(8_Suppl):Abstract nr IA14.