Abstract 4748: Snail1 regulates the tumor-infiltrating regulatory T cell population in breast cancer through Pglyrp3

Abstract

Abstract Breast cancer is the second-leading cause of cancer deaths in women. Nearly 30% of breast cancer patients developed recurrent and/or metastatic disease despite several effective receptor-targeting treatments. Although immunotherapy, especially immune checkpoint inhibitors, has proven to be efficacious against many cancers, they have shown more limited activities against poorly immunogenic cancers such as breast cancer. The cause of this relative resistance to immunotherapy is unclear but is thought to be due in part to an enrichment of inhibitory immune cells such as regulatory T cells (Tregs) in the tumor microenvironment (TME). Therefore there is an urgent need to have a better understanding of the underlying genetic and epigenetic determinants of immunotherapeutic resistance in breast cancer to develop methods to overcome it. To that end, using a computational algorithm that we have recently developed, we have discovered a novel gene regulatory subnetwork downstream of the master epithelial mesenchymal transition (EMT) regulator Snail1 in mouse models of human breast cancer. In advanced breast cancer, Snail1 is thought to initiate the epithelial mesenchymal transition (EMT) to promote local invasion and metastatic spread, while also maintaining tumor-initiating cells. On the contrary, this new Snail1-induced subnetwork operates independently of and possibly in place of its EMT function during early tumorigenic changes, when it is required to maintain a powerful tissue surveillance program to curtail transformed cells' ability to progress to advanced cancer. Breast-restricted deletion of Snail1 early in the course of tumorigenesis of several mouse models of breast cancer results in accelerated growth of the primary tumor in an immunocompetent TME, while in an immunosuppressed TME lack of Snail1 significantly reduced growth. We found that Snail1 suppressed regulatory T cells likely by tumor-associated cytokine production, possibly through several key nodes including Hmga2 and Pglyrp3, to promote immune surveillance and clearance of cancer cells. Ongoing experiments are aimed at validating the criticality of this new pathway as individual nodes and as a whole and to evaluate its utility as a novel therapeutic target to improve breast cancer's response to immunotherapy. Citation Format: Dongjiang Chen, Mathew Sebastian, Son Le, Nagheme Thomas, David D. Tran. Snail1 regulates the tumor-infiltrating regulatory T cell population in breast cancer through Pglyrp3 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4748.