Abstract 904: Heterozygous ATG7 inhibition enhances endocrine therapy responsiveness through regulation of damage associated molecular patterns and priming the immune system in ER+ breast tumors

Abstract

Abstract Breast cancer is the most prevalent cancer in women, with over 230,000 new cases diagnosed annually. The most common type of breast cancer, comprising over 70% of all cases, express the estrogen receptor (ER); these tumors are usually treated with an endocrine therapy such as an antiestrogen or aromatase inhibitor. Unfortunately, many of these tumors develop resistance, or in some instances express de novo resistance, which limits the curative potential of these therapies. Autophagy, a cellular process of “self-eating”, is implicated as possible contributor to endocrine therapy resistance in breast cancer. We previously showed that inhibiting autophagy through low-dose chloroquine treatment reversed antiestrogen therapy resistance in ER+ orthotopic breast tumors. We now show that heterozygous deletion of ATG7 decreased breast tumor multiplicity and increased endocrine targeting therapy sensitivity in a DMBA-model of ER+ mammary carcinogenesis. Knockdown of ATG7 through RNAi increased cytoplasmic to nuclear high-mobility group binding protein B1 (HMGB1) protein ratio, suggesting targeting ATG7 promotes damage associated molecular patterns (DAMP) signaling. Heterozygous deletion of ATG7 also increased cytoplasmic HMGB1 protein expression in tumor epithelial cells indicating targeting ATG7 promotes DAMP signaling in vivo. Furthermore, tumors from ATG7 heterozygous mice displayed increased CD68 staining indicating elevated macrophage infiltration. Corroborating previous literature showing the critical role of autophagy in T-cell maturation, splenic CD8+ T-cells were significantly reduced in tumor bearing ATG7 heterozygous mice. However, ATG7 heterozygous mice displayed increased tumor CD8+ T-cell population. These data suggest that while targeting ATG7 reduces overall circulating T-cell populations, inhibiting ATG7 enhances tumoral cytotoxic T-cell recruitment. Tumors from ATG7 heterozygous mice also showed a significant decrease in foxp3+ cells, indicating targeting ATG7 reduces immuno-suppressive T-reg population. Serum from ATG7 heterozygous mice showed increased circulating MDC, MCP-1, IL-6, and eotaxin cytokines. Taken together, these data suggests that ATG7 inhibition promotes an anti-tumor pro-inflammatory cytokine profile to enhance tumoral immune cell recruitment and promote endocrine therapy responsiveness. Citation Format: Robert Clarke, Pamela A.G. Clarke, Anni Wärri, Katherine L. Cook. Heterozygous ATG7 inhibition enhances endocrine therapy responsiveness through regulation of damage associated molecular patterns and priming the immune system in ER+ breast tumors. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 904.