Abstract 2812: Triple-negative breast cancer cell-intrinsic glucocorticoid receptor activity and modulation of the immune microenvironment

Abstract Background: Variation in the infiltration of TNBC immune microenvironment is not well understood. Our lab previously demonstrated that high glucocorticoid receptor (GR; nuclear hormone receptor) activity in TNBC models is associated with tumor cell-intrinsic anti-inflammatory gene expression pathways. In addition, high GR expression in early-stage TNBC is associated with a significantly lower rate of recurrence-free survival suggesting a role for GR-associated mechanisms in TNBC progression. GR activation in lymphocytes is well known to result in their apoptosis; however, a current gap in knowledge regarding GR biology is whether tumor-cell intrinsic GR activity modulates immune cells in the microenvironment. We hypothesized that TNBC cell-intrinsic GR activity may inhibit antitumor T cell activity in the tumor microenvironment. Methods and Results: We divided TCGA primary TNBC RNAseq expression data based on GR expression and determined enrichment for immune cells using two transcriptome parsing algorithms. We found that TNBCs with high GR expression are significantly enriched for the T cell-inflamed gene expression signature, suggesting the presence of T cells in the microenvironment. The xCell algorithm found that TNBCs with high GR expression are significantly enriched for the CD4+ naïve T cell transcriptome, which is absent in TNBCs with low GR-expression. To begin to determine whether GR activation in TNBC cells induces the secretion of cytokines and/or growth factors that result in the chemotaxis of CD4+ naïve T cells, we collected conditioned cell culture media from control versus GR-active TNBC cells and performed multiplex cytokine ELISA. We found that G-CSF secretion by TNBC cells was significantly increased following GR activation; G-CSF has been shown to promote immunosupressive Treg cell differentiation. Conclusions: Prior data suggest that breast tumor-infiltrating immunosuppressive Tregs arise from chemotaxis of circulating naive CD4+ T cells that differentiate into Tregs in situ. Thus targeting GR in TNBC may be an important therapeutic approach to potentiate antitumor T cell responses and suppress the Treg population in the tumor microenvironment. Ongoing work is aimed at further delineating a mechanism by which GR can modulate the immune tumor microenvironment. Citation Format: Deniz N. Dolcen, Diana West Szymanski, Ananth Panchamukhi, Xiaomeng Wang, Randy F. Sweis, Rita Nanda, Suzanne Conzen. Triple-negative breast cancer cell-intrinsic glucocorticoid receptor activity and modulation of the immune microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2812.