Background: Triple-negative breast cancer (TNBC) with high glucocorticoid receptor activity (GR-high) is associated with a high risk of relapse and chemotherapy resistance. Glucocorticoids (GC) are essential for the regulation of immune and inflammatory responses. Multiple mechanisms of GC-induced immunosuppression have been proposed, including suppression of T cell proliferation and dendritic cell antigen presentation and function. The importance of intact immune surveillance in controlling neoplastic transformation is well-established, and accumulating evidence demonstates a correlation between tumor-infiltrating lymphocytes (TILs) in cancer tissue and favorable prognosis. In particular, the presence of CD8+ T-cells and the ratio of CD8+ effector T-cells / Foxp3+ regulatory T-cells (Tregs) appears to correlate with improved prognosis and long-term survival. We hypothesized that tumor GR activity would modulate the tumor immune microenvironment (TME), thereby suppressing anti-tumor immunity in TNBC.

Methods: We identified 46 patients with TNBC who received neoadjuvant chemotherapy at The University of Chicago between 2002-2014, and had pretreatment tissue available for study. Tumors were stained for GR expression using the anti-GR rabbit monoclonal XP antibody (Cell Signaling, 1:200 dilution). GR expression was determined independently by two pathologists. Using multiplex immunohistochemistry, six phenotypes for immune cell markers (BATF3+ dendritic cells, CD8+ T-cells, Foxp3+ Tregs, PD-L1+tumor, PD-L1-tumor, PD-L1+immune cells) were identified in the tumor and stroma of the pretreatment biopsy specimens. Absolute counts of each type of immune cell as well as ratios between immune cell types were compared in GR-low, GR-moderate, and GR-high expressing TNBC specimens using the Kruskal-Wallis test.

Results: There were 8 GR-low, 23 GR-moderate, and 15 GR-high expressing tumors in our cohort. When comparing GR-low to GR-moderate or GR-moderate to GR-high expressing tumors, there were no significant difference observed in immune cell types. However, when comparing GR-high to GR-low expressing TNBCs, there were significantly higher levels of CD8+ T-cells, Foxp3+ Treg cells, and BATF3+ dendritic cells in GR-high vs GR-low TNBC tumors (p=0.0004, p=0.011, and p=0.0072, respectively). When comparing the ratio of CD8+ T-cells to Foxp3+ Treg cells, PD-L1+ tumor or immune cells, no significant differences were observed by level of GR expression (p=ns for all comparisons).

Conclusions: We report for the first time that GR-high, treatment-naïve, primary TNBCs have significantly higher CD8+ T cells, Foxp3+ T cells, and BATF3+ dendritic cells compared to GR-low TNBCs, consistent with an inflamed TME. While historically a robust immune infiltrate in the TME in early TNBC has been associated with a better response to chemotherapy and a more favorable long-term outcome, high GR activity in early TNBC has been associated with a worse outcome. Our observation that GR-high tumors have an inflamed TME, suggests that checkpoint blockade to either suppress Foxp3+ Tregs or activate CD8+ T cells may be able to restore anti-tumor immunity.

Citation Format: Deniz N Dolcen, Marie Dreyer, Aaron Miller, Anna Biernacka, Ken Hatogai, Randy Sweis, Rita Nanda, Suzanne D Conzen. Glucocorticoid receptor expression in early-stage triple-negative breast cancer is associated with a high level of tumor immune cell infiltrates [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS18-01.