High tumor glucocorticoid receptor expression in early-stage, triple-negative breast cancer is associated with increased T-regulatory cell infiltration

Purpose: In early-stage, triple-negative breast cancer (TNBC), immune cell infiltration contributes to cancer cell survival, tumor invasion, and metastasis. High TNBC glucocorticoid receptor (GR) expression in early-stage TNBC is associated with poor long-term outcomes; it is unknown if high GR expression is associated with an immunosuppressed tumor microenvironment. We hypothesized that high tumor GR expression would be associated with an immune-suppressed tumor microenvironment, which could thus account for the poor prognosis observed in GR-positive TNBC.

Methods: Formalin fixed-paraffin embedded tissue (n = 47) from patients diagnosed with early-stage TNBC from The University of Chicago (2002-2014) were evaluated for both tumor cell anti-GR immunohistochemistry and for infiltrating immune cells by immunofluorescence. Multiplexed antibodies were used to enumerate CD8+, FOXP3+, and BATF3+ immune cells infiltrating within pan-cytokeratin positive tumor cell regions of interest, and nonparametric tests compared absolute counts of each of these tumor-infiltrating immune cell types.

Results: The average age of patients represented in this study was 52 years, and 63% self-identified as Black. There was no significant association between tumor GR expression and age, race, or clinical stage at diagnosis. Compared to GR-low tumors, high GR expression in early-stage, treatment-naïve TNBC was associated with relatively increased numbers of immunosuppressive FOXP3 + regulatory T cells (p = 0.046) and BATF3+immune cells (p = 0.021). While there was a positive correlation with high GR expression and CD8+ cell infiltration, it was not significant (p = 0.068). The ratio of CD8+/FOXP3+cells was also not significant (p = 0.24).

Conclusions: These data support the hypothesis that in early-stage TNBC, high GR expression is significantly associated with infiltration of immunosuppressive regulatory T cells, suggesting a tumor-intrinsic role in shaping the immunosuppressive immune cell milieu. Furthermore, suppression of GR activity may regulate the tumor immune microenvironment and improve long-term outcomes in GR-high TNBC.