Glucocorticoid prophylaxis influences the systemic immune macroenvironment in patients with early stage, treatment naïve, HER2+ breast cancer

Vollständiger Abstract

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Abstract Background Glucocorticoid prophylaxis is routinely used in oncology. Glucocorticoids potent immunosuppressive and anti-inflammatory properties raise concerns regarding potential impairment of antitumor immune responses. Preclinical and retrospective studies suggest glucocorticoids may impair antitumor immunity, though these findings are subject to significant bias and confounding factors. Understanding the immunomodulatory effects of prophylactic glucocorticoids, isolated from other therapies, is critical to bridging the knowledge gap on their influence on antitumor immunity. Methods We performed a post hoc, retrospective analysis using cryopreserved PBMCs and plasma from patients with treatment-naïve, early stage HER2+ breast cancer, prior to neoadjuvant therapy. Of 192 patients, 129 had no prior glucocorticoid exposure and 63 received 24 mg prophylactic betamethasone before sampling. High-dimensional flow cytometry assessed monocytes, dendritic cells, and T-cell subsets. Plasma proteins were evaluated using the Olink Target 96 Immuno-Oncology proximity extension assay. Results Glucocorticoid exposure was consistently associated with a distinct immune profile. Exposed patients exhibited increased CD163+ monocytes and reduced intermediate, non-classical, and HLA-DRhi classical monocytes, plasmacytoid DCs, and conventional CD1c+ DCs. T-cell alterations included enrichment of CXCR4+ subsets, particularly terminally differentiated CD8+ T-cells, with reductions in naïve, central memory, CD27+ effector memory, and CXCR3+ populations. Inflammatory plasma proteins (IFN-γ, CCL19, CCL2, IL-12, IL-6, Granzyme A/B, CXCL10, CXCL9) were diminished, whereas IL-10 and CXCL13 were elevated. Glucocorticoid-associated immune alterations were heterogeneous across patients, highlighting interindividual variability in observed post-exposure immune states. Conclusions Prophylactic glucocorticoid exposure reshapes the circulating immune landscape, altering monocytes, dendritic cells, naïve and memory T-cell subsets, as well as key inflammatory proteins.