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Abstract Glucocorticoids are an emerging component of the tumor microenvironment and play a multifaceted role in modulating immune responses. Adrenocortical carcinoma (ACC) is a rare endocrine malignancy characterized by systemic cortisol excess in ~ 60% of cases. Responses to immune checkpoint inhibitors (ICI) in patients with ACC are variable, and currently, no reliable biomarkers exist to predict therapeutic outcomes. Here, in vitro- differentiated and glucocorticoid-polarized peripheral blood monocytes from healthy donors were characterized using NanoString nCounter gene expression analysis, western blotting, and ELISA. In vivo , ACC-bearing mice were treated with immune checkpoint inhibitors and mifepristone. In human ACC tumor samples, immunohistochemistry was employed to quantify intratumoral macrophages, while mass spectrometry was applied to measure steroid hormone concentrations. We report that ACC tumors are highly infiltrated by CD68+/CD163 + macrophages, independent of cortisol overproduction. In vitro , glucocorticoid exposure polarized macrophages towards a C1Q+ CD163 + subtype with enhanced phagocytic activity. Upon IFNγ stimulation, secretion of the T cell chemoattractant CXCL9 was higher in C1Q+ macrophages than in classical pro-inflammatory M1 macrophages. In ACC-bearing mice, treatment with immune checkpoint inhibitors and concurrent blockade of the glucocorticoid receptor with mifepristone reduced tumoral CXCL9 expression and CD4 + T cell infiltration compared to ICI monotherapy. In ACC patient samples, intratumoral macrophage marker expression positively correlated with markers indicative of T cell infiltration and improved patient survival. Moreover, the percentage of macrophages detected by immunohistochemistry positively correlated with response to immunotherapy. Collectively, this study identifies a glucocorticoid-induced C1Q+ CD163 + macrophage phenotype that may contribute to T cell recruitment and enhance the efficacy of immunotherapy in ACC.
Triebig et al. (Mon,) studied this question.