Unraveling the role of steroid hormones in cancer immunotherapy 2734

Abstract Description The immunosuppressive tumour microenvironment dampens anti-tumour immunity and reduces the efficacy of immunotherapy in aggressive malignancies like triple-negative breast cancer (TNBC) and glioblastoma (GBM). Recent research highlights the immunosuppressive effects of steroid hormones. However, the extent to which these hormones inhibit the anti-tumour immune response remains largely unknown. Through targeted metabolomics of steroids coupled with immunohistochemistry techniques, we comprehensively profiled the existence of different types of steroids in TNBC and GBM patient tumours and discerned steroidogenic activity in immune infiltrating regions. In mouse models, genetic inhibition of immune cell steroidogenesis restricted tumour progression, significantly reducing tumour-associated macrophages. Using metabolic modelling of single-cell transcriptomics, we identified mast cells as the predominant steroidogenic agent. Notably, pharmacologically inhibiting steroidogenesis curtailed tumour expansion in a humanised mouse model of TNBC. In addition to endogenous source, considering the frequent use of exogenous steroids in GBM treatments, we explored impeding glucocorticoid signalling appears to bolster the ability of dendritic cells to prime T cells. Altogether, these studies will shed light on the role of steroid hormones in promoting anti-tumour immunosuppression. The new knowledge is anticipated to create new therapeutic avenues for TNBC and GBM patients. Funding Sources Cancer Research UK (CRUK) - RCCFEL\100095 RCUK | Biotechnology and Biological Sciences Research Council (BBSRC) - BB/V006126/1 RCUK | MRC | Medical Research Foundation - MR/V028995/1 Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)