Androgen receptor activity inversely correlates with immune cell infiltration and immunotherapy response across multiple cancer lineages.

There is now increasing recognition of the important role of androgen receptor (AR) in modulating immune function. To gain a comprehensive understanding of the effects of AR activity on cancer immunity, we employed a computational approach to profile AR activity in 33 human tumor types using RNA-Seq datasets from The Cancer Genome Atlas. Our pan-cancer analysis revealed that the genes most negatively correlated with AR activity across cancers are involved in active immune system processes. Importantly, we observed a significant negative correlation between AR activity and IFNγ pathway activity at the pan-cancer level. Indeed, using a matched biopsy dataset from subjects with prostate cancer before and after AR-targeted treatment, we verified that inhibiting AR enriches immune cell abundances and is associated with higher IFNγ pathway activity. Furthermore, by analyzing immunotherapy datasets in multiple cancers, our results demonstrate that low AR activity was significantly associated with a favorable response to immunotherapy. Together, our data provide a comprehensive assessment of the relationship between AR signaling and tumor immunity.
Competing Interests: Competing interests G.B.M. is SAB/Consultant for AstraZeneca, BlueDot, Chrysallis Biotechnology, Ellipses Pharma, ImmunoMET, Infinity, Ionis, Lilly, Medacorp, Nanostring, PDX Pharmaceuticals, Signalchem Lifesciences, Tarveda, Turbine and Zentalis Pharmaceuticals; stock/ options/financial: Catena Pharmaceuticals, ImmunoMet, SignalChem, Tarveda and Turbine; licenced technology: HRD assay to Myriad Genetics, and DSP patents with NanoString. A.E.M. received research funding from AstraZeneca. J.J.A. has received consulting income from Fibrogen, Astellas, and Bristol Myers Squib. and research support to his institution from Beactica, a Pfizer/Astellas/NCCN research award, and Zenith Epigenetics. The remaining authors declare no competing interests.