Abstract
Background – Castration-resistant prostate cancer (CRPC) frequently harbors mutations in the androgen receptor (AR). Understanding the influence of these mutations on the tumor microenvironment is crucial for developing targeted treatment strategies.
Methods – For this study, we leveraged the Tempus Database, which encompasses structured de-identified clinical, imaging, and molecular data, including tumor-normal matched DNA and RNA sequencing. We analyzed 1556 de-identified patient records of patients with CRPC, focusing on AR mutations and amplifications detected from DNA and ARv7 splicing from RNA. Immune infiltration was assessed by estimated quantification of immune cell types based on bulk RNA expression using quanTIseq. Expression levels of immunotherapy targets (PD-1, PD-L1, CTLA-4),chemokine and cytokine signaling molecules and gene signatures (CYT and GEP) were also evaluated. A regression model was developed to study the relationship between AR mutations and immune infiltration, controlling for tumor mutational burden (TMB) and tumor purity.
Results – In CRPC, 58.7% of patients exhibited AR amplifications, ARv7 splicing or mutations in the AR ligand-binding domain (AR-LBD). CRPC patients with AR mutations showed significantly decreased immune infiltration compared to wild-type (WT) counterparts (median total infiltration: WT 26%, ARv7/Amp 22-23%; Wilcoxon test: Pvalue<0.001). Reduced levels of PD-1, PD-L1, CTLA-4, and chemokine signaling were observed in patients with AR mutations. Regression analysis confirmed that AR mutations were associated with decreased immune infiltration independent of TMB and tumor purity (Amplification and AR-V7 splicing: Pvalue<0.001, OR= -3.17[-4.58,-1.77]). Furthermore, in CRPC patients who acquired AR mutations following androgen deprivation therapy (ADT) or novel hormonal agents (NHA), immune cell infiltration, including total infiltration and specific immune cell subtypes, showed decreasing trends compared to pre-treatment wild-type samples. This suggests a potential link between AR mutation gain and reduced immune response in the tumor microenvironment and highlights a potential mechanism of resistance.
Conclusions – Our findings suggest that AR amplifications and ARv7 mutations in CRPC are linked to reduced immune infiltration and signaling, which may contribute to reduced immune response as a potential mechanism of resistance. These results underscore the importance of considering AR mutation status in the stratification of CRPC patients for immunotherapy and support further investigation into targeted therapeutic approaches for this subgroup.
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