Hawley and Obradovic et al. performed comprehensive scRNAseq analysis (analyzed using VIPER, a “protein activity” algorithm) of longitudinal samples from various metastatic sites of mCSPC (n=10) treated with hormonal therapy (ADT) combined with anti-PD-1 immunotherapy to profile the TME and tumor cell heterogeneity. A distinct subpopulation of tumor cells (KIF14 and TOP2A high) was associated with shortened RFS. At baseline, bone, lymph node, and liver showed similar immune compositions, while lung metastasis was relatively immune-depleted. The combination treatment significantly expanded CD8+ T cells, CD4+ T cells, and Tregs across several metastatic sites.
Contributed by Shishir Pant
ABSTRACT: When compared to other malignancies, the tumor microenvironment (TME) of primary and castration-resistant prostate cancer (CRPC) is relatively devoid of immune infiltrates. While androgen deprivation therapy (ADT) induces a complex immune infiltrate in localized prostate cancer, the composition of the TME in metastatic castration-sensitive prostate cancer (mCSPC), and the effects of ADT and other treatments in this context are poorly understood. Here, we perform a comprehensive single-cell RNA sequencing (scRNA-seq) profiling of metastatic sites from patients participating in a phase 2 clinical trial (NCT03951831) that evaluated standard-of-care chemo-hormonal therapy combined with anti-PD-1 immunotherapy. We perform a longitudinal, protein activity-based analysis of TME subpopulations, revealing immune subpopulations conserved across multiple metastatic sites. We also observe dynamic changes in these immune subpopulations in response to treatment and a correlation with clinical outcomes. Our study uncovers a therapy-resistant, transcriptionally distinct tumor subpopulation that expands in cell number in treatment-refractory patients.