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.
Author Info: (1) Division of Hematology and Oncology, Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA. (2) Columbia Center for Translational Immunology, Col
Author Info: (1) Division of Hematology and Oncology, Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA. (2) Columbia Center for Translational Immunology, Columbia University Irving Medical Center, New York, NY, USA; Department of Systems Biology, Columbia University Irving Medical Center, New York, NY, USA. (3) Division of Hematology and Oncology, Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA. (4) Division of Hematology and Oncology, Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA. (5) Division of Hematology and Oncology, Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA. (6) Department of Systems Biology, Columbia University Irving Medical Center, New York, NY, USA. (7) Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY 10032, USA; Department of Urology, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY, USA. (8) Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY 10032, USA; Department of Urology, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY, USA. (9) Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY 10032, USA; Department of Urology, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY, USA. (10) Department of Interventional Radiology, Columbia University Irving Medical Center, New York, NY, USA. (11) Department of Pathology, Columbia University Irving Medical Center, New York, NY, USA. (12) Regeneron Pharmaceuticals, Tarrytown, NY, USA. (13) Division of Hematology and Oncology, Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA; Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY 10032, USA. (14) Columbia Center for Translational Immunology, Columbia University Irving Medical Center, New York, NY, USA. (15) Columbia Center for Translational Immunology, Columbia University Irving Medical Center, New York, NY, USA. (16) Columbia Center for Translational Immunology, Columbia University Irving Medical Center, New York, NY, USA. (17) Division of Human Biology, Fred Hutchinson Cancer Center, Seattle, WA, USA; Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, USA; Division of Clinical Research, Fred Hutchinson Cancer Center, Seattle, WA, USA. (18) Department of Systems Biology, Columbia University Irving Medical Center, New York, NY, USA. (19) Division of Hematology and Oncology, Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA; Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY 10032, USA. (20) Department of Systems Biology, Columbia University Irving Medical Center, New York, NY, USA; Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY 10032, USA; Department of Biochemistry & Molecular Biophysics, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY 10032 USA; Department of Biomedical Informatics, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY 10032 USA; Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY 10032 USA; J.P. Sulzberger Columbia Genome Center, Columbia University Irving Medical Center, New York, NY 10032 USA. Electronic address: ac2248@cumc.columbia.edu. (21) Division of Hematology and Oncology, Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA; Columbia Center for Translational Immunology, Columbia University Irving Medical Center, New York, NY, USA; Department of Interventional Radiology, Columbia University Irving Medical Center, New York, NY, USA. Electronic address: cgd2139@columbia.edu.
