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.
Cancer cell. 2023 Oct 30 [Epub ahead of print]
Jessica E Hawley, Aleksandar Z Obradovic, Matthew C Dallos, Emerson A Lim, Karie Runcie, Casey R Ager, James McKiernan, Christopher B Anderson, Guarionex J Decastro, Joshua Weintraub, Renu Virk, Israel Lowy, Jianhua Hu, Matthew G Chaimowitz, Xinzheng V Guo, Ya Zhang, Michael C Haffner, Jeremy Worley, Mark N Stein, Andrea Califano, Charles G Drake
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 Systems Biology, Columbia University Irving Medical Center, New York, NY, USA., 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 Urology, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY, USA., Department of Interventional Radiology, Columbia University Irving Medical Center, New York, NY, USA., Department of Pathology, Columbia University Irving Medical Center, New York, NY, USA., Regeneron Pharmaceuticals, Tarrytown, NY, USA., 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., Columbia Center for Translational Immunology, Columbia University Irving Medical Center, New York, NY, USA., 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., 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: ., 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: .