Shuang G Zhao1, Jonathan Lehrer2, S Laura Chang3, Rajdeep Das3, Nicholas Erho2, Yang Liu2, Martin Sjöström4, Robert B Den5, Stephen J Freedland6, Eric A Klein7, R Jeffrey Karnes8, Edward M Schaeffer9, Melody Xu3, Corey Speers1, Paul L Nguyen10, Ashley E Ross11, June M Chan12,13, Matthew R Cooperberg12, Peter R Carroll12, Elai Davicioni2, Lawrence Fong14, Daniel E Spratt1, Felix Y Feng3,14,12. 1. Department of Radiation Oncology, University of Michigan, Ann Arbor, MI. 2. GenomeDx Biosciences Inc., Vancouver, BC, Canada. 3. Department of Radiation Oncology, Helen Diller Comprehensive Cancer Center, University of California at San Francisco, San Francisco, CA. 4. Division of Oncology and Pathology, Department of Clinical Sciences Lund, Faculty of Medicine, Lund University, Lund, Sweden. 5. Department of Radiation Oncology, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA. 6. Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA. 7. Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, OH. 8. Department of Urology, Mayo Clinic, Rochester, MN. 9. Department of Urology, Northwestern University, IL. 10. Dana-Farber/Brigham and Women's Cancer Center, Department of Radiation Oncology, Harvard Medical School, Boston, MA. 11. James Buchanan Brady Urological Institute, Johns Hopkins Medical Institutions, Baltimore, MD. 12. Department of Urology, Helen Diller Comprehensive Cancer Center, University of California at San Francisco, San Francisco, CA. 13. Department of Epidemiology & Biostatistics, Helen Diller Comprehensive Cancer Center, University of California at San Francisco, San Francisco, CA. 14. Department of Medicine, Helen Diller Comprehensive Cancer Center, University of California at San Francisco, San Francisco, CA.
Abstract
BACKGROUND: Immunotherapy has been less successful in treating prostate cancer than other solid tumors. We sought to better understand the immune landscape in prostate cancer and identify immune-related biomarkers and potential therapeutic targets. METHODS: We analyzed gene expression data from 7826 prospectively collected prostatectomy samples (2013-2016), and 1567 retrospective samples with long-term clinical outcomes, for a total of 9393 samples, all profiled on the same commercial clinical platform in a CLIA-certified lab. The primary outcome was distant metastasis-free survival (DMFS). Secondary outcomes included biochemical recurrence-free survival (bRFS), prostate cancer-specific survival (PCSS), and overall survival (OS). All statistical tests were two-sided. RESULTS: Unsupervised hierarchical clustering of hallmark pathways demonstrated an immune-related tumor cluster. Increased estimated immune content scores based on immune-specific genes from the literature were associated with worse bRFS (hazard ratio [HR] = 1.26 [95% confidence interval [CI] = 1.12 to 1.42]; P < .001), DMFS (HR = 1.34 [95% CI = 1.13 to 1.58]; P < .001), PCSS (HR = 1.53 [95% CI = 1.21 to 1.92]; P < .001), and OS (HR = 1.27 [95% CI = 1.07 to 1.50]; P = .006). Deconvolution using Cibersort revealed that mast cells, natural killer cells, and dendritic cells conferred improved DMFS, whereas macrophages and T-cells conferred worse DMFS. Interestingly, while PD-L1 was not prognostic, consistent with its low expression in prostate cancer, PD-L2 was expressed at statistically significantly higher levels (P < .001) and was associated with worse bRFS (HR = 1.17 [95% CI = 1.03 to 1.33]; P = .01), DMFS (HR = 1.25 [95% CI = 1.05 to 1.49]; P = .01), and PCSS (HR = 1.45 [95% CI = 1.13 to 1.86]; P = .003). PD-L2 was strongly associated with immune-related pathways on gene set enrichment analysis suggesting that it is playing an important role in immune modulation in clinical prostate cancer samples. Furthermore, PD-L2 was correlated with radiation response pathways, and also predicted response to postoperative radiation therapy (PORT) on multivariable interaction analysis (P = .03). CONCLUSION: In the largest study of its kind to date, these results illustrate the complex relationship between the tumor-immune interaction, prognosis, and response to radiotherapy, and nominate PD-L2 as a potential novel therapeutic target in prostate cancer, potentially in combination with radiotherapy.
BACKGROUND: Immunotherapy has been less successful in treating prostate cancer than other solid tumors. We sought to better understand the immune landscape in prostate cancer and identify immune-related biomarkers and potential therapeutic targets. METHODS: We analyzed gene expression data from 7826 prospectively collected prostatectomy samples (2013-2016), and 1567 retrospective samples with long-term clinical outcomes, for a total of 9393 samples, all profiled on the same commercial clinical platform in a CLIA-certified lab. The primary outcome was distant metastasis-free survival (DMFS). Secondary outcomes included biochemical recurrence-free survival (bRFS), prostate cancer-specific survival (PCSS), and overall survival (OS). All statistical tests were two-sided. RESULTS: Unsupervised hierarchical clustering of hallmark pathways demonstrated an immune-related tumor cluster. Increased estimated immune content scores based on immune-specific genes from the literature were associated with worse bRFS (hazard ratio [HR] = 1.26 [95% confidence interval [CI] = 1.12 to 1.42]; P < .001), DMFS (HR = 1.34 [95% CI = 1.13 to 1.58]; P < .001), PCSS (HR = 1.53 [95% CI = 1.21 to 1.92]; P < .001), and OS (HR = 1.27 [95% CI = 1.07 to 1.50]; P = .006). Deconvolution using Cibersort revealed that mast cells, natural killer cells, and dendritic cells conferred improved DMFS, whereas macrophages and T-cells conferred worse DMFS. Interestingly, while PD-L1 was not prognostic, consistent with its low expression in prostate cancer, PD-L2 was expressed at statistically significantly higher levels (P < .001) and was associated with worse bRFS (HR = 1.17 [95% CI = 1.03 to 1.33]; P = .01), DMFS (HR = 1.25 [95% CI = 1.05 to 1.49]; P = .01), and PCSS (HR = 1.45 [95% CI = 1.13 to 1.86]; P = .003). PD-L2 was strongly associated with immune-related pathways on gene set enrichment analysis suggesting that it is playing an important role in immune modulation in clinical prostate cancer samples. Furthermore, PD-L2 was correlated with radiation response pathways, and also predicted response to postoperative radiation therapy (PORT) on multivariable interaction analysis (P = .03). CONCLUSION: In the largest study of its kind to date, these results illustrate the complex relationship between the tumor-immune interaction, prognosis, and response to radiotherapy, and nominate PD-L2 as a potential novel therapeutic target in prostate cancer, potentially in combination with radiotherapy.
Authors: Daniel E Spratt; Mohammed Alshalalfa; Nick Fishbane; Adam B Weiner; Rohit Mehra; Brandon A Mahal; Jonathan Lehrer; Yang Liu; Shuang G Zhao; Corey Speers; Todd M Morgan; Adam P Dicker; Stephen J Freedland; R Jeffery Karnes; Sheila Weinmann; Elai Davicioni; Ashley E Ross; Robert B Den; Paul L Nguyen; Felix Y Feng; Tamara L Lotan; Arul M Chinnaiyan; Edward M Schaeffer Journal: Clin Cancer Res Date: 2019-09-12 Impact factor: 12.531