The Immune Landscape of Prostate Cancer and Nomination of PD-L2 as a Potential Therapeutic Target

Shuang G. Zhao, Jonathan Lehrer, S. Laura Chang, Rajdeep Das, Nicholas Erho, Yang Liu, Martin Sjöström, Robert B. Den, Stephen J. Freedland, Eric A. Klein, Robert Jeffrey Karnes, Edward M. Schaeffer, Melody Xu, Corey Speers, Paul L. Nguyen, Ashley E. Ross, June M. Chan, Matthew R. Cooperberg, Peter R. Carroll, Elai Davicioni & 3 others Lawrence Fong, Daniel E. Spratt, Felix Y. Feng

Research output: Contribution to journalArticle

10 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)301-310
Number of pages10
JournalJournal of the National Cancer Institute
Volume111
Issue number3
DOIs
StatePublished - Mar 1 2019

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Prostatic Neoplasms
Confidence Intervals
Neoplasm Metastasis
Radiotherapy
Therapeutics
Recurrence
Neoplasms
Prostatectomy
Mast Cells
Natural Killer Cells
Immunotherapy
Dendritic Cells
Genes
Cluster Analysis
Biomarkers
Macrophages
Radiation
T-Lymphocytes
Gene Expression

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

The Immune Landscape of Prostate Cancer and Nomination of PD-L2 as a Potential Therapeutic Target. / Zhao, Shuang G.; Lehrer, Jonathan; Chang, S. Laura; Das, Rajdeep; Erho, Nicholas; Liu, Yang; Sjöström, Martin; Den, Robert B.; Freedland, Stephen J.; Klein, Eric A.; Karnes, Robert Jeffrey; Schaeffer, Edward M.; Xu, Melody; Speers, Corey; Nguyen, Paul L.; Ross, Ashley E.; Chan, June M.; Cooperberg, Matthew R.; Carroll, Peter R.; Davicioni, Elai; Fong, Lawrence; Spratt, Daniel E.; Feng, Felix Y.

In: Journal of the National Cancer Institute, Vol. 111, No. 3, 01.03.2019, p. 301-310.

Research output: Contribution to journalArticle

Zhao, SG, Lehrer, J, Chang, SL, Das, R, Erho, N, Liu, Y, Sjöström, M, Den, RB, Freedland, SJ, Klein, EA, Karnes, RJ, Schaeffer, EM, Xu, M, Speers, C, Nguyen, PL, Ross, AE, Chan, JM, Cooperberg, MR, Carroll, PR, Davicioni, E, Fong, L, Spratt, DE & Feng, FY 2019, 'The Immune Landscape of Prostate Cancer and Nomination of PD-L2 as a Potential Therapeutic Target', Journal of the National Cancer Institute, vol. 111, no. 3, pp. 301-310. https://doi.org/10.1093/jnci/djy141
Zhao, Shuang G. ; Lehrer, Jonathan ; Chang, S. Laura ; Das, Rajdeep ; Erho, Nicholas ; Liu, Yang ; Sjöström, Martin ; Den, Robert B. ; Freedland, Stephen J. ; Klein, Eric A. ; Karnes, Robert Jeffrey ; Schaeffer, Edward M. ; Xu, Melody ; Speers, Corey ; Nguyen, Paul L. ; Ross, Ashley E. ; Chan, June M. ; Cooperberg, Matthew R. ; Carroll, Peter R. ; Davicioni, Elai ; Fong, Lawrence ; Spratt, Daniel E. ; Feng, Felix Y. / The Immune Landscape of Prostate Cancer and Nomination of PD-L2 as a Potential Therapeutic Target. In: Journal of the National Cancer Institute. 2019 ; Vol. 111, No. 3. pp. 301-310.
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title = "The Immune Landscape of Prostate Cancer and Nomination of PD-L2 as a Potential Therapeutic Target",
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.",
author = "Zhao, {Shuang G.} and Jonathan Lehrer and Chang, {S. Laura} and Rajdeep Das and Nicholas Erho and Yang Liu and Martin Sj{\"o}str{\"o}m and Den, {Robert B.} and Freedland, {Stephen J.} and Klein, {Eric A.} and Karnes, {Robert Jeffrey} and Schaeffer, {Edward M.} and Melody Xu and Corey Speers and Nguyen, {Paul L.} and Ross, {Ashley E.} and Chan, {June M.} and Cooperberg, {Matthew R.} and Carroll, {Peter R.} and Elai Davicioni and Lawrence Fong and Spratt, {Daniel E.} and Feng, {Felix Y.}",
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TY - JOUR

T1 - The Immune Landscape of Prostate Cancer and Nomination of PD-L2 as a Potential Therapeutic Target

AU - Zhao, Shuang G.

AU - Lehrer, Jonathan

AU - Chang, S. Laura

AU - Das, Rajdeep

AU - Erho, Nicholas

AU - Liu, Yang

AU - Sjöström, Martin

AU - Den, Robert B.

AU - Freedland, Stephen J.

AU - Klein, Eric A.

AU - Karnes, Robert Jeffrey

AU - Schaeffer, Edward M.

AU - Xu, Melody

AU - Speers, Corey

AU - Nguyen, Paul L.

AU - Ross, Ashley E.

AU - Chan, June M.

AU - Cooperberg, Matthew R.

AU - Carroll, Peter R.

AU - Davicioni, Elai

AU - Fong, Lawrence

AU - Spratt, Daniel E.

AU - Feng, Felix Y.

PY - 2019/3/1

Y1 - 2019/3/1

N2 - 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.

AB - 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.

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