Identification of targets for prostate cancer immunotherapy

Prostate. 2019 Apr;79(5):498-505. doi: 10.1002/pros.23756. Epub 2019 Jan 6.

Abstract

Background: We performed profiling of the immune microenvironment of castration-resistant (CRPC) and castration-sensitive (CSPC) prostate cancer (PC) in order to identify novel targets for immunotherapy.

Methods: PD-L1 and CD3/CD8 immunohistochemistry, PD-L1/2 fluorescent in situ hybridization, tumor mutation burden, microsatellite instability, and RNA-seq of 395 immune-related genes were performed in 19 CRPC and CSPC. Targeted genomic sequencing and fusion analysis were performed in 17 of these specimens.

Results: CD276, PVR, and NECTIN2 were highly expressed in PC. Comparison of CRPC versus CSPC and primary versus metastatic tissue revealed the differential expression of immunostimulatory, immunosuppressive, and epithelial-to-mesenchymal transition (EMT)-related genes. Unsupervised clustering of differentially expressed genes yielded two final clusters best segregated by CRPC and CSPC status.

Conclusion: CD276 and the alternative checkpoint inhibition PVR/NECTIN2/CD226/TIGIT pathway emerged as relevant to PC checkpoint inhibition target development.

Keywords: CD226; CD276; NECTIN2; PVR; TIGIT; aggressive prostate cancer; castration-resistant prostate cancer; castration-sensitive prostate cancer; immunotherapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Antigens, CD / biosynthesis
  • Antigens, CD / genetics
  • Antigens, CD / immunology
  • B7-H1 Antigen / biosynthesis
  • B7-H1 Antigen / genetics
  • B7-H1 Antigen / immunology
  • Humans
  • Immunohistochemistry
  • Immunotherapy / methods
  • Male
  • Microsatellite Instability
  • Middle Aged
  • Nectins / biosynthesis
  • Nectins / genetics
  • Nectins / immunology
  • Programmed Cell Death 1 Ligand 2 Protein / biosynthesis
  • Programmed Cell Death 1 Ligand 2 Protein / genetics
  • Programmed Cell Death 1 Ligand 2 Protein / immunology
  • Prostatic Neoplasms / genetics
  • Prostatic Neoplasms / immunology*
  • Prostatic Neoplasms / therapy*
  • Prostatic Neoplasms, Castration-Resistant / genetics
  • Prostatic Neoplasms, Castration-Resistant / immunology*
  • Prostatic Neoplasms, Castration-Resistant / therapy*
  • RNA, Neoplasm / biosynthesis
  • RNA, Neoplasm / genetics
  • RNA, Neoplasm / immunology
  • TOR Serine-Threonine Kinases / biosynthesis
  • TOR Serine-Threonine Kinases / genetics
  • TOR Serine-Threonine Kinases / immunology
  • Tumor Microenvironment / immunology

Substances

  • Antigens, CD
  • B7-H1 Antigen
  • CD274 protein, human
  • NECTIN2 protein, human
  • Nectins
  • PDCD1LG2 protein, human
  • Programmed Cell Death 1 Ligand 2 Protein
  • RNA, Neoplasm
  • MTOR protein, human
  • TOR Serine-Threonine Kinases