International Journal of Molecular Sciences (Nov 2021)

What Do We Have to Know about PD-L1 Expression in Prostate Cancer? A Systematic Literature Review. Part 3: PD-L1, Intracellular Signaling Pathways and Tumor Microenvironment

  • Andrea Palicelli,
  • Stefania Croci,
  • Alessandra Bisagni,
  • Eleonora Zanetti,
  • Dario De Biase,
  • Beatrice Melli,
  • Francesca Sanguedolce,
  • Moira Ragazzi,
  • Magda Zanelli,
  • Alcides Chaux,
  • Sofia Cañete-Portillo,
  • Maria Paola Bonasoni,
  • Alessandra Soriano,
  • Stefano Ascani,
  • Maurizio Zizzo,
  • Carolina Castro Ruiz,
  • Antonio De Leo,
  • Guido Giordano,
  • Matteo Landriscina,
  • Giuseppe Carrieri,
  • Luigi Cormio,
  • Daniel M. Berney,
  • Jatin Gandhi,
  • Valerio Copelli,
  • Giuditta Bernardelli,
  • Giacomo Santandrea,
  • Martina Bonacini

DOI
https://doi.org/10.3390/ijms222212330
Journal volume & issue
Vol. 22, no. 22
p. 12330

Abstract

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The tumor microenvironment (TME) includes immune (T, B, NK, dendritic), stromal, mesenchymal, endothelial, adipocytic cells, extracellular matrix, and cytokines/chemokines/soluble factors regulating various intracellular signaling pathways (ISP) in tumor cells. TME influences the survival/progression of prostate cancer (PC), enabling tumor cell immune-evasion also through the activation of the PD-1/PD-L1 axis. We have performed a systematic literature review according to the PRISMA guidelines, to investigate how the PD-1/PD-L1 pathway is influenced by TME and ISPs. Tumor immune-escape mechanisms include suppression/exhaustion of tumor infiltrating cytotoxic T lymphocytes, inhibition of tumor suppressive NK cells, increase in immune-suppressive immune cells (regulatory T, M2 macrophagic, myeloid-derived suppressor, dendritic, stromal, and adipocytic cells). IFN-γ (the most investigated factor), TGF-β, TNF-α, IL-6, IL-17, IL-15, IL-27, complement factor C5a, and other soluble molecules secreted by TME components (and sometimes increased in patients’ serum), as well as and hypoxia, influenced the regulation of PD-L1. Experimental studies using human and mouse PC cell lines (derived from either androgen-sensitive or androgen-resistant tumors) revealed that the intracellular ERK/MEK, Akt-mTOR, NF-kB, WNT and JAK/STAT pathways were involved in PD-L1 upregulation in PC. Blocking the PD-1/PD-L1 signaling by using immunotherapy drugs can prevent tumor immune-escape, increasing the anti-tumor activity of immune cells.

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