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

Abstract

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.

Keywords: PD-L1; cancer; checkpoint inhibitors; immunotherapy; prostate; signaling pathways; target-therapy; tumor microenvironment.

Figure 1

Systematic review of the literature: PRISMA flow-chart.

Figure 2

Intracellular signaling pathways involved in PD-L1 expression.

Figure 3

Results of big data analysis: CD274 genetic alterations ((left): cBioPortal; https://www.cbioportal.org/ (accessed on 12 August 2021)) and gene expression profile ((right): GEPIA database; http://gepia.cancer-pku.cn/index.html (accessed on 12 August 2021)). PC: prostate cancer; TPM: transcripts per millionset. On the right, the median TPM values of CD274 gene expression in normal prostatic tissue and PC are repoted above the respective histograms.

Figure 4

Interaction of prostate cancer cells with other cell types of the tumor microenvironment. CAFs: cancer-asssociated fibroblasts; CXCL2: Chemokine (C-X-C motif) ligand 2; IL-10: Interleukin-10; MDSC: myeloid-derived suppressor cell; MHC: major histocompatibility complex; TAMs: tumor-associated macrophages; T cell CD8+: CD8+ Cytotoxic T lymphocyte; TCR: T cell receptor; TGF-β: Tumor Growth Factor β; T helper CD4+: CD4+ helper T lymphocyte; T reg: regulatory T cell; VEGF: Vascular-Endothelial Growth Factor; PD-1: programmed death 1; PDL-1: programmed death ligand 1.