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.

PD‐L1 expression downregulation by RNF43 in gastric carcinoma enhances antitumour activity of T cells

“…Several studies have indicated that intracellular Wnt/β‐catenin, JAK/STAT, ERK/MEK, Akt–mTOR and NF‐kB signalling pathways are involved in PD‐L1 upregulation in prostate cancer 28 . RNF43 has been demonstrated to act as an inhibitor of Wnt signalling by selectively ubiquitinating frizzled receptor, and STAT1 activation and PD‐L1 expression were increased in RNF43‐deficient mice 29,30 .…”

What Do We Have to Know about PD-L1 Expression in Prostate Cancer? A Systematic Literature Review (Part 6): Correlation of PD-L1 Expression with the Status of Mismatch Repair System, BRCA, PTEN, and Other Genes

“…To better present the data of our SLR, we have split the discussion of our results into different articles, highlighting relevant subtopics: PD-L1 IHC expression in PC with discussion of pre-analytical and interpretation variables; correlations of PD-L1 expression with clinic–pathological features in PC patients; PD-L1 intracellular signaling pathways in PC cells and regulation of the tumor microenvironment; pre-clinical models (cell lines, mouse models) and experimental treatments affecting PD-L1 expression in PC cells; genetic and epigenetic regulation of PD-L1; PD-L1 expression in liquid biopsies, etc. [ 260 , 261 , 262 , 263 , 264 , 265 ].…”

Classification of pyroptosis patterns and construction of a novel prognostic model for prostate cancer based on bulk and single-cell RNA sequencing

“…The result of functional enrichment analysis at both bulk RNA-seq level and single-cell level indicated the presence of differences in the tumor immune microenvironment between the two Classes, such as cytokine pathway, humoral immune response and IL-17 signaling pathway. Programmed cell death ligand 1 (PD-L1) inhibitors kill tumor cells by triggering pyroptosis ( 65 ), while IL-17 promotes PD-L1 expression in tumor cells by PD-1+ immune cell intratumor infiltration ( 66 ), suggesting that IL-17 may be a potential target for enhancing the performance of PD-L1 inhibitors by increasing pyroptosis of tumor cells. We observed a higher infiltration of macrophages in Class1, while it has been reported that macrophages can release reactive oxygen species (ROS) and thus trigger pyroptosis ( 67 ).…”