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.
Highlights
The tumor microenvironment (TME) includes immune cells, stromal/mesenchymal cells, blood vessels, extracellular matrix, as well as cytokines, chemokines, and other soluble factors released by each TME-component
The Cancer Genome Atlas (TCGA)-studies concerning the epigenetic regulation of PD-L1 in prostate cancer (PC) are better presented and discussed in other parts of our review: here we report a brief summary of relevant data
The TME is the tumor milieu, including immune cells, stromal/mesenchymal cells, blood vessels, and extracellular matrix, as well as cytokines, chemokines, and other soluble factors released by each TME component
Summary
The tumor microenvironment (TME) includes immune cells, stromal/mesenchymal cells (such as activated fibroblasts or adipocytes), blood vessels, extracellular matrix, as well as cytokines, chemokines, and other soluble factors released by each TME-component. The interactions between these different TME elements influence tumor growth and cancer survival/progression, enabling tumor cell immune-evasion. Programmed death-1 (PD-1) is a type I transmembrane glycoprotein of the CD28/CTLA-4 family, encoded by PDCD1 gene (located on chromosome 2). The PD-1 protein consists of an extracellular IgV-type domain, a transmembrane region and an intracellular tail characterized by immunoreceptor tyrosine-based inhibitory and switch motifs responsible for the intracellular signaling cascade [1,2,3]
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