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.

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 / Palicelli, A.; Croci, S.; Bisagni, A.; Zanetti, E.; De Biase, D.; Melli, B.; Sanguedolce, F.; Ragazzi, M.; Zanelli, M.; Chaux, A.; Canete-Portillo, S.; Bonasoni, M. P.; Soriano, A.; Ascani, S.; Zizzo, M.; Ruiz, C. C.; De Leo, A.; Giordano, G.; Landriscina, M.; Carrieri, G.; Cormio, L.; Berney, D. M.; Gandhi, J.; Copelli, V.; Bernardelli, G.; Santandrea, G.; Bonacini, M.. - In: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES. - ISSN 1661-6596. - 22:22(2021), pp. 12330-12362. [10.3390/ijms222212330]

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

Melli B.;Ragazzi M.;Zizzo M.;Giordano G.;Landriscina M.;Santandrea G.;
2021

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.
2021
22
22
12330
12362
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 / Palicelli, A.; Croci, S.; Bisagni, A.; Zanetti, E.; De Biase, D.; Melli, B.; Sanguedolce, F.; Ragazzi, M.; Zanelli, M.; Chaux, A.; Canete-Portillo, S.; Bonasoni, M. P.; Soriano, A.; Ascani, S.; Zizzo, M.; Ruiz, C. C.; De Leo, A.; Giordano, G.; Landriscina, M.; Carrieri, G.; Cormio, L.; Berney, D. M.; Gandhi, J.; Copelli, V.; Bernardelli, G.; Santandrea, G.; Bonacini, M.. - In: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES. - ISSN 1661-6596. - 22:22(2021), pp. 12330-12362. [10.3390/ijms222212330]
Palicelli, A.; Croci, S.; Bisagni, A.; Zanetti, E.; De Biase, D.; Melli, B.; Sanguedolce, F.; Ragazzi, M.; Zanelli, M.; Chaux, A.; Canete-Portillo, S.; Bonasoni, M. P.; Soriano, A.; Ascani, S.; Zizzo, M.; Ruiz, C. C.; De Leo, A.; Giordano, G.; Landriscina, M.; Carrieri, G.; Cormio, L.; Berney, D. M.; Gandhi, J.; Copelli, V.; Bernardelli, G.; Santandrea, G.; Bonacini, M.
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