What Do We Have to Know about PD-L1 Expression in Prostate Cancer? A Systematic Literature Review. Part 4: Experimental Treatments in Pre-Clinical Studies (Cell Lines and Mouse Models).

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

doi:10.3390/ijms222212297

Abstract

In prostate cancer (PC), the PD-1/PD-L1 axis regulates various signaling pathways and it is influenced by extracellular factors. Pre-clinical experimental studies investigating the effects of various treatments (alone or combined) may discover how to overcome the immunotherapy-resistance in PC-patients. We performed a systematic literature review (PRISMA guidelines) to delineate the landscape of pre-clinical studies (including cell lines and mouse models) that tested treatments with effects on PD-L1 signaling in PC. NF-kB, MEK, JAK, or STAT inhibitors on human/mouse, primary/metastatic PC-cell lines variably down-modulated PD-L1-expression, reducing chemoresistance and tumor cell migration. If PC-cells were co-cultured with NK, CD8+ T-cells or CAR-T cells, the immune cell cytotoxicity increased when PD-L1 was downregulated (opposite effects for PD-L1 upregulation). In mouse models, radiotherapy, CDK4/6-inhibitors, and RB deletion induced PD-L1-upregulation, causing PC-immune-evasion. Epigenetic drugs may reduce PD-L1 expression. In some PC experimental models, blocking only the PD-1/PD-L1 pathway had limited efficacy in reducing the tumor growth. Anti-tumor effects could be increased by combining the PD-1/PD-L1 blockade with other approaches (inhibitors of tyrosine kinase, PI3K/mTOR or JAK/STAT3 pathways, p300/CBP; anti-RANKL and/or anti-CTLA-4 antibodies; cytokines; nitroxoline; DNA/cell vaccines; radiotherapy/Radium-223).

Highlights

To evade the antitumor immunity, cancer cells upregulate PD-L1, which interacts with its receptor (PD-1) on T lymphocytes, causing cytotoxic T cell dysfunction; other tumor-infiltrating immune or stromal cells may favor immunosuppression [158]
Programmed death-1 (PD-1) and PD-L1 inhibitors block the effects of their respective targets, reducing the possibility of cancer cells to escape from the antitumor immunity (Figure 2)
In prostate cancer (PC), the PD-1/PD-L1 axis regulates various signaling pathways and it is influenced by extracellular factors

Summary

Introduction

The multi-step process of cancerogenesis and tumor progression implies the acquirement of sustained proliferative signaling, evading growth suppression, reprogramming energy metabolism, and enabling replicative immortality, as well as the induction of angiogenesis and the promotion of invasion and metastatic dissemination; the escape of tumor cells from immune destruction plays an important role in cancer progression [1]. As the discovery of novel biomarkers is urgently required to develop tailored therapies for various malignancies [2], increasing attention has been paid to immunotherapy targets such as Programmed death-1 (PD-1) and its ligand (PD-L1). This pathway is involved in tumor immune-escape and it can be targeted by drugs recently approved by the Food and Drug Administration. PD-1 is expressed by activated T, B, NK cells and monocytes, while PD-L1 is found on hematopoietic and non-hematopoietic cells [5,6]

Methods

Results

Discussion

Conclusion