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      PD-1 and PD-L1 Checkpoint Signaling Inhibition for Cancer Immunotherapy: Mechanism, Combinations, and Clinical Outcome

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          Abstract

          Several cancers are highly refractory to conventional chemotherapy. The survival of tumors in several cases is assisted by checkpoint immunomodulation to maintain the imbalance between immune surveillance and cancer cell proliferation. Check point antibody inhibitors, such as anti-PD-1/PD-L1, are a novel class of inhibitors that function as a tumor suppressing factor via modulation of immune cell-tumor cell interaction. These checkpoint blockers are rapidly becoming a highly promising cancer therapeutic approach that yields remarkable antitumor responses with limited side effects. In recent times, more than four check point antibody inhibitors have been commercialized for targeting PD-1, PDL-1, and CTLA-4. Despite the huge success and efficacy of the anti-PD therapy response, it is limited to specific types of cancers, which attributes to the insufficient and heterogeneous expression of PD-1 in the tumor microenvironment. Herein, we review the current landscape of the PD-1/PD-L1 mechanistic role in tumor immune evasion and therapeutic outcome for cancer treatment. We also review the current progress in clinical trials, combination of drug therapy with immunotherapy, safety, and future of check point inhibitors for multiple types of cancer.

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          Most cited references 37

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          Enhancement of antitumor immunity by CTLA-4 blockade.

          One reason for the poor immunogenicity of many tumors may be that they cannot provide signals for CD28-mediated costimulation necessary to fully activate T cells. It has recently become apparent that CTLA-4, a second counterreceptor for the B7 family of costimulatory molecules, is a negative regulator of T cell activation. Here, in vivo administration of antibodies to CTLA-4 resulted in the rejection of tumors, including preestablished tumors. Furthermore, this rejection resulted in immunity to a secondary exposure to tumor cells. These results suggest that blockade of the inhibitory effects of CTLA-4 can allow for, and potentiate, effective immune responses against tumor cells.
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            Immunological hallmarks of stromal cells in the tumour microenvironment.

            A dynamic and mutualistic interaction between tumour cells and the surrounding stroma promotes the initiation, progression, metastasis and chemoresistance of solid tumours. Far less understood is the relationship between the stroma and tumour-infiltrating leukocytes; however, emerging evidence suggests that the stromal compartment can shape antitumour immunity and responsiveness to immunotherapy. Thus, there is growing interest in elucidating the immunomodulatory roles of the stroma that evolve within the tumour microenvironment. In this Review, we discuss the evidence that stromal determinants interact with leukocytes and influence antitumour immunity, with emphasis on the immunological attributes of stromal cells that may foster their protumorigenic function.
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              PD-1 and PD-L1 expression in molecularly selected non-small-cell lung cancer patients

              Background: Agents targeting programmed death-1 receptor (PD-1) and its ligand (PD-L1) are showing promising results in non-small-cell lung cancer (NSCLC). It is unknown whether PD-1/PD-L1 are differently expressed in oncogene-addicted NSCLC. Methods: We analysed a cohort of 125 NSCLC patients, including 56 EGFR mutated, 29 KRAS mutated, 10 ALK translocated and 30 EGFR/KRAS/ALK wild type. PD-L1 and PD-1 expression were assessed by immunohistochemistry. All cases with moderate or strong staining (2+/3+) in >5% of tumour cells were considered as positive. Results: PD-1 positive (+) was significantly associated with current smoking status (P=0.02) and with the presence of KRAS mutations (P=0.006), whereas PD-L1+ was significantly associated to adenocarcinoma histology (P=0.005) and with presence of EGFR mutations (P=0.001). In patients treated with EGFR tyrosine kinase inhibitors (N=95), sensitivity to gefitinib or erlotinib was higher in PD-L1+ vs PD-L1 negative in terms of the response rate (RR: P=0.01) time to progression (TTP: P<0.0001) and survival (OS: P=0.09), with no difference in PD1+ vs PD-1 negative. In the subset of 54 EGFR mutated patients, TTP was significantly longer in PD-L1+ than in PD-L1 negative (P=0.01). Conclusions: PD-1 and PD-L1 are differentially expressed in oncogene-addicted NSCLC supporting further investigation of specific checkpoint inhibitors in combination with targeted therapies.
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                Author and article information

                Contributors
                Journal
                Front Pharmacol
                Front Pharmacol
                Front. Pharmacol.
                Frontiers in Pharmacology
                Frontiers Media S.A.
                1663-9812
                23 August 2017
                2017
                : 8
                Affiliations
                1Use-Inspired Biomaterials and Integrated Nano Delivery Systems Laboratory, Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University Detroit, MI, United States
                2Department of Pharmaceutics and Pharmaceutical Technology, College of Pharmacy, Taif University Taif, Saudi Arabia
                3Department of Pharmaceutical Sciences, Dr. Harisingh Gour University Sagar, India
                4Molecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute, Wayne State University, School of Medicine Detroit, MI, United States
                Author notes

                Edited by: Soldano Ferrone, Partners HealthCare, United States

                Reviewed by: Paul B. Fisher, Virginia Commonwealth University, United States; Giorgio Stassi, University of Palermo, Italy; Lilian Varricchio, Icahn School of Medicine at Mount Sinai, United States

                *Correspondence: Samaresh Sau samaresh.sau@ 123456wayne.edu

                This article was submitted to Cancer Molecular Targets and Therapeutics, a section of the journal Frontiers in Pharmacology

                †These authors have contributed equally to this work.

                Article
                10.3389/fphar.2017.00561
                5572324
                Copyright © 2017 Alsaab, Sau, Alzhrani, Tatiparti, Bhise, Kashaw and Iyer.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                Page count
                Figures: 4, Tables: 2, Equations: 0, References: 67, Pages: 15, Words: 9572
                Funding
                Funded by: National Cancer Institute 10.13039/100000054
                Award ID: 1R21CA179652
                Categories
                Pharmacology
                Review

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