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      Targeting PD-1/PD-L1 interactions for cancer immunotherapy

      editorial
      1 , 2 , 3 , 4 , * , 5 , 6 , 7 , 8 , 9
      Oncoimmunology
      Landes Bioscience

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          Abstract

          Tumors have developed multiple immunosuppressive mechanisms to turn down the innate and the effector arms of the immune system, thus compromising most of the immunotherapeutic strategies that have been proposed during the last decade. Right after the pioneering success of Ipilimumab (anti-CTLA4) in metastatic melanoma, several groups have conducted trials aiming at subverting other immune checkpoints. Two articles that recently appeared in the New England Journal of Medicine. 1 , 2 highlight the therapeutic potential of agents that target PD-1 or its ligand PD-L1 in patients with advanced cancer, even individuals with lung or brain metastases. If confirmed, this clinical breakthrough will open novel avenues for cancer immunotherapy.

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          Most cited references13

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          Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade.

          PD-1 is a receptor of the Ig superfamily that negatively regulates T cell antigen receptor signaling by interacting with the specific ligands (PD-L) and is suggested to play a role in the maintenance of self-tolerance. In the present study, we examined possible roles of the PD-1/PD-L system in tumor immunity. Transgenic expression of PD-L1, one of the PD-L, in P815 tumor cells rendered them less susceptible to the specific T cell antigen receptor-mediated lysis by cytotoxic T cells in vitro, and markedly enhanced their tumorigenesis and invasiveness in vivo in the syngeneic hosts as compared with the parental tumor cells that lacked endogenous PD-L. Both effects could be reversed by anti-PD-L1 Ab. Survey of murine tumor lines revealed that all of the myeloma cell lines examined naturally expressed PD-L1. Growth of the myeloma cells in normal syngeneic mice was inhibited significantly albeit transiently by the administration of anti-PD-L1 Ab in vivo and was suppressed completely in the syngeneic PD-1-deficient mice. These results suggest that the expression of PD-L1 can serve as a potent mechanism for potentially immunogenic tumors to escape from host immune responses and that blockade of interaction between PD-1 and PD-L may provide a promising strategy for specific tumor immunotherapy.
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            T cell receptor signaling controls Foxp3 expression via PI3K, Akt, and mTOR.

            Regulatory T (Treg) cells safeguard against autoimmunity and immune pathology. Because determinants of the Treg cell fate are not completely understood, we have delineated signaling events that control the de novo expression of Foxp3 in naive peripheral CD4 T cells and in thymocytes. We report that premature termination of TCR signaling and inibition of phosphatidyl inositol 3-kinase (PI3K) p110alpha, p110delta, protein kinase B (Akt), or mammalian target of rapamycin (mTOR) conferred Foxp3 expression and Treg-like gene expression profiles. Conversely, continued TCR signaling and constitutive PI3K/Akt/mTOR activity antagonised Foxp3 induction. At the chromatin level, di- and trimethylation of lysine 4 of histone H3 (H3K4me2 and -3) near the Foxp3 transcription start site (TSS) and within the 5' untranslated region (UTR) preceded active Foxp3 expression and, like Foxp3 inducibility, was lost upon continued TCR stimulation. These data demonstrate that the PI3K/Akt/mTOR signaling network regulates Foxp3 expression.
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              Tumor cell expression of programmed cell death-1 ligand 1 is a prognostic factor for malignant melanoma.

              : Melanoma tends to be refractory to various immunotherapies because of tumor-induced immunosuppression. To investigate the mechanism underlining the immunosuppression of melanoma patients, the authors focused on programmed cell death-1 (PD-1)/PD-1 ligand 1 (PD-L1) interaction between tumor cells and T cells. : Melanoma specimens were collected from 59 primary tumors, 16 lymph nodes, and 4 lesions of in-transit metastasis. Specimens stained with anti-PD-L1 monoclonal antibodies were digitalized to jpg files. To evaluate the intensity of PD-L1 expression, histograms were used, and the red density (RD) was measured. PD-1 expression on T cells was analyzed in blood samples from 10 patients who had stage IV melanoma and in 4 samples of in-transit metastases. : Twenty-five patients comprised the "low" PD-L1 expression group (RD value, or =90). Breslow tumor thickness in the high-expression group was significantly higher than in the low-expression group. Univariate and multivariate analyses revealed that the overall survival rate of the high-expression group was significantly lower than that of the low-expression group. In all patients with stage IV disease who were examined, both CD8-positive and CD4-positive T cells had significantly higher PD-1 expression levels in the peripheral blood. Tumor-infiltrating T cells expressed high levels of PD-1, and its expression was elevated further during the clinical course. : The current results indicated that there is a correlation between the degree of PD-L1 expression and the vertical growth of primary tumors in melanoma. Multivariate analysis demonstrated that PD-L1 expression is an independent prognostic factor for melanoma. Cancer 2010. (c) 2010 American Cancer Society.
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                Author and article information

                Journal
                Oncoimmunology
                Oncoimmunology
                ONCI
                Oncoimmunology
                Landes Bioscience
                2162-4011
                2162-402X
                01 November 2012
                01 November 2012
                : 1
                : 8
                : 1223-1225
                Affiliations
                [1 ]INSERM; U1015; Institut Gustave Roussy; Villejuif, France
                [2 ]Center of Clinical Investigations CBT507; Institut Gustave Roussy; Villejuif, France
                [3 ]Institut Gustave Roussy; Villejuif, France
                [4 ]University of Paris Sud; Villejuif, France
                [5 ]INSERM; U848; Villejuif, France
                [6 ]Metabolomics Platform; Institut Gustave Roussy; Villejuif, France
                [7 ]Centre de Recherche des Cordeliers; Paris, France
                [8 ]Pôle de Biologie; Hôpital Européen Georges Pompidou; AP-HP; Paris, France
                [9 ]Université Paris Descartes; Faculté de Médecine; Paris, France
                Author notes
                [* ]Correspondence to: Laurence Zitvogel, Email: zitvogel@ 123456igr.fr
                Article
                2012ONCOIMM226 21335
                10.4161/onci.21335
                3518493
                23243584
                1f28a5ce-a2d7-4c63-bb26-20e1d4d2d579
                Copyright © 2012 Landes Bioscience

                This is an open-access article licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported License. The article may be redistributed, reproduced, and reused for non-commercial purposes, provided the original source is properly cited.

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