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      Co-expression of AFAP1-AS1 and PD-1 predicts poor prognosis in nasopharyngeal carcinoma

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          Abstract

          Nasopharyngeal carcinoma (NPC) carries a high potential for metastasis and immune escape, with a great risk of relapse after primary treatment. Through analysis of whole genome expression profiling data in NPC samples, we found that the expression of a long non-coding RNA (lncRNA), actin filament-associated protein 1 antisense RNA 1 ( AFAP1-AS1), is significantly correlated with the immune escape marker programmed death 1 ( PD-1). We therefore assessed the expression of AFAP1-AS1 and PD-1 in a cohort of 96 paraffin-embedded NPC samples and confirmed that AFAP1-AS1 and PD-1 are co-expressed in infiltrating lymphocytes in NPC tissue. Moreover, patients with high expression of AFAP1-AS1 or PD-1 in infiltrating lymphocytes were more prone to distant metastasis, and NPC patients with positive expression of both AFAP1-AS1 and PD-1 had the poorest prognosis. This study suggests that AFAP1-AS1 and PD-1 may be potential therapeutic targets in NPC and that patients with co-expression of AFAP1-AS1 and PD-1 may be ideal candidates for future clinical trials of anti-PD-1 immune therapy.

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          Most cited references68

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          EBV-driven LMP1 and IFN-γ up-regulate PD-L1 in nasopharyngeal carcinoma: Implications for oncotargeted therapy

          PD-L1 expression is a feature of Epstein-Barr virus (EBV) associated malignancies such as nasopharyngeal carcinoma (NPC). Here, we found that EBV-induced latent membrane protein 1 (LMP1) and IFN-γ pathways cooperate to regulate programmed cell death protein 1 ligand (PD-L1). Expression of PD-L1 was higher in EBV positive NPC cell lines compared with EBV negative cell lines. PD-L1 expression could be increased by exogenous and endogenous induction of LMP1 induced PD-L1. In agreement, expression of PD-L1 was suppressed by knocking down LMP1 in EBV positive cell lines. We further demonstrated that LMP1 up-regulated PD-L1 through STAT3, AP-1, and NF-κB pathways. Besides, IFN-γ was independent of but synergetic with LMP1 in up-regulating PD-L1 in NPC. Furthermore, we showed that PD-L1 was associated with worse disease-free survival in NPC patients. These results imply that blocking both the LMP1 oncogenic pathway and PD-1/PD-L1 checkpoints may be a promising therapeutic approach for EBV positive NPC patients.
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            The presence of programmed death 1 (PD-1)-positive tumor-infiltrating lymphocytes is associated with poor prognosis in human breast cancer.

            Programmed death 1 (PD-1) is a co-inhibitory receptor in the CD28/CTL-4 family, and functions as a negative regulator of the immune system. Tumor-infiltrating lymphocytes (TIL) in many epithelial cancers express PD-1, suggesting that antitumor immunity may be modulated by the PD-1/PD-L1 signaling pathway, and promising results from two recent clinical trials with monoclonal antibodies targeting PD-1 or PD-L1 confirm the clinical relevance of this pathway in human cancer. To explore the role of PD-1(+) TIL in human breast cancer, we performed immunohistochemistry studies on a tissue microarray encompassing 660 breast cancer cases with detailed clinical annotation and outcomes data. PD-1(+) TIL were present in 104 (15.8 %) of the 660 breast cancer cases. Their presence was associated with tumor size, grade, and lymph node status, and was differentially associated with the intrinsic subtypes of breast cancer. In univariate survival analyses, the presence of PD-1(+) TIL was associated with a significantly worse overall survival (HR = 2.736, p < 0.001). In subset analyses, the presence of PD-1(+) TIL was associated with significantly worse overall survival in the luminal B HER2(-) subtype (HR = 2.678, p < 0.001), the luminal B HER2(+) subtype (HR = 3.689, p < 0.001), and the basal-like subtype (HR = 3.140, p < 0.001). This is the first study to demonstrate that the presence of PD-1(+) TIL is associated with poor prognosis in human breast cancer, with important implications for the potential application of antibody therapies targeting the PD-1/PD-L1 signaling pathway in this disease.
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              Anti-PD-1 antitumor immunity is enhanced by local and abrogated by systemic chemotherapy in GBM.

              The immunosuppressive effects of chemotherapy present a challenge for designing effective cancer immunotherapy strategies. We hypothesized that although systemic chemotherapy (SC) exhibits negative immunologic effects, local chemotherapy (LC) can potentiate an antitumor immune response. We show that LC combined with anti-programmed cell death protein 1 (PD-1) facilitates an antitumor immune response and improves survival (P < 0.001) in glioblastoma. LC-treated mice had increased infiltration of tumor-associated dendritic cells and clonal expansion of antigen-specific T effector cells. In comparison, SC resulted in systemic and intratumoral lymphodepletion, with decreased immune memory in long-term survivors. Furthermore, adoptive transfer of CD8(+) cells from LC-treated mice partially rescued SC-treated mice after tumor rechallenge. Last, the timing of chemo- and immunotherapy had differential effects on anti-PD-1 efficacy. This study suggests that both mode of delivery and timing have distinct effects on the efficacy of anti-PD-1. The results of this work could help guide the selection and scheduling of combination treatment for patients with glioblastoma and other tumor types.
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                Author and article information

                Journal
                Oncotarget
                Oncotarget
                Oncotarget
                ImpactJ
                Oncotarget
                Impact Journals LLC
                1949-2553
                13 June 2017
                24 March 2017
                : 8
                : 24
                : 39001-39011
                Affiliations
                1 The Key Laboratory of Carcinogenesis of the Chinese Ministry of Health, Xiangya Hospital, Central South University, Changsha, Hunan, China
                2 The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, Hunan, China
                3 Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Disease Genome Research Center, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China
                4 Hunan Key Laboratory of Translational Radiation Oncology, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China
                5 Department of pathology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
                6 School of Information Science and Engineering, Central South University, Changsha, Hunan, China
                7 Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
                Author notes
                Correspondence to: Zhaoyang Zeng, zengzhaoyang@ 123456csu.edu.cn
                Article
                16545
                10.18632/oncotarget.16545
                5503590
                28380458
                520f3c32-5275-4a34-82eb-12bcbaaf5941
                Copyright: © 2017 Tang et al.

                This article is distributed under the terms of the Creative Commons Attribution License (CC-BY), which permits unrestricted use and redistribution provided that the original author and source are credited.

                History
                : 13 January 2017
                : 15 February 2017
                Categories
                Research Paper

                Oncology & Radiotherapy
                long non-coding rna,afap1-as1,programmed death 1 (pd-1),prognosis,nasopharyngeal carcinoma (npc)

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