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      Prognostic implications of PD-L1 expression in patients with soft tissue sarcoma

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          Abstract

          Background

          The PD-1/PD-L1 axis plays a paramount role in the immune escape of tumor cells by negative regulation of T-cell functions. The aim of the present study was to characterize the PD-L1 expression pattern and its clinical implication in soft-tissue sarcomas (STS).

          Methods

          We analyzed PD-L1 expression in 82 STS patients with 5 subtypes: rhabdomyosarcoma, synovial sarcoma, Ewing sarcoma, epithelioid sarcoma, and mesenchymal chondrosarcoma.

          Results

          The median age at diagnosis was 26 (range: 1–78) and the male to female ratio was 1.6. The majority (80 %) of patients showed locoregional disease rather than metastatic disease at diagnosis. Thirty-five cases (43 %) showed PD-L1 expression and the proportion of PD-L1 expression was significantly different according to histologic subtypes ( P = 0.004); highest in epithelioid sarcoma (100 %, 7/7), followed by synovial sarcoma (53 %, 10/19), rhabdomyosarcoma (38 %, 12/32), and Ewing sarcoma (33 %, 6/18), while it was not expressed in mesenchymal chondrosarcoma (0 %, 0/6). STS patients with PD-L1 expression had worse overall survival compared with those without PD-L1 expression (5-year survival rate: 48 % vs. 68 %, P = 0.015). The Cox proportional hazard model adjusted for histologic subtype, initial metastasis, and PD-L1 expression showed that PD-L1 expression was significantly associated with shorter overall survival ( P = 0.037, HR 2.57, 95 % CI 1.060–6.231).

          Conclusion

          We have confirmed PD-L1 expression in various STS of young population and demonstrated its independent negative prognostic role, thereby suggesting the PD-1/PD-L1 axis as a potential therapeutic target for the treatment of young STS patients.

          Electronic supplementary material

          The online version of this article (doi:10.1186/s12885-016-2451-6) contains supplementary material, which is available to authorized users.

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          Most cited references13

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          Doxorubicin alone versus intensified doxorubicin plus ifosfamide for first-line treatment of advanced or metastatic soft-tissue sarcoma: a randomised controlled phase 3 trial.

          Effective targeted treatment is unavailable for most sarcomas and doxorubicin and ifosfamide-which have been used to treat soft-tissue sarcoma for more than 30 years-still have an important role. Whether doxorubicin alone or the combination of doxorubicin and ifosfamide should be used routinely is still controversial. We assessed whether dose intensification of doxorubicin with ifosfamide improves survival of patients with advanced soft-tissue sarcoma compared with doxorubicin alone.
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            High expression of PD-L1 in lung cancer may contribute to poor prognosis and tumor cells immune escape through suppressing tumor infiltrating dendritic cells maturation.

            The immunohistochemical analysis was used to evaluate the expression of PD-L1 in 109 non-small cell lung cancer (NSCLC) tissues and para-tumor tissues. Associations between expressed PD-L1 and tumor histological types, degree of differentiation, and lymph node metastasis were calculated, and overall survival was assessed. Meanwhile, immunohistochemistry and immunofluorescence double labeling technique were performed to detect the expressions of PD-L1, CD1α, and CD83 on TIDC of 20 lung cancer tissues, and the expression of PD-L1 in CD1α+DCs and CD83+DCs and their significances were also explored. We found that the expression rate of PD-L1 in NSCLC was associated with histological types and overall survival. Patients with either adenocarcinoma or survival time after surgery less than 3 years showed higher expression rate of PD-L1. Furthermore, Cox model analysis indicated that PD-L1 might be regarded as a poor prognostic factor. PD-L1 could be also detected in CD1α+ immature DC in NSCLC, indicating that as a class of key anti-tumor immunocyte in tumor microenvironment, DC expressing PD-L1 itself might play an important role in keeping its immature status and contributing to tumor cells immune escape and disease progression.
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              In situ tumor PD-L1 mRNA expression is associated with increased TILs and better outcome in breast carcinomas.

              Blockade of the PD-1/PD-L1 axis emerged as a promising new therapeutic option for cancer that has resulted in lasting responses in metastatic renal, lung carcinomas, and melanomas. Tumor PD-L1 protein expression may predict response to drugs targeting this pathway. Measurement of PD-L1 protein is limited by the lack of standardized immunohistochemical methods and variable performance of antibodies. Our goal was to correlate PD-L1 mRNA expression with clinical variables in primary breast carcinomas. The fluorescent RNAscope paired-primer assay was used to quantify in situ PD-L1 mRNA levels in 636 stage I-III breast carcinomas on two sets of tissue microarrays [YTMA128 (n = 238) and YTMA201 (n = 398)]. Tumor-infiltrating lymphocytes (TIL) were assessed by hematoxylin/eosin stain and quantitative fluorescence. On YTMA128 and YTMA201, 55.7% and 59.5% of cases showed PD-L1 mRNA expression, respectively. Higher PD-L1 mRNA expression was significantly associated with increased TILs (P = 0.04) but not with other clinical variables. Elevated TILs (scores 2 and 3+) occurred in 16.5% on YTMA128 and 14.8% on YTMA201 and was associated with estrogen receptor-negative status (P = 0.01 on YTMA128 and 0.0001 on YTMA201). PD-L1 mRNA expression was associated with longer recurrence-free survival (log-rank P = 0.01), which remained significant in multivariate analysis including age, tumor size, histologic grade, nodal metastasis, hormone receptor, HER2 status, and the extent of TILs (HR, 0.268; CI, 0.099-0.721; P = 0.009). PD-L1 mRNA expression is identified in nearly 60% of breast tumors and it is associated with increased TILs and improved recurrence-free survival. These observations support the evaluation of PD-1/PD-L1-targeted therapies in breast cancer. ©2014 American Association for Cancer Research.
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                Author and article information

                Contributors
                chan@cha.ac.kr
                dalsoon00@yuhs.ac
                hun.jung@merck.com
                minidoctor@cha.ac.kr
                JWHAN@yuhs.ac
                qshin@yuhs.ac
                hhyuk@yuhs.ac
                kskim88@yuhs.ac
                youngd74@yuhs.ac
                shkim70@yuhs.ac
                SANDO@yuhs.ac
                JSS@yuhs.ac
                VVSWM513@yuhs.ac
                unchung8@yuhs.ac
                sunghoonn@yuhs.ac
                rha7655@yuhs.ac
                luhi7@naver.com
                +82 2 2228 8124 , hyosong77@yuhs.ac
                Journal
                BMC Cancer
                BMC Cancer
                BMC Cancer
                BioMed Central (London )
                1471-2407
                8 July 2016
                8 July 2016
                2016
                : 16
                : 434
                Affiliations
                [ ]Division of Medical Oncology, Department of Internal Medicine, Yonsei University College of Medicine, 134 Shinchondong, Seodaemun-gu, Seoul, 03722 Korea
                [ ]Department of Pathology, Yonsei University College of Medicine, Seoul, Korea
                [ ]Oncology, Merck Sharp & Dohme, Seoul, Korea
                [ ]Department of Pediatric Hemato-Oncology, Yonsei University College of Medicine, Seoul, Korea
                [ ]Department of Orthopedic Surgery, Yonsei University College of Medicine, Seoul, Korea
                [ ]Department of Surgery, Yonsei University College of Medicine, Seoul, Korea
                [ ]Department of Urology, Yonsei University College of Medicine, Seoul, Korea
                [ ]Department of Obstetrics and Gynecology, Yonsei University College of Medicine, Seoul, Korea
                [ ]Department of Radiology, Yonsei University College of Medicine, Seoul, Korea
                [ ]Medical Oncology, CHA Bundang Medical Center, CHA University, Seongnam, Korea
                [ ]Anatomic Pathology Reference Lab, Seegene Medical Foundation, Seoul, 05548 Korea
                Article
                2451
                10.1186/s12885-016-2451-6
                4938996
                27393385
                61653413-7780-4eda-9681-3d3e6862674e
                © The Author(s). 2016

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 14 April 2016
                : 24 June 2016
                Categories
                Research Article
                Custom metadata
                © The Author(s) 2016

                Oncology & Radiotherapy
                soft tissue sarcoma,pd-l1,biomarker,prognosis
                Oncology & Radiotherapy
                soft tissue sarcoma, pd-l1, biomarker, prognosis

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