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      PD-L1 expression and tumor mutational burden status for prediction of response to chemotherapy and targeted therapy in non-small cell lung cancer

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          Abstract

          Background

          Several targeted immunotherapies have recently showed significant advances in treatment of non-small cell lung cancer (NSCLC), including antibodies and inhibitors targeting programmed death-1 (PD-1) and its ligand (PD-L1).

          Methods

          Tumor tissue samples were prospectively collected from 183 patients with NSCLC including lung adenocarcinoma (ADC) and squamous cell carcinoma (SQCC). PD-L1 expression level was measured by immunohistochemistry assay and tumor mutational burden (TMB) status was assessed by next generation sequencing. Correlations between PD-L1 expressions, TMB status with clinicopathological characteristics were analyzed.

          Results

          PD-L1 expression was detected in 37% of ADC group and 55% in SQCC group while all clinicopathological characteristics were found comparable between these two groups. PD-L1 expression was negatively associated with overall survival in ADC group ( P < 0.0001) but not in SQCC group ( P = 0.418). In consistent with PD-L1 expression level, TMB status was significantly lower in ADC subjects as compared to SQCC subjects ( P = 0.024) while PD-L1 positive subgroup and TMB high subgroup shared less subjects within ADC group than SQCC group. More importantly, the combination of TMB status and PD-L1 expression successfully identified responders, who showed significant longer median overall survival than non-responders (32 months vs. 8.5 months) in ADC subjects ( P < 0.0001) but not in SQCC subjects.

          Conclusions

          Here we tested the hypothesis that monitoring TMB, in addition to the existing PD-L1 expression level, could represent valuable non-invasive biomarkers for the chemotherapy and targeted therapy. Further analyses are in need to further assess the prognostic value of TMB for ADC and SQCC patients receiving immunotherapy .

          Electronic supplementary material

          The online version of this article (10.1186/s13046-019-1192-1) contains supplementary material, which is available to authorized users.

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          Most cited references21

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          Facilitating T Cell Infiltration in Tumor Microenvironment Overcomes Resistance to PD-L1 Blockade.

          Immune checkpoint blockade therapies fail to induce responses in the majority of cancer patients, so how to increase the objective response rate becomes an urgent challenge. Here, we demonstrate that sufficient T cell infiltration in tumor tissues is a prerequisite for response to PD-L1 blockade. Targeting tumors with tumor necrosis factor superfamily member LIGHT activates lymphotoxin β-receptor signaling, leading to the production of chemokines that recruit massive numbers of T cells. Furthermore, targeting non-T cell-inflamed tumor tissues by antibody-guided LIGHT creates a T cell-inflamed microenvironment and overcomes tumor resistance to checkpoint blockade. Our data indicate that targeting LIGHT might be a potent strategy to increase the responses to checkpoint blockades and other immunotherapies in non-T cell-inflamed tumors.
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            PD-L1 expression as a predictive biomarker in advanced non-small-cell lung cancer: updated survival data.

            The treatment of non-small-cell lung cancer has changed after the development of the immune checkpoint inhibitors. Although the most studied biomarker is PD-L1 expression, its clinical significance is still debatable. In this article, we show the updated survival analysis of all published data.
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              Utility of PD-L1 immunohistochemistry assays for predicting PD-1/PD-L1 inhibitor response

              We have seen a notable increase in the application of PD-1/PD-L1 inhibitors for the treatment of several solid and hematogenous malignancies including metastatic melanoma, non-small-cell lung cancer and lymphoma to name a few. The need for biomarkers for identification of a suitable patient population for this type of therapy is now pressing. While specific biomarker assays have been developed for these checkpoint inhibitors based on their respective epitopes, the available studies suggested the clinical utility of these biomarker assays is for response stratification and not patient selection. Further improvement in assay development is needed to utilize this type of assay in identification of ideal patient population for this therapy.
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                Author and article information

                Contributors
                chenyanhui377@163.com
                quanxing9999@qq.com
                chzm_md@163.com
                liulixiao0115@126.com
                332611680@qq.com
                nxjyhuying@163.com
                newtonappale@126.com
                zenghui@ccmu.edu.cn
                +86-0512-65223637 , mht7403@163.com
                +86-023-68755114 , 691057831@qq.com
                +86-10-84322621 , zhhbao@ccmu.edu.cn
                Journal
                J Exp Clin Cancer Res
                J. Exp. Clin. Cancer Res
                Journal of Experimental & Clinical Cancer Research : CR
                BioMed Central (London )
                0392-9078
                1756-9966
                14 May 2019
                14 May 2019
                2019
                : 38
                : 193
                Affiliations
                [1 ]ISNI 0000 0004 0369 153X, GRID grid.24696.3f, Institute of Infectious Diseases, , Beijing Ditan Hospital, Capital Medical University, Beijing Key Laboratory of Emerging Infectious Diseases, ; No.8 Jingshundongjie, Beijing, 100015 China
                [2 ]Department of Thoracic Surgery, Xinqiao Hospital, Third Military Medical University (Army Medical University), 183 Xin Qiao Zheng jie, Chongqing, 400037 China
                [3 ]ISNI 0000 0004 1757 8861, GRID grid.411405.5, Department of Thoracic Surgery, , Huashan Hospital, ; 12 Wu Lu Mu Qi Road (M), Shanghai, 200040 China
                [4 ]Genecast Precision Medicine Technology Institute, Huayuanbeilu 35, Beijing, 100089 China
                [5 ]GRID grid.429222.d, Department of Thoracic Surgery, , The First Affiliated Hospital of Soochow University, ; No. 188 Shizi Street, Suzhou, 215006 China
                Article
                1192
                10.1186/s13046-019-1192-1
                6518807
                31088500
                3deaf911-1914-4763-ab15-36f93ce26ed5
                © The Author(s). 2019

                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
                : 29 December 2018
                : 25 April 2019
                Funding
                Funded by: the National Key Sci-Tech Special Project of China
                Award ID: No. 2018ZX10302207
                Categories
                Research
                Custom metadata
                © The Author(s) 2019

                Oncology & Radiotherapy
                pd-l1,tmb,biomarker,targeted therapy,non-small cell lung cancer,prognosis
                Oncology & Radiotherapy
                pd-l1, tmb, biomarker, targeted therapy, non-small cell lung cancer, prognosis

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