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      A comprehensive pan-cancer analysis of CDH5 in immunological response

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          Abstract

          Background

          Cadherin 5 (CDH5) functions critically in maintaining cell adhesion and integrity of endothelial and vascular cells. The expression of CDH5 is abnormal in tumor cells, which may have great potential to serve as a new immune checkpoint. The current pan-cancer analysis was performed to better understand the role of CDH5 in tumor.

          Methods

          The clinical significance and immunological function of CDH5 in pan-cancers were comprehensively analyzed based on the correlations between CDH5 and clinicopathologic features, prognosis values, tumor mutation burden (TMB), microsatellite instability (MSI), immune cells infiltration and immune response genes using 33 datasets from The Cancer Genome Atlas (TCGA). We further confirmed the expression of CDH5 in bladder cancer (BCa) tissues and cell lines. The CD8 + T cells were screened from peripheral blood of healthy controls and activated. BCa cell-CD8 + T cell co-culture assay and ELISA assay were carried out to verify the immunological function of CDH5.

          Results

          The expression of CDH5 was down-regulated in 8 types of tumors including in BCa but up-regulated in 4 types of tumors. CDH5 was significantly correlated with tumor stage in 6 types of tumors. In addition, CDH5 was positively or negatively correlated with tumor prognosis. Furthermore, CDH5 was closely associated with TMB in 15 types of tumors and with MSI in 9 types of tumors. KEGG-GSEA and Hallmarks-GSEA analyses results indicated that CDH5 was positively related to immune response in most tumor types. In many tumors, CDH5 showed a positive correlation with immune cell infiltration. Enrichment analyses demonstrated that CDH5 was significantly related to the expression of many immunomodulators and chemokines. Further experiments showed that CDH5 was low-expressed in BCa tissues and cell lines in comparison to adjacent normal tissues and normal urothelial cell line, but it was positively associated with a better prognosis of BCa patients. The results of in vitro co-culture assay and ELISA assay demonstrated that CDH5 could promote the function of CD8 + T cells in TME of BCa.

          Conclusion

          In summary, CDH5 was positively associated with a favorable prognosis and effective immune response in tumors, showing a great potential to serve as a novel tumor biomarker and immune checkpoint.

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          Most cited references38

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          Cancer statistics, 2023

          Each year, the American Cancer Society estimates the numbers of new cancer cases and deaths in the United States and compiles the most recent data on population-based cancer occurrence and outcomes using incidence data collected by central cancer registries and mortality data collected by the National Center for Health Statistics. In 2023, 1,958,310 new cancer cases and 609,820 cancer deaths are projected to occur in the United States. Cancer incidence increased for prostate cancer by 3% annually from 2014 through 2019 after two decades of decline, translating to an additional 99,000 new cases; otherwise, however, incidence trends were more favorable in men compared to women. For example, lung cancer in women decreased at one half the pace of men (1.1% vs. 2.6% annually) from 2015 through 2019, and breast and uterine corpus cancers continued to increase, as did liver cancer and melanoma, both of which stabilized in men aged 50 years and older and declined in younger men. However, a 65% drop in cervical cancer incidence during 2012 through 2019 among women in their early 20s, the first cohort to receive the human papillomavirus vaccine, foreshadows steep reductions in the burden of human papillomavirus-associated cancers, the majority of which occur in women. Despite the pandemic, and in contrast with other leading causes of death, the cancer death rate continued to decline from 2019 to 2020 (by 1.5%), contributing to a 33% overall reduction since 1991 and an estimated 3.8 million deaths averted. This progress increasingly reflects advances in treatment, which are particularly evident in the rapid declines in mortality (approximately 2% annually during 2016 through 2020) for leukemia, melanoma, and kidney cancer, despite stable/increasing incidence, and accelerated declines for lung cancer. In summary, although cancer mortality rates continue to decline, future progress may be attenuated by rising incidence for breast, prostate, and uterine corpus cancers, which also happen to have the largest racial disparities in mortality.
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            Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: a single-arm, multicentre, phase 2 trial.

            First-line chemotherapy for patients with cisplatin-ineligible locally advanced or metastatic urothelial carcinoma is associated with short response duration, poor survival, and high toxicity. This study assessed atezolizumab (anti-programmed death-ligand 1 [PD-L1]) as treatment for metastatic urothelial cancer in cisplatin-ineligible patients.
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              Immune cells within the tumor microenvironment: biological functions and roles in cancer immunotherapy

              The immune cells within the tumor microenvironment (TME) play important roles in tumorigenesis. It has been known that these tumor associated immune cells may possess tumor-antagonizing or tumor-promoting functions. Although the tumor-antagonizing immune cells within TME tend to target and kill the cancer cells in the early stage of tumorigenesis, the cancer cells seems to eventually escape from immune surveillance and even inhibit the cytotoxic function of tumor-antagonizing immune cells through a variety of mechanisms. The immune evasion capability, as a new hallmark of cancer, accidently provides opportunities for new strategies of cancer therapy, namely harnessing the immune cells to battle the cancer cells. Recently, the administrations of immune checkpoint modulators (represented by anti-CTLA4 and anti-PD antibodies) and adoptive immune cells (represented by CAR-T) have exhibited unexpected antitumor effect in multiple types of cancer, bringing a new era for cancer therapy. Here, we review the biological functions of immune cells within TME and their roles in cancer immunotherapy, and discuss the perspectives of the basic studies for improving the effectiveness of the clinical use.
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                Author and article information

                Contributors
                Journal
                Front Immunol
                Front Immunol
                Front. Immunol.
                Frontiers in Immunology
                Frontiers Media S.A.
                1664-3224
                21 September 2023
                2023
                : 14
                : 1239875
                Affiliations
                [1] 1 Department of Gastroenterology, Linyi County People’s Hospital , Dezhou, China
                [2] 2 Laboratory of Urology and Andrology , Jiangsu Clinical Medicine Research Institution, Nanjing, China
                [3] 3 Department of Urology, The First People's Hospital of Xiushui County , Jiujiang, Jiangxi, China
                Author notes

                Edited by: Madduri Srinivasarao, Eradivir, Inc., United States

                Reviewed by: Yucheng Ma, Sichuan University, China; Hailin Tang, Sun Yat-sen University Cancer Center (SYSUCC), China; Venkatesh Chelvam, Indian Institute of Technology Indore, India

                *Correspondence: Jiancheng Lv, doctorjiancheng@ 123456sina.com ; Junwei Gu, 483101273@ 123456qq.com

                †These authors have contributed equally to this work

                Article
                10.3389/fimmu.2023.1239875
                10551168
                37809080
                0d1ae756-4683-46ff-9520-68b28e2f0f10
                Copyright © 2023 Li, Wu, Lv and Gu

                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) and the copyright owner(s) 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.

                History
                : 14 June 2023
                : 28 August 2023
                Page count
                Figures: 10, Tables: 0, Equations: 0, References: 38, Pages: 15, Words: 4434
                Categories
                Immunology
                Original Research
                Custom metadata
                Cancer Immunity and Immunotherapy

                Immunology
                cdh5,pan-cancer,prognosis,immune response,cd8 + t cells
                Immunology
                cdh5, pan-cancer, prognosis, immune response, cd8 + t cells

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