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      The establishment of immune infiltration based novel recurrence predicting nomogram in prostate cancer

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          Abstract

          Prostate cancer (PCa), a severe health burden for males, accounts for the second frequent cancer and fifth tumor specific death cancer around the world. Several studies on tumor‐infiltrating immune cells (TIICs) have shown inconsistent and controversial results to PCa. We downloaded a gene expression matrix and clinical information from TCGA, and CIBERSORT was used to identify the proportion of TIICs. Wilcoxon's Sign Rank Test evaluated different gene expression levels in PCa and normal tissues. Kaplan‐Meier curves were used to evaluate the associations of TIICs and recurrence‐free survival (RFS). Finally, based on the preset P‐value of .05, the distribution of TIICs in 73 PCa tissues and 11 normal tissues was illustrated. Activated CD4 + T cells and M0 macrophages account for a high proportion in PCa tissues, while neutrophils and monocytes were found at a high density in normal tissues. Further results showed that the density of plasma cells, Treg cells and resting mast cells were associated with advanced PCa. Additionally, M2 macrophages affected the RFS of PCa patients, and AR was also involved. In the current study, we first evaluated the immune infiltration among PCa and revealed that M2 macrophages could predict the prognosis of PCa patients. Meanwhile, based on the LASSO regression analysis, we established a novel nomogram to assess the recurrence risk of PCa based on immune cell proportions and clinical features.

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          Most cited references31

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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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            CD4+ T cells are required for secondary expansion and memory in CD8+ T lymphocytes.

            A long-standing paradox in cellular immunology concerns the conditional requirement for CD4+ T-helper (T(H)) cells in the priming of cytotoxic CD8+ T lymphocyte (CTL) responses in vivo. Whereas CTL responses against certain viruses can be primed in the absence of CD4+ T cells, others, such as those mediated through 'cross-priming' by host antigen-presenting cells, are dependent on T(H) cells. A clearer understanding of the contribution of T(H) cells to CTL development has been hampered by the fact that most T(H)-independent responses have been demonstrated ex vivo as primary cytotoxic effectors, whereas T(H)-dependent responses generally require secondary in vitro re-stimulation for their detection. Here, we have monitored the primary and secondary responses of T(H)-dependent and T(H)-independent CTLs and find in both cases that CD4+ T cells are dispensable for primary expansion of CD8+ T cells and their differentiation into cytotoxic effectors. However, secondary CTL expansion (that is, a secondary response upon re-encounter with antigen) is wholly dependent on the presence of T(H) cells during, but not after, priming. Our results demonstrate that T-cell help is 'programmed' into CD8+ T cells during priming, conferring on these cells a hallmark of immune response memory: the capacity for functional expansion on re-encounter with antigen.
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              PD-L1 expression and tumor mutational burden are independent biomarkers in most cancers

              BACKGROUND. PD-L1 expression and tumor mutational burden (TMB) have emerged as important biomarkers of response to immune checkpoint inhibitor (ICI) therapy. These biomarkers have each succeeded and failed in predicting responders for different cancer types. We sought to describe the PD-L1 expression landscape across the spectrum of ICI-responsive human cancers, and to determine the relationship between PD-L1 expression, TMB, and response rates to ICIs. METHODS. We assessed 9887 clinical samples for PD-L1 expression and TMB. RESULTS. PD-L1 expression and TMB are not significantly correlated within most cancer subtypes, and they show only a marginal association at the tumor sample level (Pearson’s correlation 0.084). Across distinct tumor types, PD-L1 expression and TMB have nonoverlapping effects on the response rate to PD-1/PD-L1 inhibitors and can broadly be used to categorize the immunologic subtypes of cancer. CONCLUSION. Our results indicate that PD-L1 expression and TMB may each inform the use of ICIs, point to different mechanisms by which PD-L1 expression regulates ICI responsiveness, and identify new opportunities for therapeutic development. FUNDING. Funding was provided by Foundation Medicine Inc., the Johns Hopkins Bloomberg–Kimmel Institute for Cancer Immunotherapy, the Viragh Foundation, the National Cancer Institute Specialized Program of Research Excellence (SPORE) in Gastrointestinal Cancers (P50 CA062924), the NIH Center Core Grant (P30 CA006973), the Norman & Ruth Rales Foundation, and the Conquer Cancer Foundation. PD-L1 expression and tumor mutational burden, two widely utilized biomarkers for cancer immunotherapy, are not significantly correlated within most cancer subtypes.
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                Author and article information

                Contributors
                zhangmeng1930@126.com
                liang_chaozhao@ahmu.edu.cn
                Journal
                Cancer Med
                Cancer Med
                10.1002/(ISSN)2045-7634
                CAM4
                Cancer Medicine
                John Wiley and Sons Inc. (Hoboken )
                2045-7634
                29 July 2019
                September 2019
                : 8
                : 11 ( doiID: 10.1002/cam4.v8.11 )
                : 5202-5213
                Affiliations
                [ 1 ] Department of Urology The First Affiliated Hospital of Anhui Medical University Hefei China
                [ 2 ] Institute of Urology Anhui Medical University Hefei China
                [ 3 ] Anhui Province Key Laboratory of Genitourinary Diseases Anhui Medical University Hefei China
                [ 4 ] Department of Epidemiology and Biostatistics, School of Public Health Anhui Medical University Hefei China
                Author notes
                [*] [* ] Correspondence

                Meng Zhang and Chaozhao Liang, Department of Urology, The First Affiliated Hospital of Anhui Medical University, 218 th Jixi Road, Hefei, Anhui, China.

                Emails: zhangmeng1930@ 123456126.com (MZ) and liang_chaozhao@ 123456ahmu.edu.cn (CL)

                Author information
                https://orcid.org/0000-0002-4622-833X
                https://orcid.org/0000-0003-3533-2139
                https://orcid.org/0000-0003-4935-4005
                Article
                CAM42433
                10.1002/cam4.2433
                6718526
                31355524
                f3dc75cb-55b6-41e9-a744-e9050132aa57
                © 2019 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 18 April 2019
                : 09 July 2019
                : 10 July 2019
                Page count
                Figures: 6, Tables: 1, Pages: 12, Words: 6291
                Funding
                Funded by: National Science Foundation for Young Scientists
                Award ID: 81802827
                Funded by: Scientific Research Foundation of the Institute for Translational Medicine of Anhui Province
                Award ID: 2017ZHYX02
                Funded by: National Natural Science Foundation of China
                Award ID: 31430028
                Award ID: 81630019
                Award ID: 81870519
                Categories
                Original Research
                Clinical Cancer Research
                Original Research
                Custom metadata
                2.0
                cam42433
                September 2019
                Converter:WILEY_ML3GV2_TO_NLMPMC version:5.6.8 mode:remove_FC converted:02.09.2019

                Oncology & Radiotherapy
                macrophages,nomogram,prognosis,prostate cancer,recurrence‐free survival,tumor‐infiltrating immune cells

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