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      Immunological Hallmarks for Clinical Response to BCG in Bladder Cancer

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          Abstract

          Intravesical Bacillus Calmette-Guerin (BCG) is an effective immunotherapy for non-muscle invasive bladder cancer (NMIBC). However, recurrence and progression remain frequent warranting deeper insights into its mechanism. We herein comprehensively profiled blood and tissues obtained from NMIBC patients before, during and after BCG treatment using cytometry by time-of-flight (CyTOF) and RNA sequencing to identify the key immune subsets crucial for anti-tumor activity. We observed the temporal changes of peripheral immune subsets including NKT cells, central memory CD4 + T cells, CD8 + T cells and regulatory T cells (Treg) during the course of BCG. Gene expression analysis revealed enriched immune pathways involving in T cell activation and chemotaxis, as well as a more diversified T cell receptor repertoire in post-BCG tissues. Moreover, tissue multiplexed-immunofluorescence (mIF) showed baseline densities of non-Treg and CD8 +PD-1 + T cells were predictive of response and better recurrence-free survival after BCG. Remarkably, post-BCG tissues from responders were found to be infiltrated with more active CD8 +PD-1 - T cells and non-Treg CD4 +FOXP3 - T cells; but increased exhausted CD8 +PD-1 + T cells were found in non-responders. Taken together, we identified predictive biomarkers for response and uncovered the post-treatment expansion of exhausted PD-1 +CD8 + T cells as key to BCG resistance, which could potentially be restored by combining with anti-PD-1 immunotherapy.

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          Most cited references 41

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          HTSeq—a Python framework to work with high-throughput sequencing data

          Motivation: A large choice of tools exists for many standard tasks in the analysis of high-throughput sequencing (HTS) data. However, once a project deviates from standard workflows, custom scripts are needed. Results: We present HTSeq, a Python library to facilitate the rapid development of such scripts. HTSeq offers parsers for many common data formats in HTS projects, as well as classes to represent data, such as genomic coordinates, sequences, sequencing reads, alignments, gene model information and variant calls, and provides data structures that allow for querying via genomic coordinates. We also present htseq-count, a tool developed with HTSeq that preprocesses RNA-Seq data for differential expression analysis by counting the overlap of reads with genes. Availability and implementation: HTSeq is released as an open-source software under the GNU General Public Licence and available from http://www-huber.embl.de/HTSeq or from the Python Package Index at https://pypi.python.org/pypi/HTSeq. Contact: sanders@fs.tum.de
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            Chemokines and chemokine receptors: new insights into cancer-related inflammation.

            Chemokines are involved in cellular interactions and tropism in situations frequently associated with inflammation. Recently, the importance of chemokines and chemokine receptors in inflammation associated with carcinogenesis has been highlighted. Increasing evidence suggests that chemokines are produced by tumor cells as well as by cells of the tumor microenvironment including cancer-associated fibroblasts (CAFs), mesenchymal stem cells (MSCs), endothelial cells, tumor-associated macrophages (TAMs) and more recently tumor-associated neutrophils (TANs). In addition to affecting tumor cell proliferation, angiogenesis and metastasis, chemokines also seem to modulate senescence and cell survival. Here, we review recent progress on the roles of chemokines and chemokine receptors in cancer-related inflammation, and discuss the mechanisms underlying chemokine action in cancer that might facilitate the development of novel therapies in the future. Copyright 2010 Elsevier Ltd. All rights reserved.
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              Comprehensive Transcriptional Analysis of Early-Stage Urothelial Carcinoma

              Non-muscle-invasive bladder cancer (NMIBC) is a heterogeneous disease with widely different outcomes. We performed a comprehensive transcriptional analysis of 460 early-stage urothelial carcinomas and showed that NMIBC can be subgrouped into three major classes with basal- and luminal-like characteristics and different clinical outcomes. Large differences in biological processes such as the cell cycle, epithelial-mesenchymal transition, and differentiation were observed. Analysis of transcript variants revealed frequent mutations in genes encoding proteins involved in chromatin organization and cytoskeletal functions. Furthermore, mutations in well-known cancer driver genes (e.g., TP53 and ERBB2) were primarily found in high-risk tumors, together with APOBEC-related mutational signatures. The identification of subclasses in NMIBC may offer better prognostication and treatment selection based on subclass assignment.
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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
                29 January 2021
                2020
                : 11
                Affiliations
                1 Translational Immunology Institute (TII), SingHealth-DukeNUS Academic Medical Centre , Singapore, Singapore
                2 Duke-NUS Medical School , Singapore, Singapore
                3 Division of Pathology, Singapore General Hospital , Singapore, Singapore
                4 Institute of Molecular Cell Biology (IMCB), Agency of Science, Technology and Research (ASTAR) , Singapore, Singapore
                5 Department of Urology, Singapore General Hospital , Singapore, Singapore
                Author notes

                Edited by: Ilaria Marigo, Veneto Institute of Oncology (IRCCS), Italy

                Reviewed by: Antonella Sistigu, Catholic University of the Sacred Heart, Italy; María Marcela Barrio, Fundación Cáncer, Argentina; Sergei Kusmartsev, University of Florida, United States

                *Correspondence: Valerie Chew, valerie.chew.s.p@ 123456singhealth.com.sg

                This article was submitted to Cancer Immunity and Immunotherapy, a section of the journal Frontiers in Immunology

                Article
                10.3389/fimmu.2020.615091
                7879685
                Copyright © 2021 Lim, Nguyen, Wasser, Kumar, Lee, Nasir, Chua, Lai, Hazirah, Loh, Khor, Yeong, Lim, Low, Albani, Chong and Chew

                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.

                Page count
                Figures: 6, Tables: 0, Equations: 0, References: 41, Pages: 130, Words: 6705
                Funding
                Funded by: National Medical Research Council 10.13039/501100001349
                Categories
                Immunology
                Original Research

                Immunology

                biomarkers, immunotherapy, bladder cancer, bacillus calmette–guerin (bcg), pd-1

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