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      The Contribution of Race to Breast Tumor Microenvironment Composition and Disease Progression

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          Abstract

          Breast cancer is the second most commonly diagnosed cancer in American women following skin cancer. Despite overall decrease in breast cancer mortality due to advances in treatment and earlier screening, black patients continue to have 40% higher risk of breast cancer related death compared to white patients. This disparity in outcome persists even when controlled for access to care and stage at presentation and has been attributed to differences in tumor subtypes or gene expression profiles. There is emerging evidence that the tumor microenvironment (TME) may contribute to the racial disparities in outcome as well. Here, we provide a comprehensive review of current literature available regarding race-dependent differences in the TME. Notably, black patients tend to have a higher density of pro-tumorigenic immune cells (e.g., M2 macrophages, regulatory T cells) and microvasculature. Although immune cells are classically thought to be anti-tumorigenic, increase in M2 macrophages and angiogenesis may lead to a paradoxical increase in metastasis by forming doorways of tumor cell intravasation called tumor microenvironment of metastasis (TMEM). Furthermore, black patients also have higher serum levels of inflammatory cytokines, which provide a positive feedback loop in creating a pro-metastatic TME. Lastly, we propose that the higher density of immune cells and angiogenesis observed in the TME of black patients may be a result of evolutionary selection for a more robust immune response in patients of African geographic ancestry. Better understanding of race-dependent differences in the TME will aid in overcoming the racial disparity in breast cancer mortality.

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          Prognostic value of tumor-infiltrating lymphocytes in triple-negative breast cancers from two phase III randomized adjuvant breast cancer trials: ECOG 2197 and ECOG 1199.

          Recent studies suggest that tumor-infiltrating lymphocytes (TILs) are associated with disease-free (DFS) and overall survival (OS) in operable triple-negative breast cancer (TNBC). We seek to validate the prognostic impact of TILs in primary TNBCs in two adjuvant phase III trials conducted by the Eastern Cooperative Oncology Group (ECOG). Full-face hematoxylin and eosin–stained sections of 506 tumors from ECOG trials E2197 and E1199 were evaluated for density of TILs in intraepithelial (iTILs) and stromal compartments (sTILs). Patient cases of TNBC from E2197 and E1199 were randomly selected based on availability of sections. For the primary end point of DFS, association with TIL scores was determined by fitting proportional hazards models stratified on study. Secondary end points were OS and distant recurrence–free interval (DRFI). Reporting recommendations for tumor marker prognostic studies criteria were followed, and all analyses were prespecified. The majority of 481 evaluable cancers had TILs (sTILs, 80%; iTILs, 15%). With a median follow-up of 10.6 years, higher sTIL scores were associated with better prognosis; for every 10% increase in sTILs, a 14% reduction of risk of recurrence or death (P = .02), 18% reduction of risk of distant recurrence (P = .04), and 19% reduction of risk of death (P = .01) were observed. Multivariable analysis confirmed sTILs to be an independent prognostic marker of DFS, DRFI, and OS. In two national randomized clinical trials using contemporary adjuvant chemotherapy, we confirm that stromal lymphocytic infiltration constitutes a robust prognostic factor in TNBCs. Studies assessing outcomes and therapeutic efficacies should consider stratification for this parameter.
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            Cancer immunotherapy: the beginning of the end of cancer?

            These are exciting times for cancer immunotherapy. After many years of disappointing results, the tide has finally changed and immunotherapy has become a clinically validated treatment for many cancers. Immunotherapeutic strategies include cancer vaccines, oncolytic viruses, adoptive transfer of ex vivo activated T and natural killer cells, and administration of antibodies or recombinant proteins that either costimulate cells or block the so-called immune checkpoint pathways. The recent success of several immunotherapeutic regimes, such as monoclonal antibody blocking of cytotoxic T lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD1), has boosted the development of this treatment modality, with the consequence that new therapeutic targets and schemes which combine various immunological agents are now being described at a breathtaking pace. In this review, we outline some of the main strategies in cancer immunotherapy (cancer vaccines, adoptive cellular immunotherapy, immune checkpoint blockade, and oncolytic viruses) and discuss the progress in the synergistic design of immune-targeting combination therapies.
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              Cancer cells induce metastasis-supporting neutrophil extracellular DNA traps.

              Neutrophils, the most abundant type of leukocytes in blood, can form neutrophil extracellular traps (NETs). These are pathogen-trapping structures generated by expulsion of the neutrophil's DNA with associated proteolytic enzymes. NETs produced by infection can promote cancer metastasis. We show that metastatic breast cancer cells can induce neutrophils to form metastasis-supporting NETs in the absence of infection. Using intravital imaging, we observed NET-like structures around metastatic 4T1 cancer cells that had reached the lungs of mice. We also found NETs in clinical samples of triple-negative human breast cancer. The formation of NETs stimulated the invasion and migration of breast cancer cells in vitro. Inhibiting NET formation or digesting NETs with deoxyribonuclease I (DNase I) blocked these processes. Treatment with NET-digesting, DNase I-coated nanoparticles markedly reduced lung metastases in mice. Our data suggest that induction of NETs by cancer cells is a previously unidentified metastasis-promoting tumor-host interaction and a potential therapeutic target.
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                Author and article information

                Contributors
                Journal
                Front Oncol
                Front Oncol
                Front. Oncol.
                Frontiers in Oncology
                Frontiers Media S.A.
                2234-943X
                30 June 2020
                2020
                : 10
                : 1022
                Affiliations
                [1] 1Department of Anatomy and Structural Biology, Montefiore Medical Center, Einstein College of Medicine , Bronx, NY, United States
                [2] 2Integrated Imaging Program, Montefiore Medical Center, Einstein College of Medicine , Bronx, NY, United States
                [3] 3Department of Surgery, Montefiore Medical Center, Einstein College of Medicine , Bronx, NY, United States
                [4] 4Gruss-Lipper Biophotonics Center, Montefiore Medical Center, Einstein College of Medicine , Bronx, NY, United States
                [5] 5Department of Medicine (Oncology), Montefiore Medical Center, Einstein College of Medicine , Bronx, NY, United States
                [6] 6School of Health & Life Sciences, Teesside University , Middlesbrough, United Kingdom
                [7] 7National Horizons Centre, Teesside University , Darlington, United Kingdom
                [8] 8Department of Pathology, Montefiore Medical Center, Einstein College of Medicine , Bronx, NY, United States
                Author notes

                Edited by: Cesar Augusto Santa-Maria, Johns Hopkins Medicine, United States

                Reviewed by: Prashant Trikha, Nationwide Children's Hospital, United States; Daniel Christian Hoessli, University of Karachi, Pakistan

                *Correspondence: Maja H. Oktay maja.oktay@ 123456einsteinmed.org

                This article was submitted to Molecular and Cellular Oncology, a section of the journal Frontiers in Oncology

                Article
                10.3389/fonc.2020.01022
                7344193
                32714862
                6a148a2b-ce42-4a33-b4e8-d268e94fe3d3
                Copyright © 2020 Kim, Pastoriza, Condeelis, Sparano, Filippou, Karagiannis and Oktay.

                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
                : 11 March 2020
                : 22 May 2020
                Page count
                Figures: 1, Tables: 2, Equations: 0, References: 126, Pages: 11, Words: 9640
                Categories
                Oncology
                Review

                Oncology & Radiotherapy
                breast cancer,tumor microenvironment,breast cancer racial disparity,breast cancer outcome,tumor microenvironment of metastasis (tmem)

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