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      Tumor‐infiltrating M2 macrophage in pretreatment biopsy sample predicts response to chemotherapy and survival in esophageal cancer

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          Abstract

          The association between the tumor microenvironment (TME) and treatment response or survival has been a recent focus in several types of cancer. However, most study materials are resected specimens that were completely modified by prior chemotherapy; therefore, the unmodified host immune condition has not yet been clarified. The aim of the present study was to evaluate the relationship between TME assessed in pre–therapeutic biopsy samples and chemoresistance in esophageal cancer (EC). A total of 86 endoscopic biopsy samples from EC patients who received neoadjuvant chemotherapy (NAC) prior to surgery were evaluated for the number of intratumoral CD4 + lymphocytes (with/without Foxp3 expression), CD8 + lymphocytes (with/without PD‐1 expression), monocytes (CD14 +) and macrophages (CD86 +, CD163 + and CD206 +) by multiplex immunohistochemistry (IHC). The number of tumor‐infiltrating CD206 + macrophages I significantly correlated with cT, cM, cStage and neutrophil/lymphocyte ratio (NLR), whereas the number of lymphocytes (including expression of Foxp3 and PD‐1) was not associated with clinico‐pathological features. The high infiltration of CD163 + or CD206 + macrophages was significantly associated with poor pathological response to NAC ( P = 0.0057 and 0.0196, respectively). Expression of arginase‐1 in CD163 + macrophages tended to be higher in non–responders (29.4% vs 18.2%, P = 0.17). In addition, patients with high infiltration of M2 macrophages exhibited unfavorable overall survival compared to those without high infiltration of M2 macrophages (5‐year overall survival 57.2% vs 71.0%, P = 0.0498). Thus, a comprehensive analysis of TME using multiplex IHC revealed that M2 macrophage infiltration would be useful in predicting the response to NAC and long‐term survival in EC patients.

          Abstract

          The present study confirmed that pre–therapeutic M2 macrophage infiltration would be a useful biomarker in predicting the response to NAC and unfavorable survival among a variety of immune cells in EC patients. Our results support the possibility of using immunotherapy, targeting M2 macrophages, alongside conventional neoadjuvant chemotherapy.

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          Most cited references24

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          Leukocyte complexity predicts breast cancer survival and functionally regulates response to chemotherapy.

          Immune-regulated pathways influence multiple aspects of cancer development. In this article we demonstrate that both macrophage abundance and T-cell abundance in breast cancer represent prognostic indicators for recurrence-free and overall survival. We provide evidence that response to chemotherapy is in part regulated by these leukocytes; cytotoxic therapies induce mammary epithelial cells to produce monocyte/macrophage recruitment factors, including colony stimulating factor 1 (CSF1) and interleukin-34, which together enhance CSF1 receptor (CSF1R)-dependent macrophage infiltration. Blockade of macrophage recruitment with CSF1R-signaling antagonists, in combination with paclitaxel, improved survival of mammary tumor-bearing mice by slowing primary tumor development and reducing pulmonary metastasis. These improved aspects of mammary carcinogenesis were accompanied by decreased vessel density and appearance of antitumor immune programs fostering tumor suppression in a CD8+ T-cell-dependent manner. These data provide a rationale for targeting macrophage recruitment/response pathways, notably CSF1R, in combination with cytotoxic therapy, and identification of a breast cancer population likely to benefit from this novel therapeutic approach. These findings reveal that response to chemotherapy is in part regulated by the tumor immune microenvironment and that common cytotoxic drugs induce neoplastic cells to produce monocyte/macrophage recruitment factors, which in turn enhance macrophage infiltration into mammary adenocarcinomas. Blockade of pathways mediating macrophage recruitment, in combination with chemotherapy, significantly decreases primary tumor progression, reduces metastasis, and improves survival by CD8+ T-cell-dependent mechanisms, thus indicating that the immune microenvironment of tumors can be reprogrammed to instead foster antitumor immunity and improve response to cytotoxic therapy.
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            Understanding the Mysterious M2 Macrophage through Activation Markers and Effector Mechanisms

            The alternatively activated or M2 macrophages are immune cells with high phenotypic heterogeneity and are governing functions at the interface of immunity, tissue homeostasis, metabolism, and endocrine signaling. Today the M2 macrophages are identified based on the expression pattern of a set of M2 markers. These markers are transmembrane glycoproteins, scavenger receptors, enzymes, growth factors, hormones, cytokines, and cytokine receptors with diverse and often yet unexplored functions. This review discusses whether these M2 markers can be reliably used to identify M2 macrophages and define their functional subdivisions. Also, it provides an update on the novel signals of the tissue environment and the neuroendocrine system which shape the M2 activation. The possible evolutionary roots of the M2 macrophage functions are also discussed.
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              A randomized trial comparing postoperative adjuvant chemotherapy with cisplatin and 5-fluorouracil versus preoperative chemotherapy for localized advanced squamous cell carcinoma of the thoracic esophagus (JCOG9907).

              Patients with esophageal carcinoma receiving postoperative chemotherapy showed superior disease-free survival than those receiving surgery alone in a Japan Clinical Oncology Group trial (JCOG9204). The purpose of this study was to evaluate optimal perioperative timing-that is, before or after surgery-for providing chemotherapy in patients with locally advanced esophageal squamous cell carcinoma. Eligible patients with clinical stage II or III, excluding T4, squamous cell carcinoma were randomized to undergo surgery followed (group 1) or preceded (group 2) by chemotherapy consisting of two courses of cisplatin plus 5-fluorouracil. The primary end point was progression-free survival. We randomized 330 patients, with 166 assigned to group 1 and 164 to group 2, between May 2000 and May 2006. The planned interim analysis was conducted after completion of patient accrual. Progression-free survival did not reach the stopping boundary, but overall survival in group 2 was superior to that of group 1 (P = 0.01). Therefore, the Data and Safety Monitoring Committee recommended early publication. Updated analyses showed the 5-year overall survival to be 43% in group 1 and 55% in group 2 (hazard ratio 0.73, 95% confidence interval 0.54-0.99, P = 0.04), where the median follow-up of censored patients was 61.6 months. Concerning operative morbidity, renal dysfunction after surgery in group 2 was slightly higher than in group 1. Preoperative chemotherapy with cisplatin plus 5-fluorouracil can be regarded as standard treatment for patients with stage II/III squamous cell carcinoma.
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                Author and article information

                Contributors
                tmakino@gesurg.med.osaka-u.ac.jp
                Journal
                Cancer Sci
                Cancer Sci
                10.1111/(ISSN)1349-7006
                CAS
                Cancer Science
                John Wiley and Sons Inc. (Hoboken )
                1347-9032
                1349-7006
                18 February 2020
                April 2020
                : 111
                : 4 ( doiID: 10.1111/cas.v111.4 )
                : 1103-1112
                Affiliations
                [ 1 ] Department of Gastroenterological Surgery Graduate School of Medicine Osaka University Osaka Japan
                [ 2 ] Department of Clinical Research in Tumor Immunology Osaka University Graduate School of Medicine Osaka Japan
                [ 3 ] Department of Pathology Institute of Medical Science (Medical Research Center) Tokyo Medical University Tokyo Japan
                [ 4 ] Department of Surgery and Science Graduate School of Medical Sciences Kyushu University Fukuoka Japan
                Author notes
                [*] [* ] Correspondence

                Tomoki Makino, Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, 2‐2‐E2, Yamada‐oka, Suita, Osaka 565‐0871, Japan.

                Email: tmakino@ 123456gesurg.med.osaka-u.ac.jp

                Author information
                https://orcid.org/0000-0001-7918-4217
                Article
                CAS14328
                10.1111/cas.14328
                7156837
                31981293
                2205f690-a621-4df0-945a-e363fcf4c1e5
                © 2020 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

                History
                : 18 November 2019
                : 08 January 2020
                : 16 January 2020
                Page count
                Figures: 4, Tables: 2, Pages: 10, Words: 5952
                Categories
                Original Article
                Original Articles
                Basic and Clinical Immunology
                Custom metadata
                2.0
                April 2020
                Converter:WILEY_ML3GV2_TO_JATSPMC version:5.8.0 mode:remove_FC converted:15.04.2020

                Oncology & Radiotherapy
                biopsy,esophageal cancer,m2 macrophage,multiplex immunohistochemistry,neoadjuvant chemotherapy

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