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Cancer"],"accepted":{"date-parts":[[2021,3,18]]},"published-print":{"date-parts":[[2021,4]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Myeloid cells represent an abundant yet heterogeneous cell population in the colorectal cancer microenvironment, and their roles remain poorly understood.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We used multiplexed immunofluorescence combined with digital image analysis to identify CD14\n                      <jats:sup>+<\/jats:sup>\n                      monocytic and CD15\n                      <jats:sup>+<\/jats:sup>\n                      granulocytic cells and to evaluate their maturity (HLA-DR and CD33), immunosuppressive potential (ARG1) and proximity to cytokeratin (KRT)-positive tumor cells in 913 colorectal carcinomas. Using covariate data of 4465 incident colorectal cancers in two prospective cohort studies, the inverse probability weighting method was used with multivariable-adjusted Cox proportional hazards models to assess cancer-specific mortality according to ordinal quartiles (Q1\u2013Q4) of myeloid cell densities. Immune cell\u2013tumor cell proximity was measured with the nearest neighbor method and the G-cross function, which determines the likelihood of any tumor cell having at least one immune cell of the specified type within a certain radius.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Higher intraepithelial (\n                      <jats:italic>P<\/jats:italic>\n                      <jats:sub>trend<\/jats:sub>\n                      =0.0002; HR for Q4 (vs Q1), 0.48, 95%\u2009CI 0.31 to 0.76) and stromal (\n                      <jats:italic>P<\/jats:italic>\n                      <jats:sub>trend<\/jats:sub>\n                      &lt;0.0001; HR for Q4 (vs Q1), 0.42, 95%\u2009CI 0.29 to 0.63) densities of CD14\n                      <jats:sup>+<\/jats:sup>\n                      HLA-DR\n                      <jats:sup>+<\/jats:sup>\n                      cells were associated with lower colorectal cancer-specific mortality while, conversely, higher intraepithelial densities of CD14\n                      <jats:sup>+<\/jats:sup>\n                      HLA-DR\n                      <jats:sup>\u2212<\/jats:sup>\n                      cells were associated with higher colorectal cancer-specific mortality (\n                      <jats:italic>P<\/jats:italic>\n                      <jats:sub>trend<\/jats:sub>\n                      =0.0003; HR for Q4 (vs Q1), 1.78, 95%\u2009CI 1.25 to 2.55). Spatial analyses indicated that CD15\n                      <jats:sup>+<\/jats:sup>\n                      cells were located closer to tumor cells than CD14\n                      <jats:sup>+<\/jats:sup>\n                      cells, and CD14\n                      <jats:sup>+<\/jats:sup>\n                      HLA-DR\n                      <jats:sup>+<\/jats:sup>\n                      cells were closer to tumor than CD14\n                      <jats:sup>+<\/jats:sup>\n                      HLA-DR\n                      <jats:sup>\u2212<\/jats:sup>\n                      cells (p&lt;0.0001). The G-cross proximity measurement, evaluating the difference in the likelihood of any tumor cell being colocated with at least one CD14\n                      <jats:sup>+<\/jats:sup>\n                      HLA-DR\n                      <jats:sup>+<\/jats:sup>\n                      cell versus CD14\n                      <jats:sup>+<\/jats:sup>\n                      HLA-DR\n                      <jats:sup>\u2212<\/jats:sup>\n                      cell within a 20\u2009\u00b5m radius, was associated with lower colorectal cancer-specific mortality (\n                      <jats:italic>P<\/jats:italic>\n                      <jats:sub>trend<\/jats:sub>\n                      &lt;0.0001; HR for Q4 (vs Q1), 0.37, 95%\u2009CI 0.24 to 0.57).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      Myeloid cell populations occur in spatially distinct distributions and exhibit divergent, subset-specific prognostic significance in colorectal cancer, with mature CD14\n                      <jats:sup>+<\/jats:sup>\n                      HLA-DR\n                      <jats:sup>+<\/jats:sup>\n                      and immature CD14\n                      <jats:sup>+<\/jats:sup>\n                      HLA-DR\n                      <jats:sup>\u2212<\/jats:sup>\n                      monocytic phenotypes most notably showing opposite associations. These results highlight the prognostic utility of multimarker evaluation of myeloid cell infiltrates and reveal a previously unrecognized degree of spatial organization for myeloid cells in the immune microenvironment.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/jitc-2020-002297","type":"journal-article","created":{"date-parts":[[2021,4,30]],"date-time":"2021-04-30T11:24:30Z","timestamp":1619781870000},"page":"e002297","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":42,"title":["Prognostic significance of myeloid immune cells and their spatial distribution in the colorectal cancer microenvironment"],"prefix":"10.1136","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8683-2996","authenticated-orcid":false,"given":"Juha P","family":"V\u00e4yrynen","sequence":"first","affiliation":[{"name":"Cancer and Translational Medicine Research Unit, Medical Research Center Oulu, Oulu University Hospital, and University of Oulu, Oulu, Finland"},{"name":"Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, USA"},{"name":"Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Koichiro","family":"Haruki","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, USA"},{"name":"Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA"},{"name":"Department of Surgery, Jikei University School of Medicine, Tokyo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara A","family":"V\u00e4yrynen","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mai Chan","family":"Lau","sequence":"additional","affiliation":[{"name":"Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andressa","family":"Dias Costa","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer","family":"Borowsky","sequence":"additional","affiliation":[{"name":"Conjoint Gastroenterology Department, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melissa","family":"Zhao","sequence":"additional","affiliation":[{"name":"Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomotaka","family":"Ugai","sequence":"additional","affiliation":[{"name":"Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA"},{"name":"Department of Epidemiology, Harvard University T.H. Chan School of Public Health, Boston, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junko","family":"Kishikawa","sequence":"additional","affiliation":[{"name":"Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naohiko","family":"Akimoto","sequence":"additional","affiliation":[{"name":"Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rong","family":"Zhong","sequence":"additional","affiliation":[{"name":"Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shanshan","family":"Shi","sequence":"additional","affiliation":[{"name":"Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tzuu-Wang","family":"Chang","sequence":"additional","affiliation":[{"name":"Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenji","family":"Fujiyoshi","sequence":"additional","affiliation":[{"name":"Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kota","family":"Arima","sequence":"additional","affiliation":[{"name":"Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tyler S","family":"Twombly","sequence":"additional","affiliation":[{"name":"Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annacarolina","family":"Da Silva","sequence":"additional","affiliation":[{"name":"Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingyang","family":"Song","sequence":"additional","affiliation":[{"name":"Department of Nutrition, Harvard University T.H. Chan School of Public Health, Boston, Massachusetts, USA"},{"name":"Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA"},{"name":"Division of Gastroenterology, Massachusetts General Hospital, Boston, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kana","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Epidemiology, Harvard University T.H. Chan School of Public Health, Boston, Massachusetts, USA"},{"name":"Department of Nutrition, Harvard University T.H. Chan School of Public Health, Boston, Massachusetts, USA"},{"name":"Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuehong","family":"Zhang","sequence":"additional","affiliation":[{"name":"Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew T","family":"Chan","sequence":"additional","affiliation":[{"name":"Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA"},{"name":"Division of Gastroenterology, Massachusetts General Hospital, Boston, Massachusetts, USA"},{"name":"Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA"},{"name":"Department of Immunology and Infectious Diseases, Harvard University T.H. 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