{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T20:27:42Z","timestamp":1792787262225,"version":"4.5.0"},"reference-count":50,"publisher":"BMJ","issue":"2","license":[{"start":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T00:00:00Z","timestamp":1789948800000},"content-version":"unspecified","delay-in-days":82,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100001299","name":"Prevent Cancer Foundation","doi-asserted-by":"publisher","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}],"id":[{"id":"10.13039\/100001299","id-type":"DOI","asserted-by":"publisher"}]},{"name":"American Institute for Cancer Research","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}],"id":[{"id":"https:\/\/ror.org\/03b3akj74","id-type":"ROR","asserted-by":"crossref"}]},{"name":"Cancer Research","award":["C10674\/A27140"],"award-info":[{"award-number":["C10674\/A27140"]}]},{"DOI":"10.13039\/100008732","name":"Uehara Memorial Foundation","doi-asserted-by":"publisher","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}],"id":[{"id":"10.13039\/100008732","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Harvey V. 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Patients with colon and rectal adenocarcinomas were included.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Interventions<\/jats:title>\n                    <jats:p>Not applicable.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Main outcome measures<\/jats:title>\n                    <jats:p>\n                      In situ single-cell multispectral immunofluorescence combined with computational machine learning for CD3, CD8, CD274 (PD-L1), HAVCR2 (TIM-3), PDCD1 (PD-1) and KRT (keratin) was used to characterise non-exhausted, progenitor-exhausted and exhausted CD3\n                      <jats:sup>+<\/jats:sup>\n                      CD8\n                      <jats:sup>+<\/jats:sup>\n                      cells according to PDCD1 (PD-1) and HAVCR2 (TIM-3) expression. Primary measures included densities of CD3\n                      <jats:sup>+<\/jats:sup>\n                      CD8\n                      <jats:sup>+<\/jats:sup>\n                      cell exhaustion subsets and their associations with clinicopathological characteristics, age at CRC diagnosis, selected tumour tissue bacteria, CRC-specific mortality and spatial proximity to tumour cells.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Younger age of CRC diagnosis generally correlated with lower densities of CD3\n                      <jats:sup>+<\/jats:sup>\n                      CD8\n                      <jats:sup>+<\/jats:sup>\n                      cells. Multivariable-adjusted ORs (with 95% CI) in age &lt;55 (vs age \u226570) for overall, progenitor-exhausted and exhausted CD3\n                      <jats:sup>+<\/jats:sup>\n                      CD8\n                      <jats:sup>+<\/jats:sup>\n                      cell stromal densities (all quartiles) were 0.39 (0.22 to 0.69; P\n                      <jats:sub>trend<\/jats:sub>\n                      =0.0033), 0.40 (0.23 to 0.68; P\n                      <jats:sub>trend<\/jats:sub>\n                      =0.0048) and 0.44 (0.25 to 0.78; P\n                      <jats:sub>trend<\/jats:sub>\n                      =0.0082), respectively. Multivariable-adjusted ORs (with 95%\u2009CI) for stromal non-exhausted CD3\n                      <jats:sup>+<\/jats:sup>\n                      CD8\n                      <jats:sup>+<\/jats:sup>\n                      cells (quartiles) were 0.81 (0.56 to 1.17)\u2009and 0.52 (0.37 to 0.74) (P\n                      <jats:sub>trend<\/jats:sub>\n                      =0.0004) for low-level and high-level\n                      <jats:italic>Bacteroides fragilis<\/jats:italic>\n                      (vs negativity), respectively. Multivariable-adjusted ORs for stromal exhausted CD3\n                      <jats:sup>+<\/jats:sup>\n                      CD8\n                      <jats:sup>+<\/jats:sup>\n                      cells (quartiles) were 0.37 (0.19 to 0.72)\u2009and 0.60 (0.30 to 1.17) (P\n                      <jats:sub>trend<\/jats:sub>\n                      =0.0081) for low-level and high-level enterotoxigenic\n                      <jats:italic>Bacteroides fragilis<\/jats:italic>\n                      (vs negativity), respectively. Multivariable-adjusted CRC-specific mortality HRs (with 95%\u2009CI) in quartile 4 (Q4; vs Q1) of progenitor-exhausted CD3\n                      <jats:sup>+<\/jats:sup>\n                      CD8\n                      <jats:sup>+<\/jats:sup>\n                      cells in the intraepithelial region and their proximity to tumour cells were 0.42 (0.26 to 0.67; P\n                      <jats:sub>trend<\/jats:sub>\n                      &lt;0.0001) and 0.50 (0.32 to 0.78; P\n                      <jats:sub>trend<\/jats:sub>\n                      =0.0004), respectively.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      This PCIBM-based study provides evidence that progenitor-exhausted CD3\n                      <jats:sup>+<\/jats:sup>\n                      CD8\n                      <jats:sup>+<\/jats:sup>\n                      cell density and their proximity to tumour cells are favourable prognostic biomarkers in CRC. Moreover, lower stromal densities of overall, progenitor-exhausted and exhausted CD3\n                      <jats:sup>+<\/jats:sup>\n                      CD8\n                      <jats:sup>+<\/jats:sup>\n                      cells are associated with younger-onset CRC.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/bmjonc-2026-001159","type":"journal-article","created":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T14:12:29Z","timestamp":1789999949000},"page":"e001159","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":0,"title":["Cytotoxic T-cell exhaustion analyses by in situ single-cell immunofluorescence in relation to colorectal cancer patient age, tissue bacteria and mortality"],"prefix":"10.1136","volume":"5","clinical-trial-number":[{"clinical-trial-number":"nct00005182","registry":"10.18810\/clinical-trials-gov"}],"author":[{"given":"Nobuhiro","family":"Nakazawa","sequence":"first","affiliation":[{"name":"Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women\u2019s Hospital, Boston, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kosuke","family":"Matsuda","sequence":"additional","affiliation":[{"name":"Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women\u2019s Hospital, Boston, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Satoko","family":"Ugai","sequence":"additional","affiliation":[{"name":"Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women\u2019s Hospital, Boston, Massachusetts, USA"},{"name":"Department of Epidemiology, Harvard T.H. 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