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play an important role in lung carcinogenesis. We investigated the associations for circulating levels of tryptophan, kynurenine, kynurenine:tryptophan ratio (KTR), quinolinic acid (QA) and neopterin as markers of immune regulation and inflammation with lung cancer risk in 5,364 smoking\u2010matched case\u2013control pairs from 20 prospective cohorts included in the international Lung Cancer Cohort Consortium. All biomarkers were quantified by mass spectrometry\u2010based methods in serum\/plasma samples collected on average 6 years before lung cancer diagnosis. Odds ratios (ORs) and 95% confidence intervals (CIs) for lung cancer associated with individual biomarkers were calculated using conditional logistic regression with adjustment for circulating cotinine. Compared to the lowest quintile, the highest quintiles of kynurenine, KTR, QA and neopterin were associated with a 20\u201330% higher risk, and tryptophan with a 15% lower risk of lung cancer (all <jats:italic>p<\/jats:italic><jats:sub>trend<\/jats:sub> &lt; 0.05). The strongest associations were seen for current smokers, where the adjusted ORs (95% CIs) of lung cancer for the highest quintile of KTR, QA and neopterin were 1.42 (1.15\u20131.75), 1.42 (1.14\u20131.76) and 1.45 (1.13\u20131.86), respectively. A stronger association was also seen for KTR and QA with risk of lung squamous cell carcinoma followed by adenocarcinoma, and for lung cancer diagnosed within the first 2 years after blood draw. This study demonstrated that components of the tryptophan\u2013kynurenine pathway with immunomodulatory effects are associated with risk of lung cancer overall, especially for current smokers. Further research is needed to evaluate the role of these biomarkers in lung carcinogenesis and progression.<\/jats:p>","DOI":"10.1002\/ijc.32555","type":"journal-article","created":{"date-parts":[[2019,7,5]],"date-time":"2019-07-05T15:58:06Z","timestamp":1562342286000},"page":"2394-2405","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["Circulating markers of cellular immune activation in prediagnostic blood sample and lung cancer risk in the Lung Cancer Cohort Consortium (LC3)"],"prefix":"10.1002","volume":"146","author":[{"given":"Joyce Y.","family":"Huang","sequence":"first","affiliation":[{"name":"Division of Cancer Control and Population Sciences, UPMC Hillman Cancer Center University of Pittsburgh  Pittsburgh PA"},{"name":"Department of Epidemiology Graduate School of Public Health, University of Pittsburgh  Pittsburgh PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tricia L.","family":"Larose","sequence":"additional","affiliation":[{"name":"Genetic Epidemiology Group, International Agency for Research on Cancer  Lyon France"},{"name":"K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health &amp; Nursing, Faculty of Medicine and Health Sciences Norwegian University of Science and Technology  Trondheim Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2172-1849","authenticated-orcid":false,"given":"Hung N.","family":"Luu","sequence":"additional","affiliation":[{"name":"Division of Cancer Control and Population Sciences, UPMC Hillman Cancer Center University of Pittsburgh  Pittsburgh PA"},{"name":"Department of Epidemiology Graduate School of Public Health, University of Pittsburgh  Pittsburgh PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Renwei","family":"Wang","sequence":"additional","affiliation":[{"name":"Division of Cancer Control and Population Sciences, UPMC Hillman Cancer Center University of Pittsburgh  Pittsburgh PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anouar","family":"Fanidi","sequence":"additional","affiliation":[{"name":"Genetic Epidemiology Group, International Agency for Research on Cancer  Lyon France"},{"name":"MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine  Cambridge United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karine","family":"Alcala","sequence":"additional","affiliation":[{"name":"Genetic Epidemiology Group, International Agency for Research on Cancer  Lyon France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victoria L.","family":"Stevens","sequence":"additional","affiliation":[{"name":"Behavior and Epidemiology Research Group American Cancer Society, Inc.  Atlanta GA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephanie J.","family":"Weinstein","sequence":"additional","affiliation":[{"name":"Division of Cancer Epidemiology and Genetics National Cancer Institute, NIH  Rockville MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Demetrius","family":"Albanes","sequence":"additional","affiliation":[{"name":"Division of Cancer Epidemiology and Genetics National Cancer Institute, NIH  Rockville MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neil E.","family":"Caporaso","sequence":"additional","affiliation":[{"name":"Division of Cancer Epidemiology and Genetics National Cancer Institute, NIH  Rockville MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1177-3108","authenticated-orcid":false,"given":"Mark P.","family":"Purdue","sequence":"additional","affiliation":[{"name":"Division of Cancer Epidemiology and Genetics National Cancer Institute, NIH  Rockville MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Regina G.","family":"Ziegler","sequence":"additional","affiliation":[{"name":"Division of Cancer Epidemiology and Genetics National Cancer Institute, NIH  Rockville MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neal D.","family":"Freedman","sequence":"additional","affiliation":[{"name":"Division of Cancer Epidemiology and Genetics National Cancer Institute, NIH  Rockville MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qing","family":"Lan","sequence":"additional","affiliation":[{"name":"Division of Cancer Epidemiology and Genetics National Cancer Institute, NIH  Rockville MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ross L.","family":"Prentice","sequence":"additional","affiliation":[{"name":"Division of Public Health Sciences, Fred Hutchinson Cancer Research Center  Seattle WA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mary","family":"Pettinger","sequence":"additional","affiliation":[{"name":"Division of Public Health Sciences, Fred Hutchinson Cancer Research Center  Seattle WA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cynthia A.","family":"Thomson","sequence":"additional","affiliation":[{"name":"Department of Health Promotion Science Mel &amp; Enid Zuckerman College of Public Health, University of Arizona  Tucson AZ"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiuyin","family":"Cai","sequence":"additional","affiliation":[{"name":"Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center and Vanderbilt\u2010Ingram Cancer Center Vanderbilt University School of Medicine  Nashville TN"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Wu","sequence":"additional","affiliation":[{"name":"Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center and Vanderbilt\u2010Ingram Cancer Center Vanderbilt University School of Medicine  Nashville TN"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William J.","family":"Blot","sequence":"additional","affiliation":[{"name":"Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center and Vanderbilt\u2010Ingram Cancer Center Vanderbilt University School of Medicine  Nashville TN"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0711-8314","authenticated-orcid":false,"given":"Xiao\u2010Ou","family":"Shu","sequence":"additional","affiliation":[{"name":"Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center and Vanderbilt\u2010Ingram Cancer Center Vanderbilt University School of Medicine  Nashville TN"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1226-070X","authenticated-orcid":false,"given":"Wei","family":"Zheng","sequence":"additional","affiliation":[{"name":"Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center and Vanderbilt\u2010Ingram Cancer Center Vanderbilt University School of Medicine  Nashville TN"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alan A.","family":"Arslan","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Population Health, Environmental Medicine and Perlmutter Cancer Center New York University School of Medicine  New York NY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne","family":"Zeleniuch\u2010Jacquotte","sequence":"additional","affiliation":[{"name":"Department of Population Health and Environmental Medicine and Perlmutter Cancer Centre New York University School of Medicine  New York NY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lo\u00efc","family":"Le Marchand","sequence":"additional","affiliation":[{"name":"Epidemiology Program, University of Hawaii Cancer Center  Honolulu HI"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lynn R.","family":"Wilkens","sequence":"additional","affiliation":[{"name":"Epidemiology Program, University of Hawaii Cancer Center  Honolulu HI"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher A.","family":"Haiman","sequence":"additional","affiliation":[{"name":"Department of Prevention, Keck School of Medicine University of Southern California  Los Angeles CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8260-8508","authenticated-orcid":false,"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 MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meir J.","family":"Stampfer","sequence":"additional","affiliation":[{"name":"Channing Division of Network Medicine, Department of Medicine Brigham and Women's Hospital and Harvard Medical School  Boston MA"},{"name":"Department of Epidemiology Harvard T. 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