{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T07:01:41Z","timestamp":1791615701480,"version":"4.3.4"},"reference-count":43,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2021,4,22]],"date-time":"2021-04-22T00:00:00Z","timestamp":1619049600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004486","name":"Fondazione Cassa di Risparmio di Perugia","doi-asserted-by":"publisher","award":["2315\/16"],"award-info":[{"award-number":["2315\/16"]}],"id":[{"id":"10.13039\/501100004486","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The enzyme indoleamine 2,3-dioxygenase 1 (IDO1) degrade tryptophan (Trp) into kynurenine (Kyn) at the initial step of an enzymatic pathway affecting T cell proliferation. IDO1 is highly expressed in various cancer types and associated with poor prognosis. Nevertheless, the serum Kyn\/Trp concentration ratio has been suggested as a marker of cancer-associated immune suppression. We measured Kyn and Trp in blood samples of a wide cohort of non-small-cell lung cancer (NSCLC) patients, before they underwent surgery, and analyzed possible correlations of the Kyn\/Trp ratio with either IDO1 expression or clinical\u2013pathological parameters. Low Kyn\/Trp significantly correlated with low IDO1 expression and never-smoker patients; while high Kyn\/Trp was significantly associated with older (\u226568 years) patients, advanced tumor stage, and squamous cell carcinoma (Sqcc), rather than the adenocarcinoma (Adc) histotype. Moreover, high Kyn\/Trp was associated, among the Adc group, with higher tumor stages (II and III), and, among the Sqcc group, with a high density of tumor-infiltrating lymphocytes. A trend correlating the high Kyn\/Trp ratio with the probability of recurrences from NSCLC was also found. In conclusion, high serum Kyn\/Trp ratio, associated with clinical and histopathological parameters, may serve as a serum biomarker to optimize risk stratification and therapy of NSCLC patients.<\/jats:p>","DOI":"10.3390\/ijms22094403","type":"journal-article","created":{"date-parts":[[2021,4,22]],"date-time":"2021-04-22T13:59:14Z","timestamp":1619099954000},"page":"4403","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":63,"title":["Kynurenine\/Tryptophan Ratio as a Potential Blood-Based Biomarker in Non-Small Cell Lung Cancer"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5019-4825","authenticated-orcid":false,"given":"Martina","family":"Mandarano","sequence":"first","affiliation":[{"name":"Section of Anatomic Pathology and Histology, Department of Medicine and Surgery, University of Perugia, 06129 Perugia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Orecchini","sequence":"additional","affiliation":[{"name":"Section of Pharmacology, Department of Medicine and Surgery, University of Perugia, 06129 Perugia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guido","family":"Bellezza","sequence":"additional","affiliation":[{"name":"Section of Anatomic Pathology and Histology, Department of Medicine and Surgery, University of Perugia, 06129 Perugia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacopo","family":"Vannucci","sequence":"additional","affiliation":[{"name":"Section of Thoracic Surgery, Department of Medicine and Surgery, University of Perugia, 06129 Perugia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2524-5824","authenticated-orcid":false,"given":"Vienna","family":"Ludovini","sequence":"additional","affiliation":[{"name":"Medical Oncology Division, Santa Maria della Misericordia Hospital, 06132 Perugia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Baglivo","sequence":"additional","affiliation":[{"name":"Medical Oncology Division, Santa Maria della Misericordia Hospital, 06132 Perugia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca Romana","family":"Tofanetti","sequence":"additional","affiliation":[{"name":"Medical Oncology Division, Santa Maria della Misericordia Hospital, 06132 Perugia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rita","family":"Chiari","sequence":"additional","affiliation":[{"name":"Division of Medical Oncology, Ospedali Riuniti Padova Sud, 35043 Monselice, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisabetta","family":"Loreti","sequence":"additional","affiliation":[{"name":"Section of Anatomic Pathology and Histology, Department of Medicine and Surgery, University of Perugia, 06129 Perugia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesco","family":"Puma","sequence":"additional","affiliation":[{"name":"Section of Thoracic Surgery, Department of Medicine and Surgery, University of Perugia, 06129 Perugia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angelo","family":"Sidoni","sequence":"additional","affiliation":[{"name":"Section of Anatomic Pathology and Histology, Department of Medicine and Surgery, University of Perugia, 06129 Perugia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6522-0870","authenticated-orcid":false,"given":"Maria Laura","family":"Belladonna","sequence":"additional","affiliation":[{"name":"Section of Pharmacology, Department of Medicine and Surgery, University of Perugia, 06129 Perugia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,4,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Barta, J.A., Powell, C.A., and Wisnivesky, J.P. (2019). Global Epidemiology of Lung Cancer. Ann. Glob. Health, 85.","DOI":"10.5334\/aogh.2419"},{"key":"ref_2","unstructured":"Howlader, N., Noone, A.M., Krapcho, M., Miller, D., Brest, A., Yu, M., Ruhl, J., Tatalovich, Z., Mariotto, A., and Lewis, D.R. (2020). Cronin KA SEER Cancer Statistics Review, 1975\u20132017."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"321","DOI":"10.5858\/arpa.2017-0388-CP","article-title":"Updated Molecular Testing Guideline for the Selection of Lung Cancer Patients for Treatment With Targeted Tyrosine Kinase Inhibitors: Guideline From the College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology","volume":"142","author":"Lindeman","year":"2018","journal-title":"Arch. Pathol. Lab. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"iv192","DOI":"10.1093\/annonc\/mdy275","article-title":"Metastatic non-small cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up","volume":"29","author":"Planchard","year":"2018","journal-title":"Ann. Oncol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"e470","DOI":"10.1016\/S1470-2045(18)30455-8","article-title":"Will liquid biopsies improve outcomes for patients with small-cell lung cancer?","volume":"19","author":"Blackhall","year":"2018","journal-title":"Lancet Oncol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"3889","DOI":"10.1038\/onc.2008.35","article-title":"Immune escape as a fundamental trait of cancer: Focus on IDO","volume":"27","author":"Prendergast","year":"2008","journal-title":"Oncogene"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1038\/nrc2639","article-title":"Inhibitors of indoleamine-2,3-dioxygenase for cancer therapy: Can we see the wood for the trees?","volume":"9","author":"Rammensee","year":"2009","journal-title":"Nat. Rev. Cancer"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1016\/j.it.2012.10.001","article-title":"Indoleamine 2,3 dioxygenase and metabolic control of immune responses","volume":"34","author":"Munn","year":"2013","journal-title":"Trends Immunol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"531491","DOI":"10.3389\/fimmu.2020.531491","article-title":"IDO Expression in Cancer: Different Compartment, Different Functionality?","volume":"11","author":"Meireson","year":"2020","journal-title":"Front. Immunol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2394","DOI":"10.1002\/ijc.32555","article-title":"Circulating markers of cellular immune activation in prediagnostic blood sample and lung cancer risk in the Lung Cancer Cohort Consortium (LC3)","volume":"146","author":"Huang","year":"2020","journal-title":"Int. J. Cancer"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"687","DOI":"10.1158\/1078-0432.CCR-14-1860","article-title":"Immune escape mechanisms as a guide for cancer immunotherapy","volume":"21","author":"Beatty","year":"2015","journal-title":"Clin. Cancer Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"83","DOI":"10.2217\/imt-2016-0118","article-title":"Modulation of cancer-specific immune responses by amino acid degrading enzymes","volume":"9","author":"Timosenko","year":"2017","journal-title":"Immunotherapy"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1069","DOI":"10.1038\/sj.cdd.4401073","article-title":"T cell apoptosis by tryptophan catabolism","volume":"9","author":"Fallarino","year":"2002","journal-title":"Cell Death Differ."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2640","DOI":"10.1167\/iovs.10-5793","article-title":"3-Hydroxykynurenine Suppresses CD4+ T-Cell Proliferation, Induces T-Regulatory-Cell Development, and Prolongs Corneal Allograft Survival","volume":"52","author":"Zaher","year":"2011","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"151","DOI":"10.3389\/fimmu.2018.00151","article-title":"The Role of Indoleamine-2,3-Dioxygenase in Cancer Development, Diagnostics, and Therapy","volume":"9","author":"Dobos","year":"2018","journal-title":"Front. Immunol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1159\/000492849","article-title":"The Clinicopathological and Prognostic Significance of IDO1 Expression in Human Solid Tumors: Evidence from a Systematic Review and Meta-Analysis","volume":"49","author":"Yu","year":"2018","journal-title":"Cell Physiol. Biochem."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1111\/bju.15205","article-title":"Tryptophan-kynurenine ratio as a biomarker of bladder cancer","volume":"127","author":"Lee","year":"2021","journal-title":"BJU Int."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"4346","DOI":"10.1038\/s41467-019-12361-9","article-title":"Metabolomic adaptations and correlates of survival to immune checkpoint blockade","volume":"10","author":"Li","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1964","DOI":"10.1016\/j.jocn.2015.06.018","article-title":"The kynurenine to tryptophan ratio as a prognostic tool for glioblastoma patients enrolling in immunotherapy","volume":"22","author":"Zhai","year":"2015","journal-title":"J. Clin. Neurosci."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1243","DOI":"10.3389\/fimmu.2020.01243","article-title":"Tryptophan Catabolism as Immune Mechanism of Primary Resistance to Anti-PD-1","volume":"11","author":"Botticelli","year":"2020","journal-title":"Front. Immunol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1007\/s00428-018-2483-1","article-title":"Assessment of TILs, IDO-1, and PD-L1 in resected non-small cell lung cancer: An immunohistochemical study with clinicopathological and prognostic implications","volume":"474","author":"Mandarano","year":"2019","journal-title":"Virchows Arch."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"173921","DOI":"10.1016\/j.ejphar.2021.173921","article-title":"The footprint of kynurenine pathway in every cancer: A new target for chemotherapy","volume":"896","author":"Ala","year":"2021","journal-title":"Eur. J. Pharmacol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1016\/j.ejca.2017.01.011","article-title":"The rationale of indoleamine 2,3-dioxygenase inhibition for cancer therapy","volume":"76","author":"Brochez","year":"2017","journal-title":"Eur. J. Cancer"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1186\/s13046-021-01847-4","article-title":"What is the prospect of indoleamine 2,3-dioxygenase 1 inhibition in cancer? Extrapolation from the past","volume":"40","author":"Yao","year":"2021","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"3269","DOI":"10.1158\/1078-0432.CCR-16-2272","article-title":"First-in-Human Phase I Study of the Oral Inhibitor of Indoleamine 2,3-Dioxygenase-1 Epacadostat (INCB024360) in Patients with Advanced Solid Malignancies","volume":"23","author":"Beatty","year":"2017","journal-title":"Clin. Cancer Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1016\/j.lungcan.2009.05.001","article-title":"Increased serum kynurenine\/tryptophan ratio correlates with disease progression in lung cancer","volume":"67","author":"Suzuki","year":"2010","journal-title":"Lung Cancer"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1159\/000096906","article-title":"Decreased serum tryptophan concentration predicts poor prognosis in malignant melanoma patients","volume":"214","author":"Weinlich","year":"2007","journal-title":"Dermatology"},{"key":"ref_28","first-page":"1320","article-title":"Serum tryptophan and kynurenine concentrations as parameters for indoleamine 2,3-dioxygenase activity in patients with endometrial, ovarian, and vulvar cancer","volume":"21","author":"Nijman","year":"2011","journal-title":"Int. J. Gynecol. Cancer"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2565","DOI":"10.3389\/fimmu.2019.02565","article-title":"Tryptophan Metabolism in Inflammaging: From Biomarker to Therapeutic Target","volume":"10","author":"Sorgdrager","year":"2019","journal-title":"Front. Immunol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1016\/j.mad.2015.03.006","article-title":"MARK-AGE biomarkers of ageing","volume":"151","author":"Bernhard","year":"2015","journal-title":"Mech. Ageing Dev."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"469","DOI":"10.1111\/j.1365-2249.2006.03166.x","article-title":"The activity of the immunoregulatory enzyme indoleamine 2,3-dioxygenase is decreased in smokers","volume":"145","author":"Pertovaara","year":"2006","journal-title":"Clin. Exp. Immunol."},{"key":"ref_32","first-page":"171","article-title":"The Positive Relationship Between \u03b3H2AX and PD-L1 Expression in Lung Squamous Cell Carcinoma","volume":"32","author":"Osoegawa","year":"2018","journal-title":"In Vivo"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"5435","DOI":"10.1158\/0008-5472.CAN-12-0569","article-title":"Tryptophan catabolism in cancer: Beyond IDO and tryptophan depletion","volume":"72","author":"Platten","year":"2012","journal-title":"Cancer Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"e981457","DOI":"10.4161\/2162402X.2014.981457","article-title":"Indoleamine-2,3-dioxygenase (IDO) metabolic activity is detrimental for cervical cancer patient survival","volume":"4","author":"Ferns","year":"2015","journal-title":"Oncoimmunology"},{"key":"ref_35","first-page":"1","article-title":"The Kynurenine\/Tryptophan Ratio and Glioblastoma Patients Treated with Hsppc-96 Vaccine","volume":"2","author":"Lenzen","year":"2016","journal-title":"Immunotherapy"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"3557","DOI":"10.2147\/OTT.S136259","article-title":"The status of immunosuppression in patients with stage IIIB or IV non-small-cell lung cancer correlates with the clinical characteristics and response to chemotherapy","volume":"10","author":"Wang","year":"2017","journal-title":"OncoTargets Ther."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"590","DOI":"10.21037\/tlcr-20-573","article-title":"Emerging biomarkers for neoadjuvant immune checkpoint inhibitors in operable non-small cell lung cancer","volume":"10","author":"Pradhan","year":"2021","journal-title":"Transl. Lung Cancer Res."},{"key":"ref_38","first-page":"11","article-title":"The New Immunotherapy Combinations in the Treatment of Advanced Non-Small Cell Lung Cancer: Reality and Perspectives","volume":"15","author":"Rocco","year":"2020","journal-title":"Curr. Clin. Pharmacol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1963","DOI":"10.1002\/ijc.32951","article-title":"Phase 1 study of epacadostat in combination with atezolizumab for patients with previously treated advanced nonsmall cell lung cancer","volume":"147","author":"Hellmann","year":"2020","journal-title":"Int. J. Cancer"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"3220","DOI":"10.1158\/1078-0432.CCR-18-2740","article-title":"Phase I Study of the Indoleamine 2,3-Dioxygenase 1 (IDO1) Inhibitor Navoximod (GDC-0919) Administered with PD-L1 Inhibitor (Atezolizumab) in Advanced Solid Tumors","volume":"25","author":"Jung","year":"2019","journal-title":"Clin. Cancer Res."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"3585","DOI":"10.1111\/1759-7714.13721","article-title":"Association between serum level soluble programmed cell death ligand 1 and prognosis in patients with non-small cell lung cancer treated with anti-PD-1 antibody","volume":"11","author":"Murakami","year":"2020","journal-title":"Thorac. Cancer"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"102948","DOI":"10.1016\/j.critrevonc.2020.102948","article-title":"Systematic review: Soluble immunological biomarkers in advanced non-small-cell lung cancer (NSCLC)","volume":"153","author":"Mildner","year":"2020","journal-title":"Crit. Rev. Oncol. Hematol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1158\/2326-6066.CIR-14-0137","article-title":"Extensive profiling of the expression of the indoleamine 2,3-dioxygenase 1 protein in normal and tumoral human tissues","volume":"3","author":"Pilotte","year":"2015","journal-title":"Cancer Immunol. Res."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/9\/4403\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T05:51:37Z","timestamp":1760161897000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/9\/4403"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,4,22]]},"references-count":43,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2021,5]]}},"alternative-id":["ijms22094403"],"URL":"https:\/\/doi.org\/10.3390\/ijms22094403","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,4,22]]}}}