{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T10:18:17Z","timestamp":1785406697550,"version":"3.56.0"},"reference-count":30,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T00:00:00Z","timestamp":1777593600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Brown Cancer Center, University of Louisville"},{"id":[{"id":"https:\/\/ror.org\/01ckdn478","id-type":"ROR","asserted-by":"publisher"}]},{"name":"NIH NCI fund","award":["1R01CA251755-01"],"award-info":[{"award-number":["1R01CA251755-01"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Current Oncology"],"abstract":"<jats:p>Background: Macrophage migration inhibitory factor (MIF) is a critical modulator of the tumor immune microenvironment (TME). Its clinical significance in head and neck squamous cell carcinoma (HNSCC) remains controversial because of HPV-dependent tumor biology and the limitations of single-timepoint biomarker assessments. This preliminary study evaluates whether dynamic changes in circulating MIF (\u0394MIF) in an HPV-stratified longitudinal cohort reflect disease severity and treatment response. Methods: Ninety-six serial serum samples were analyzed from 27 HNSCC patients (22 HPV-positive, 5 HPV-negative) from diagnosis through therapy and follow-up. Serum MIF and anti-HPV16 E7 IgG were quantified by ELISA, and \u0394MIF was defined as the change in MIF concentration between consecutive visits. Results: Baseline MIF did not correlate with clinical stage in the total cohort (p = 0.63). However, 56% of HPV-positive patients exhibited a positive correlation between elevated MIF and advanced stage. Following chemoradiotherapy, the HPV-negative group showed a consistent and significant decline in MIF (mean \u0394MIF = \u22121.23, p = 0.031), corresponding with no evidence of disease (NED). In contrast, the HPV-positive group showed heterogeneous trajectories (mean \u0394MIF = +0.21, p = 0.94), with several patients demonstrating paradoxical declines in MIF during active disease or relapse, followed by recovery upon reaching NED. In select cases, MIF dynamics were closely synchronized with anti-E7 IgG levels. Conclusions: Serum MIF dynamics are strongly dependent on HPV status. While MIF serves as a reliable therapy-monitoring marker in HPV-negative HNSCC, it may play a complex and paradoxical immunomodulatory role in HPV-positive disease. These preliminary findings support the need for larger prospective, HPV-stratified trials.<\/jats:p>","DOI":"10.3390\/curroncol33050265","type":"journal-article","created":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T09:33:17Z","timestamp":1777627997000},"page":"265","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Association of Macrophage Migration Inhibitory Factor (MIF) with Therapy Response and Clinical Outcomes in HPV-Related Head and Neck Squamous Cell Carcinoma: A Preliminary Report"],"prefix":"10.3390","volume":"33","author":[{"given":"Janki","family":"Naidugari","sequence":"first","affiliation":[{"name":"Department of Medicine, University of Louisville School of Medicine, Louisville, KY 40202, USA"},{"name":"Brown Cancer Center, University of Louisville School of Medicine, Louisville, KY 40202, USA"},{"name":"Center for Cancer Immunology, Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-7923-5698","authenticated-orcid":false,"given":"Shruti","family":"Wadhwa","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Louisville School of Medicine, Louisville, KY 40202, USA"},{"name":"Brown Cancer Center, University of Louisville School of Medicine, Louisville, KY 40202, USA"},{"name":"Center for Cancer Immunology, Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin","family":"Xie","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Louisville School of Medicine, Louisville, KY 40202, USA"},{"name":"Brown Cancer Center, University of Louisville School of Medicine, Louisville, KY 40202, USA"},{"name":"Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Taheri","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Louisville School of Medicine, Louisville, KY 40202, USA"},{"name":"Brown Cancer Center, University of Louisville School of Medicine, Louisville, KY 40202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Indraneel","family":"Kulkarni","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Louisville School of Medicine, Louisville, KY 40202, USA"},{"name":"Brown Cancer Center, University of Louisville School of Medicine, Louisville, KY 40202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luke","family":"Johnson","sequence":"additional","affiliation":[{"name":"Department of Dermatology, West Virginia University, Morgantown, WV 26506, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heehwa G.","family":"Son","sequence":"additional","affiliation":[{"name":"Center for Cancer Immunology, Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA"},{"name":"Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Strickley","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Louisville School of Medicine, Louisville, KY 40202, USA"},{"name":"Division of Dermatology, University of Louisville School of Medicine, Louisville, KY 40202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7913-2641","authenticated-orcid":false,"given":"Shadmehr","family":"Demehri","sequence":"additional","affiliation":[{"name":"Center for Cancer Immunology, Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA"},{"name":"Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7576-5994","authenticated-orcid":false,"given":"Joongho J.","family":"Joh","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Louisville School of Medicine, Louisville, KY 40202, USA"},{"name":"Brown Cancer Center, University of Louisville School of Medicine, Louisville, KY 40202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Mitchell","sequence":"additional","affiliation":[{"name":"Brown Cancer Center, University of Louisville School of Medicine, Louisville, KY 40202, USA"},{"name":"Department of Surgery, Division of Immunotherapy, University of Louisville School of Medicine, Louisville, KY 40202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca","family":"Redman","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Louisville School of Medicine, Louisville, KY 40202, USA"},{"name":"Brown Cancer Center, University of Louisville School of Medicine, Louisville, KY 40202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Amaral, M.N., Fa\u00edsca, P., Ferreira, H.A., Gaspar, M.M., and Reis, C.P. (2022). Current Insights and Progress in the Clinical Management of Head and Neck Cancer. Cancers, 14.","DOI":"10.3390\/cancers14246079"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1038\/nrc.2018.11","article-title":"The molecular landscape of head and neck cancer","volume":"18","author":"Leemans","year":"2018","journal-title":"Nat. Rev. Cancer"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1093\/jnci\/djn025","article-title":"Distinct risk factor profiles for human papillomavirus type 16-positive and human papillomavirus type 16-negative head and neck cancers","volume":"100","author":"Gillison","year":"2008","journal-title":"J. Natl. Cancer Inst."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1056\/NEJMoa0912217","article-title":"Human papillomavirus and survival of patients with oropharyngeal cancer","volume":"363","author":"Ang","year":"2010","journal-title":"N. Engl. J. Med."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Gordis, T.M., Cagle, J.L., Nguyen, S.A., and Newman, J.G. (2022). Human Papillomavirus-Associated Oropharyngeal Squamous Cell Carcinoma: A Systematic Review and Meta-Analysis of Clinical Trial Demographics. Cancers, 14.","DOI":"10.3390\/cancers14164061"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Zhou, Q., Yuan, O., Cui, H., Hu, T., Xiao, G.G., Wei, J., Zhang, H., and Wu, C. (2022). Bioinformatic analysis identifies HPV-related tumor microenvironment remodeling prognostic biomarkers in head and neck squamous cell carcinoma. Front. Cell. Infect. Microbiol., 12.","DOI":"10.3389\/fcimb.2022.1007950"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1108","DOI":"10.1016\/j.tranon.2019.05.009","article-title":"HPV and Oropharyngeal Cancer in the Eighth Edition of the TNM Classification: Pitfalls in Practice","volume":"12","author":"Hoffmann","year":"2019","journal-title":"Transl. Oncol."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Youness, R.A., Elemam, N.M., Abdelhamid, A.M., Mohamed, A.H., Elsherbiny, L.M., Ramzy, A., and Assal, R.A. (2025). Macrophage migration inhibitory factor (MIF) and the tumor ecosystem: A tale of inflammation, immune escape, and tumor growth. Front. Immunol., 16.","DOI":"10.3389\/fimmu.2025.1636839"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Mora Barthelmess, R., Stijlemans, B., and Van Ginderachter, J.A. (2023). Hallmarks of Cancer Affected by the MIF Cytokine Family. Cancers, 15.","DOI":"10.3390\/cancers15020395"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Noe, J.T., and Mitchell, R.A. (2020). MIF-Dependent Control of Tumor Immunity. Front. Immunol., 11.","DOI":"10.3389\/fimmu.2020.609948"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1007\/s00401-011-0858-3","article-title":"Macrophage migration inhibitory factor (MIF) expression in human malignant gliomas contributes to immune escape and tumour progression","volume":"122","author":"Mittelbronn","year":"2011","journal-title":"Acta Neuropathol."},{"key":"ref_12","first-page":"2760","article-title":"Pleiotropic role of macrophage migration inhibitory factor in cancer","volume":"9","author":"Guda","year":"2019","journal-title":"Am. J. Cancer Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"769","DOI":"10.1093\/qjmed\/hcy163","article-title":"Oral squamous carcinoma cells promote macrophage polarization in an MIF-dependent manner","volume":"111","author":"Kim","year":"2018","journal-title":"QJM"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"5533","DOI":"10.4049\/jimmunol.1201161","article-title":"Macrophage Migration Inhibitory Factor promotes tumor growth and metastasis by inducing Myeloid Derived Suppressor Cells in the tumor microenvironment","volume":"189","author":"Simpson","year":"2012","journal-title":"J. Immunol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"188","DOI":"10.1016\/j.cyto.2006.01.006","article-title":"Tumor-derived macrophage migration inhibitory factor (MIF) inhibits T lymphocyte activation","volume":"33","author":"Yan","year":"2006","journal-title":"Cytokine"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Kindt, N., Descamps, G., Lechien, J.R., Remmelink, M., Colet, J.M., Wattiez, R., Berchem, G., Journe, F., and Saussez, S. (2019). Involvement of HPV Infection in the Release of Macrophage Migration Inhibitory Factor in Head and Neck Squamous Cell Carcinoma. J. Clin. Med., 8.","DOI":"10.3390\/jcm8010075"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"167345","DOI":"10.1016\/j.bbadis.2024.167345","article-title":"Host derived macrophage migration inhibitory factor expression attenuates anti-tumoral immune cell accumulation and promotes immunosuppression in the tumor microenvironment of head and neck squamous cell carcinoma","volume":"1870","author":"Ryan","year":"2024","journal-title":"Biochim. Biophys. Acta Mol. Basis Dis."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"10650","DOI":"10.18632\/oncotarget.12890","article-title":"Macrophage migration inhibitory factor: A potential driver and biomarker for head and neck squamous cell carcinoma","volume":"8","author":"Kindt","year":"2017","journal-title":"Oncotarget"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"107126","DOI":"10.1016\/j.oraloncology.2024.107126","article-title":"Targeting Macrophage Migration Inhibitory Factor to inhibit T cell immunosuppression in the tumor microenvironment and improve cancer outcomes in Head and Neck Squamous Cell Carcinoma","volume":"160","author":"Pracha","year":"2024","journal-title":"Oral Oncol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"6199","DOI":"10.3390\/cimb46060370","article-title":"Bioinformatics Analysis Reveals E6 and E7 of HPV 16 Regulate Metabolic Reprogramming in Cervical Cancer, Head and Neck Cancer, and Colorectal Cancer through the PHD2-VHL-CUL2-ELOC-HIF-1\u03b1 Axis","volume":"46","year":"2024","journal-title":"Curr. Issues Mol. Biol."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Perri, F., Della Vittoria Scarpati, G., Pontone, M., Marciano, M.L., Ottaiano, A., Cascella, M., Sabbatino, F., Guida, A., Santorsola, M., and Maiolino, P. (2022). Cancer Cell Metabolism Reprogramming and Its Potential Implications on Therapy in Squamous Cell Carcinoma of the Head and Neck: A Review. Cancers, 14.","DOI":"10.3390\/cancers14153560"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"3107990","DOI":"10.1155\/2022\/3107990","article-title":"Trending Anti-E7 Serology Predicts Mortality and Recurrence of HPV-Associated Cancers of the Oropharynx","volume":"2022","author":"Johnson","year":"2022","journal-title":"J. Oncol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1016\/j.yexmp.2015.06.018","article-title":"Human papillomavirus E7 serology and association with p16 immunohistochemistry in squamous cell carcinoma of the head and neck","volume":"99","author":"Khanal","year":"2015","journal-title":"Exp. Mol. Pathol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"312","DOI":"10.1007\/s11095-005-9045-3","article-title":"Fit-for-purpose method development and validation for successful biomarker measurement","volume":"23","author":"Lee","year":"2006","journal-title":"Pharm. Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1002\/hed.21974","article-title":"p16 expression as a surrogate marker for HPV-related oropharyngeal carcinoma: A guide for interpretative relevance and consistency","volume":"34","author":"Westra","year":"2012","journal-title":"Head Neck"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1088","DOI":"10.1097\/PAS.0b013e3181e84652","article-title":"p16 positive oropharyngeal squamous cell carcinoma: An entity with a favorable prognosis regardless of tumor HPV status","volume":"34","author":"Lewis","year":"2010","journal-title":"Am. J. Surg. Pathol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"20587384211038417","DOI":"10.1177\/20587384211038417","article-title":"Macrophage migration inhibitory factor: A promising oncogenic serological biomarker for oral squamous cell carcinoma","volume":"35","author":"Cruz","year":"2021","journal-title":"Int. J. Immunopathol. Pharmacol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"727","DOI":"10.1007\/s00432-013-1375-7","article-title":"Macrophage migration inhibitory factor in head and neck squamous cell carcinoma: Clinical and experimental studies","volume":"139","author":"Kindt","year":"2013","journal-title":"J. Cancer Res. Clin. Oncol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"364","DOI":"10.1016\/j.ejphar.2014.07.025","article-title":"Cisplatin in cancer therapy: Molecular mechanisms of action","volume":"740","author":"Dasari","year":"2014","journal-title":"Eur. J. Pharmacol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2447403","DOI":"10.1080\/07853890.2024.2447403","article-title":"The role of cisplatin in modulating the tumor immune microenvironment and its combination therapy strategies: A new approach to enhance anti-tumor efficacy","volume":"57","author":"Li","year":"2025","journal-title":"Ann. Med."}],"container-title":["Current Oncology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1718-7729\/33\/5\/265\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T10:00:45Z","timestamp":1777629645000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1718-7729\/33\/5\/265"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,1]]},"references-count":30,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2026,5]]}},"alternative-id":["curroncol33050265"],"URL":"https:\/\/doi.org\/10.3390\/curroncol33050265","relation":{},"ISSN":["1718-7729"],"issn-type":[{"value":"1718-7729","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,1]]}}}