{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T06:19:38Z","timestamp":1787552378013,"version":"build-2736575974"},"reference-count":29,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T00:00:00Z","timestamp":1787529600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Oncol."],"abstract":"<jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>To determine whether unsupervised integration of routinely accessible immunohistochemical immune features can identify clinically relevant tumor immune microenvironment phenotypes in cervical cancer.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We performed a retrospective exploratory analysis of surgically treated cervical cancer cases with complete scoring for a 20-feature immunohistochemical immune panel. The features were derived from approximately 11 antibody-defined markers, including separate intratumoral (IT) and stromal (ST) scores where applicable. Hierarchical clustering was performed using standardized feature values, Euclidean distance, and Ward.D2 linkage. The three-cluster solution was the primary unsupervised analysis. The comparison between C2 and combined C1\/C3 was an exploratory, outcome-informed contrast generated after inspection of the primary three-cluster survival curves. Cluster-defining features, clinicopathological associations, overall survival, cause-specific Cox models, and competing-risk endpoints were assessed.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>The source dataset included 226 patients; 177 had pT1b-region disease and 169 had complete data for the 20-feature panel. Three tumor immune microenvironment clusters were identified: C1 (n=50), C2 (n=78), and C3 (n=41). The most discriminatory features were CD8-ST, CD8-IT, CD3-ST, PD-1-ST, PD-1-IT, CD3-IT, CD4-ST, CD68-IT, CD20-ST, and CD57-ST. C2 showed relative depletion of several stromal and intratumoral lymphoid and checkpoint-associated features. In the exploratory C2 versus C1\/C3 contrast, C2 was associated with inferior overall survival by Kaplan-Meier analysis (log-rank p=0.012) and univariable Cox regression (HR 2.14, 95% CI 1.16-3.92, p=0.014). After adjustment for age, nodal status, and histology, the association was attenuated and borderline (HR 1.84, 95% CI 0.99-3.42, p=0.055). Fine-Gray analysis showed a similar adverse direction for neoplasm-specific death (SHR 2.37, 95% CI 0.95-5.87, p=0.063).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Routine compartment-aware immunohistochemical immune profiling identified exploratory cervical cancer immune phenotypes, including an immune-depleted C2 cluster with unfavorable survival signals. These findings are hypothesis-generating and require independent validation before clinical implementation.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fonc.2026.1914836","type":"journal-article","created":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T05:31:29Z","timestamp":1787549489000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Unsupervised 20-feature immunohistochemical immune profiling identifies exploratory cervical cancer phenotypes with unfavorable survival signals"],"prefix":"10.3389","volume":"16","author":[{"given":"Angel Danchev","family":"Yordanov","sequence":"first","affiliation":[{"name":"Department of Gynecologic Oncology, Medical University Pleven","place":["Pleven, Bulgaria"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eva","family":"Tsoneva","sequence":"additional","affiliation":[{"name":"Clinic of General and Oncogynaecology, Military Medical Academy","place":["Sofia, Bulgaria"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Polina Damqnova","family":"Dimitrova","sequence":"additional","affiliation":[{"name":"Department of General and Clinical Pathology, Heart and Brain Center of Clinical Excellence","place":["Pleven, Bulgaria"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stoyan Georgiev","family":"Kostov","sequence":"additional","affiliation":[{"name":"Department of Gynecology, Hospital \u201cSaint Anna\u201d, Medical University \u201cProf. Dr. Paraskev Stoyanov\u201d","place":["Varna, Bulgaria"]},{"name":"Research Institute, Medical University\u2013Pleven","place":["Pleven, Bulgaria"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ihsan","family":"Hasan","sequence":"additional","affiliation":[{"name":"Obstetrics and Gynaecology Center \u201c Tiara\u201d","place":["Sofia, Bulgaria"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Velizar Stefanov","family":"Shivarov","sequence":"additional","affiliation":[{"name":"Department of Clinical Hematology, St. Sophia General Hospital","place":["Sofia, Bulgaria"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,8,24]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/s0140-6736(25)01635-6","article-title":"The global, regional, and national burden of cancer, 1990-2023, with forecasts to 2050: a systematic analysis for the Global Burden of Disease Study 2023","volume":"406","author":"Force","year":"2025","journal-title":"Lancet"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21834","article-title":"Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"74","author":"Bray","year":"2024","journal-title":"CA Cancer J Clin"},{"key":"B3","doi-asserted-by":"publisher","first-page":"56","DOI":"10.1097\/01.ogx.0001119040.12307.32","article-title":"Cervical cancer","volume":"392","author":"Tewari","year":"2025","journal-title":"N Engl J Med"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1136\/ijgc-2021-002492","article-title":"Advances in immunotherapy for cervical cancer: recent developments and future directions","volume":"32","author":"Sherer","year":"2022","journal-title":"Int J Gynecol Cancer"},{"key":"B5","doi-asserted-by":"publisher","first-page":"812","DOI":"10.1016\/j.immuni.2018.03.023","article-title":"The immune landscape of cancer","volume":"48","author":"Thorsson","year":"2018","journal-title":"Immunity"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1038\/s41416-020-01184-x","article-title":"Infiltrating T-cell markers in cervical carcinogenesis: a systematic review and meta-analysis","volume":"124","author":"Litwin","year":"2021","journal-title":"Br J Cancer"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1016\/j.omto.2021.07.006","article-title":"Prognostic and therapeutic TILs of cervical cancer-current advances and future perspectives","volume":"22","author":"Tang","year":"2021","journal-title":"Mol Ther Oncolytics"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1038\/modpathol.2016.64","article-title":"Prognostic effect of different PD-L1 expression patterns in squamous cell carcinoma and adenocarcinoma of the cervix","volume":"29","author":"Heeren","year":"2016","journal-title":"Mod Pathol"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.7150\/jca.22532","article-title":"PD-L1 expression correlates with tumor infiltrating lymphocytes and response to neoadjuvant chemotherapy in cervical cancer","volume":"9","author":"Meng","year":"2018","journal-title":"J Cancer"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.596825","article-title":"PD-L1 and PD-L2 expression in cervical cancer: regulation and biomarker potential","volume":"11","author":"Rotman","year":"2020","journal-title":"Front Immunol"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.7150\/jca.21444","article-title":"Clinical significance of CD163+ and CD68+ tumor-associated macrophages in high-risk HPV-related cervical cancer","volume":"8","author":"Chen","year":"2017","journal-title":"J Cancer"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1042\/bsr20203145","article-title":"The correlation between tumor-associated macrophage infiltration and progression in cervical carcinoma","volume":"41","author":"Guo","year":"2021","journal-title":"Biosci Rep"},{"key":"B13","doi-asserted-by":"publisher","first-page":"234","DOI":"10.1038\/s42003-020-0964-7","article-title":"Omics-wide quantitative B-cell infiltration analyses identify GPR18 for human cancer prognosis with superiority over CD20","volume":"3","author":"Liu","year":"2020","journal-title":"Commun Biol"},{"key":"B14","doi-asserted-by":"publisher","first-page":"5482","DOI":"10.1016\/j.cell.2021.09.014","article-title":"Atlas of clinically distinct cell states and ecosystems across human solid tumors","volume":"184","author":"Luca","year":"2021","journal-title":"Cell"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.15252\/embj.2022110757","article-title":"Single-cell dissection of cervical cancer reveals key subsets of the tumor immune microenvironment","volume":"42","author":"Cao","year":"2023","journal-title":"EMBO J"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.add8977","article-title":"Single-cell dissection of cellular and molecular features underlying human cervical squamous cell carcinoma initiation and progression","volume":"9","author":"Liu","year":"2023","journal-title":"Sci Adv"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.3390\/medicina59040728","article-title":"Infiltration by intratumor and stromal CD8 and CD68 in cervical cancer","volume":"59","author":"Dimitrova","year":"2023","journal-title":"Med (Kaunas)"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.3390\/ijms25169117","article-title":"Integrated analysis of phagocytic and immunomodulatory markers in cervical cancer reveals constellations of potential prognostic relevance","volume":"25","author":"Yordanov","year":"2024","journal-title":"Int J Mol Sci"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.3390\/biomedicines13092206","article-title":"Clinical significance of tumor infiltrating T-helper and regulatory cells in Bulgarian cervical cancer patients","volume":"13","author":"Yordanov","year":"2025","journal-title":"Biomedicines"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.3390\/diagnostics13010052","article-title":"Prognostic utility of CD47 in cancer of the uterine cervix and the sensitivity of immunohistochemical scores","volume":"13","author":"Yordanov","year":"2022","journal-title":"Diagnostics (Basel)"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.21873\/anticanres.16368","article-title":"CD8-positive tumor-infiltrating lymphocytes and prognosis in radiotherapy for uterine cervical squamous cell carcinoma","volume":"43","author":"Miyasaka","year":"2023","journal-title":"Anticancer Res"},{"key":"B22","doi-asserted-by":"publisher","first-page":"3349","DOI":"10.21417\/atr2021nc","article-title":"B cell signatures and tertiary lymphoid structures contribute to outcome in head and neck squamous cell carcinoma","volume":"12","author":"Ruffin","year":"2021","journal-title":"Nat Commun"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.996721","article-title":"A review of spatial profiling technologies for characterizing the tumor microenvironment in immuno-oncology","volume":"13","author":"Hu","year":"2022","journal-title":"Front Immunol"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2023.01.010","article-title":"Spatial profiling technologies illuminate the tumor microenvironment","volume":"41","author":"Elhanani","year":"2023","journal-title":"Cancer Cell"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.4143\/crt.2023.1302","article-title":"Applicability of spatial technology in cancer research","volume":"56","author":"Ahn","year":"2024","journal-title":"Cancer Res Treat"},{"key":"B26","doi-asserted-by":"publisher","first-page":"194","DOI":"10.1186\/s13046-025-03432-5","article-title":"Deciphering the tumor immune microenvironment: single-cell and spatial transcriptomic insights into cervical cancer fibroblasts","volume":"44","author":"Lin","year":"2025","journal-title":"J Exp Clin Cancer Res"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2025.1612623","article-title":"Integrated multi-omics analysis of single-cell and spatial transcriptomics reveals distinct HPV-associated immune microenvironment features and prognostic signatures in cervical cancer","volume":"16","author":"Su","year":"2025","journal-title":"Front Immunol"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.3390\/ijms25010676","article-title":"Programmed cell death ligand 1 immunohistochemical expression and cutaneous melanoma: a controversial relationship","volume":"25","author":"Fiorentino","year":"2024","journal-title":"Int J Mol Sci"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.3390\/cancers17152420","article-title":"Predictive biomarkers for immunotherapy in endometrial carcinoma","volume":"17","author":"Pizzimenti","year":"2025","journal-title":"Cancers (Basel)"}],"container-title":["Frontiers in Oncology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2026.1914836\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T05:31:29Z","timestamp":1787549489000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2026.1914836\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,24]]},"references-count":29,"alternative-id":["10.3389\/fonc.2026.1914836"],"URL":"https:\/\/doi.org\/10.3389\/fonc.2026.1914836","relation":{},"ISSN":["2234-943X"],"issn-type":[{"value":"2234-943X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,24]]},"article-number":"1914836"}}