{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,14]],"date-time":"2026-05-14T23:49:06Z","timestamp":1778802546266,"version":"3.51.4"},"reference-count":27,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2024,4,1]],"date-time":"2024-04-01T00:00:00Z","timestamp":1711929600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100006769","name":"Russian Science Foundation","doi-asserted-by":"publisher","award":["20-75-10033"],"award-info":[{"award-number":["20-75-10033"]}],"id":[{"id":"10.13039\/501100006769","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Only one-third of patients with advanced MSS\/pMMR endometrial cancer exhibit a lasting response to the combination treatment of Pembrolizumab and Lenvatinib. The combined administration of these two drugs is based on Lenvatinib\u2019s ability to modulate the tumor microenvironment, enabling Pembrolizumab to exert its effect. These findings underscore the importance of exploring tumor microenvironment parameters to identify markers that can accurately select candidates for this type of therapy. An open non-randomized observational association study was conducted at six clinical centers, involving a total of 28 patients with advanced MSS\/pMMR endometrial cancer who received Pembrolizumab and Lenvatinib therapy. Using TSA-associated multiplex immunofluorescence, we analyzed the proportion of CD8+ T lymphocytes, CD20+ B lymphocytes, FoxP3+ T regulatory lymphocytes, and CD163+ macrophages in tumor samples prior to immunotargeted therapy. The percentage of CD20+ B lymphocytes and the CD8-to-CD20 lymphocytes ratio was significantly higher in patients who responded to treatment compared to non-responders (responders vs. non-responders: 0.24 (0.1\u20131.24)% vs. 0.08 (0.00\u20130.15)%, p = 0.0114; 1.44 (0.58\u20132.70) arb. unit vs. 19.00 (3.80\u201334.78) arb. unit, p = 0.0031). The sensitivity and specificity of these biomarkers were 85.71% and 70.59%, and 85.71% and 85.71%, respectively. The proportion of CD20+ B lymphocytes and the CD8-to-CD20 lymphocytes ratio in the stroma of endometrial cancer serves as both a prognostic marker of response to immunotargeted therapy and a prognostic factor for progression-free survival in patients.<\/jats:p>","DOI":"10.3390\/ijms25073933","type":"journal-article","created":{"date-parts":[[2024,4,1]],"date-time":"2024-04-01T05:44:36Z","timestamp":1711950276000},"page":"3933","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Predicting Response to Immunotargeted Therapy in Endometrial Cancer via Tumor Immune Microenvironment: A Multicenter, Observational Study"],"prefix":"10.3390","volume":"25","author":[{"given":"Anastasia","family":"Maltseva","sequence":"first","affiliation":[{"name":"Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, Tomsk 634050, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anna","family":"Kalinchuk","sequence":"additional","affiliation":[{"name":"Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, Tomsk 634050, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-1194-4150","authenticated-orcid":false,"given":"Nataliya","family":"Chernorubashkina","sequence":"additional","affiliation":[{"name":"Irkutsk Regional Oncology Center, 32 Frunze St., Irkutsk 664035, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Virab","family":"Sisakyan","sequence":"additional","affiliation":[{"name":"Novosibirsk Regional Clinical Oncology Center, 2 Plakhotnogo St., Novosibirsk 630108, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Igor","family":"Lots","sequence":"additional","affiliation":[{"name":"Novosibirsk Regional Clinical Oncology Center, 2 Plakhotnogo St., Novosibirsk 630108, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alina","family":"Gofman","sequence":"additional","affiliation":[{"name":"Altai Regional Oncological Dispensary, 110 Zmeinogorsky tr., Barnaul 656000, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yulia","family":"Anzhiganova","sequence":"additional","affiliation":[{"name":"Krasnoyarsk Regional Clinical Oncological Dispensary Named after A. I. Kryzhanovsky, 16 1-ya Smolenskaya St., Krasnoyarsk 660133, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elizaveta","family":"Martynova","sequence":"additional","affiliation":[{"name":"Krasnoyarsk Regional Clinical Oncological Dispensary Named after A. I. Kryzhanovsky, 16 1-ya Smolenskaya St., Krasnoyarsk 660133, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ruslan","family":"Zukov","sequence":"additional","affiliation":[{"name":"Krasnoyarsk Regional Clinical Oncological Dispensary Named after A. I. Kryzhanovsky, 16 1-ya Smolenskaya St., Krasnoyarsk 660133, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elena","family":"Aleksandrova","sequence":"additional","affiliation":[{"name":"Yakut Republican Oncology Center, Build. 1, 81 Stadukhina St., Yakutsk 677005, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Larisa","family":"Kolomiets","sequence":"additional","affiliation":[{"name":"Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, Tomsk 634050, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2061-8417","authenticated-orcid":false,"given":"Liubov","family":"Tashireva","sequence":"additional","affiliation":[{"name":"Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, Tomsk 634050, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,4,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"209","DOI":"10.3322\/caac.21660","article-title":"Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries","volume":"71","author":"Sung","year":"2021","journal-title":"CA Cancer J. Clin."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"860","DOI":"10.1016\/j.annonc.2022.05.009","article-title":"Endometrial cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up","volume":"33","author":"Oaknin","year":"2022","journal-title":"Ann. Oncol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"3753","DOI":"10.1158\/1078-0432.CCR-18-4070","article-title":"FDA Approval Summary: Pembrolizumab for the Treatment of Microsatellite Instability-High Solid Tumors","volume":"25","author":"Marcus","year":"2019","journal-title":"Clin. Cancer Res."},{"key":"ref_4","first-page":"1","article-title":"A Review of Immune Checkpoint Blockade Therapy in Endometrial Cancer","volume":"40","author":"Green","year":"2020","journal-title":"Am. Soc. Clin. Oncol. Educ. Book"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1056\/NEJMoa2108330","article-title":"Lenvatinib plus Pembrolizumab for Advanced Endometrial Cancer","volume":"386","author":"Makker","year":"2022","journal-title":"N. Engl. J. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1136\/ijgc-2021-003017","article-title":"Phase 3, randomized, open-label study of pembrolizumab plus lenvatinib versus chemotherapy for first-line treatment of advanced or recurrent endometrial cancer: ENGOT-en9\/LEAP-001","volume":"32","author":"Marth","year":"2022","journal-title":"Int. J. Gynecol. Cancer"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"844801","DOI":"10.3389\/fonc.2022.844801","article-title":"How Immunotherapy Modified the Therapeutic Scenario of Endometrial Cancer: A Systematic Review","volume":"12","author":"Maiorano","year":"2022","journal-title":"Front. Oncol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1186\/2045-824X-6-18","article-title":"Lenvatinib, an angiogenesis inhibitor targeting VEGFR\/FGFR, shows broad antitumor activity in human tumor xenograft models associated with microvessel density and pericyte coverage","volume":"6","author":"Yamamoto","year":"2014","journal-title":"Vasc. Cell"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Kato, Y., Tabata, K., Kimura, T., Yachie-Kinoshita, A., Ozawa, Y., Yamada, K., Ito, J., Tachino, S., Hori, Y., and Matsuki, M. (2019). Lenvatinib plus anti-PD-1 antibody combination treatment activates CD8+ T cells through reduction of tumor-associated macrophage and activation of the interferon pathway. PLoS ONE, 14.","DOI":"10.1371\/journal.pone.0212513"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"3993","DOI":"10.1111\/cas.13806","article-title":"Immunomodulatory activity of lenvatinib contributes to antitumor activity in the Hepa1-6 hepatocellular carcinoma model","volume":"109","author":"Kimura","year":"2018","journal-title":"Cancer Sci."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2544","DOI":"10.1002\/hep.31921","article-title":"Lenvatinib Targets FGF Receptor 4 to Enhance Antitumor Immune Response of Anti-Programmed Cell Death-1 in HCC","volume":"74","author":"Yi","year":"2021","journal-title":"Hepatology"},{"key":"ref_12","first-page":"1121","article-title":"Clinical endpoints in oncology\u2014A primer","volume":"11","author":"Delgado","year":"2021","journal-title":"Am. J. Cancer Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1016\/j.ccr.2005.04.014","article-title":"De novo carcinogenesis promoted by chronic inflammation is B lymphocyte dependent","volume":"7","author":"Korets","year":"2005","journal-title":"Cancer Cell"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"809","DOI":"10.1016\/j.ccr.2014.04.026","article-title":"B cells regulate macrophage phenotype and response to chemotherapy in squamous carcinomas","volume":"25","author":"Affara","year":"2014","journal-title":"Cancer Cell"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"934","DOI":"10.1016\/j.cell.2017.09.028","article-title":"Tumor and Microenvironment Evolution during Immunotherapy with Nivolumab","volume":"171","author":"Riaz","year":"2017","journal-title":"Cell"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"544","DOI":"10.1002\/eji.202048747","article-title":"Combined anti-PD-1 and anti-CTLA-4 checkpoint blockade: Treatment of melanoma and immune mechanisms of action","volume":"51","author":"Willsmore","year":"2021","journal-title":"Eur. J. Immunol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"hoab043","DOI":"10.1093\/hropen\/hoab043","article-title":"The role of endometrial B cells in normal endometrium and benign female reproductive pathologies: A systematic review","volume":"2022","author":"Shen","year":"2021","journal-title":"Hum. Reprod. Open"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Shen, M., Child, T., Mittal, M., Sarodey, G., Salim, R., Granne, I., and Southcombe, J.H. (2021). B Cell Subset Analysis and Gene Expression Characterization in Mid-Luteal Endometrium. Front. Cell Dev. Biol., 9.","DOI":"10.3389\/fcell.2021.709280"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"865596","DOI":"10.3389\/fimmu.2022.865596","article-title":"CD20+CD22+ADAM28+ B Cells in Tertiary Lymphoid Structures Promote Immunotherapy Response","volume":"13","author":"Wu","year":"2022","journal-title":"Front Immunol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"S28","DOI":"10.1016\/S0090-8258(21)00699-5","article-title":"Immune markers of response to pembrolizumab and guadecitabine in platinum resistant ovarian cancer utilizing multiplex immunohistochemistry (mIHC)","volume":"162","author":"Cowan","year":"2021","journal-title":"Gynecol. Oncol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"294","DOI":"10.1038\/s41577-019-0257-x","article-title":"B cells, plasma cells and antibody repertoires in the tumour microenvironment","volume":"20","author":"Sharonov","year":"2020","journal-title":"Nat. Rev. Immunol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"105829","DOI":"10.1016\/j.phrs.2021.105829","article-title":"Lenvatinib enhances T cell immunity and the efficacy of adoptive chimeric antigen receptor-modified T cells by decreasing myeloid-derived suppressor cells in cancer","volume":"174","author":"Lu","year":"2021","journal-title":"Pharmacol. Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1813","DOI":"10.1084\/jem.20112142","article-title":"Macrophages induce differentiation of plasma cells through CXCL10\/IP-10","volume":"209","author":"Xu","year":"2012","journal-title":"J. Exp. Med."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1373","DOI":"10.1038\/s41467-022-29040-x","article-title":"Tertiary lymphoid structures critical for prognosis in endometrial cancer patients","volume":"13","author":"Horeweg","year":"2022","journal-title":"Nat. Commun."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Zheng, W. (2023). Molecular Classification of Endometrial Cancer and the 2023 FIGO Staging: Exploring the Challenges and Opportunities for Pathologists. Cancers, 15.","DOI":"10.3390\/cancers15164101"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1038\/nature12113","article-title":"Integrated genomic characterization of endometrial carcinoma","volume":"497","author":"Levine","year":"2013","journal-title":"Nature"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"608","DOI":"10.1007\/s12031-023-02142-x","article-title":"Integrative Analysis of Inflammatory Response-Related Gene for Predicting Prognosis and Immunotherapy in Glioma","volume":"73","author":"Zhao","year":"2023","journal-title":"J. Mol. Neurosci."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/7\/3933\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T14:22:09Z","timestamp":1760106129000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/7\/3933"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,4,1]]},"references-count":27,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2024,4]]}},"alternative-id":["ijms25073933"],"URL":"https:\/\/doi.org\/10.3390\/ijms25073933","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,4,1]]}}}