<?xml version="1.0" encoding="UTF-8"?>
<!DOCTYPE article PUBLIC "-//NLM//DTD JATS (Z39.96) Journal Publishing DTD v1.3 20210610//EN" "JATS-journalpublishing1-3.dtd">
<article article-type="research-article" dtd-version="1.3" xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" xml:lang="ru"><front><journal-meta><journal-id journal-id-type="publisher-id">oncotomsk</journal-id><journal-title-group><journal-title xml:lang="ru">Сибирский онкологический журнал</journal-title><trans-title-group xml:lang="en"><trans-title>Siberian journal of oncology</trans-title></trans-title-group></journal-title-group><issn pub-type="ppub">1814-4861</issn><issn pub-type="epub">2312-3168</issn><publisher><publisher-name>Tomsk National Research Medical Сепtеr of the Russian Academy of Sciences</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="doi">10.21294/1814-4861-2023-22-5-71-83</article-id><article-id custom-type="elpub" pub-id-type="custom">oncotomsk-2762</article-id><article-categories><subj-group subj-group-type="heading"><subject>Research Article</subject></subj-group><subj-group subj-group-type="section-heading" xml:lang="ru"><subject>ЛАБОРАТОРНЫЕ И ЭКСПЕРИМЕНТАЛЬНЫЕ ИССЛЕДОВАНИЯ</subject></subj-group><subj-group subj-group-type="section-heading" xml:lang="en"><subject>LABORATORY AND EXPERIMENTAL STUDIES</subject></subj-group></article-categories><title-group><article-title>Особенности экспрессии PD-L1 в клетках стромы опухоли, перитуморальных микрососудах и изолированных кластерах опухолевых клеток в ткани рака молочной железы и их корреляции с клинико-морфологическими характеристиками рака молочной железы</article-title><trans-title-group xml:lang="en"><trans-title>The features of PD-L1 expression in tumor stromal cells, peritumoral microvessels and isolated clusters of tumor cells in breast cancer tissue and their correlation with clinical and morphological characteristics of breast cancer</trans-title></trans-title-group></title-group><contrib-group><contrib contrib-type="author" corresp="yes"><contrib-id contrib-id-type="orcid">https://orcid.org/0000-0001-7025-0206</contrib-id><name-alternatives><name name-style="eastern" xml:lang="ru"><surname>Зубарева</surname><given-names>Е. Ю.</given-names></name><name name-style="western" xml:lang="en"><surname>Zubareva</surname><given-names>E. Yu.</given-names></name></name-alternatives><bio xml:lang="ru"><p>Зубарева Евгения Юрьевна - врач-онколог.</p><p>460021, Оренбург, пр. Гагарина, 11</p></bio><bio xml:lang="en"><p>Evgenia Yu. Zubareva - MD, Oncologist.</p><p>11, Gagarin ave., Orenburg, 460021</p></bio><email xlink:type="simple">tishkova_evgeniy@mail.ru</email><xref ref-type="aff" rid="aff-1"/></contrib><contrib contrib-type="author" corresp="yes"><contrib-id contrib-id-type="orcid">https://orcid.org/0000-0001-8371-740X</contrib-id><name-alternatives><name name-style="eastern" xml:lang="ru"><surname>Сеньчукова</surname><given-names>М. А.</given-names></name><name name-style="western" xml:lang="en"><surname>Senchukova</surname><given-names>M. A.</given-names></name></name-alternatives><bio xml:lang="ru"><p>Сеньчукова Марина Алексеевна, доктор медицинских наук, врач-онколог хирургического торакального отделения, ГАУЗ «Оренбургский ОКОД; профессор кафедры онкологии, ФГБОУ ВО «Оренбургский ГМУ» МР.</p><p>460021, Оренбург, пр. Гагарина, 11; 460000, Оренбург, ул. Советская, 6</p></bio><bio xml:lang="en"><p>Marina A. Senchukova - MD, DSc, Oncologist of the Surgical Thoracic Department, Orenburg RCOC; Professor of the Department of Oncology, Orenburg SMU MHR.</p><p>11, Gagarin ave., Orenburg, 460021; 6, Sovetskaya st., Orenburg, 460000</p></bio><xref ref-type="aff" rid="aff-2"/></contrib><contrib contrib-type="author" corresp="yes"><contrib-id contrib-id-type="orcid">https://orcid.org/0000-0002-8017-5657</contrib-id><name-alternatives><name name-style="eastern" xml:lang="ru"><surname>Кармакова</surname><given-names>Т. А.</given-names></name><name name-style="western" xml:lang="en"><surname>Karmakova</surname><given-names>T. A.</given-names></name></name-alternatives><bio xml:lang="ru"><p>Кармакова Татьяна Анатольевна - доктор биологических наук, ведущий научный сотрудник отделения прогноза эффективности консервативного лечения.</p><p>125284, Москва, 2-й Боткинский пр-д, 3</p></bio><bio xml:lang="en"><p>Tatyana A. Karmakova, DSc, Leading Researcher, Department of Prediction of Treatment Response.</p><p>3, 2nd Botkinsky drive, Moscow, 125284</p></bio><xref ref-type="aff" rid="aff-3"/></contrib><contrib contrib-type="author" corresp="yes"><contrib-id contrib-id-type="orcid">https://orcid.org/0000-0003-3134-1273</contrib-id><name-alternatives><name name-style="eastern" xml:lang="ru"><surname>Зайцев</surname><given-names>Н. В.</given-names></name><name name-style="western" xml:lang="en"><surname>Zaitsev</surname><given-names>N. V.</given-names></name></name-alternatives><bio xml:lang="ru"><p>Зайцев Никон Владимирович, заведующий патологоанатомическим отделением.</p><p>460021, Оренбург, пр. Гагарина, 11</p></bio><bio xml:lang="en"><p>Nikon V. Zaitsev - MD, Head of the Pathology Department.</p><p>11, Gagarin ave., Orenburg, 460021</p></bio><xref ref-type="aff" rid="aff-1"/></contrib></contrib-group><aff-alternatives id="aff-1"><aff xml:lang="ru"><institution>ГАУЗ «Оренбургский областной клинический онкологический диспансер»</institution><country>Россия</country></aff><aff xml:lang="en"><institution>Orenburg Regional Clinical Oncology Center</institution><country>Russian Federation</country></aff></aff-alternatives><aff-alternatives id="aff-2"><aff xml:lang="ru"><institution>ГАУЗ «Оренбургский областной клинический онкологический диспансер»; ФГБОУ ВО «Оренбургский государственный медицинский университет» Минздрава России</institution><country>Россия</country></aff><aff xml:lang="en"><institution>Orenburg Regional Clinical Oncology Center; Orenburg state medical university of the Ministry of Health of the Russia</institution><country>Russian Federation</country></aff></aff-alternatives><aff-alternatives id="aff-3"><aff xml:lang="ru"><institution>Московский научно-исследовательский онкологический институт им. П.А. Герцена – филиал ФГБУ «Национальный медицинский исследовательский центр радиологии» Минздрава России</institution><country>Россия</country></aff><aff xml:lang="en"><institution>P.A. Hertsen Moscow Oncology Research Institute – Branch of the National Medical Research Radiological Centre of the Ministryof Health of the Russia</institution><country>Russian Federation</country></aff></aff-alternatives><pub-date pub-type="collection"><year>2023</year></pub-date><pub-date pub-type="epub"><day>15</day><month>11</month><year>2023</year></pub-date><volume>22</volume><issue>5</issue><fpage>71</fpage><lpage>83</lpage><permissions><copyright-statement>Copyright &amp;#x00A9; Зубарева Е.Ю., Сеньчукова М.А., Кармакова Т.А., Зайцев Н.В., 2023</copyright-statement><copyright-year>2023</copyright-year><copyright-holder xml:lang="ru">Зубарева Е.Ю., Сеньчукова М.А., Кармакова Т.А., Зайцев Н.В.</copyright-holder><copyright-holder xml:lang="en">Zubareva E.Y., Senchukova M.A., Karmakova T.A., Zaitsev N.V.</copyright-holder><license xml:lang="ru" license-type="creative-commons-attribution" xlink:href="https://creativecommons.org/licenses/by/4.0/" xlink:type="simple"><license-p>Данная работа распространяется под лицензией Creative Commons Attribution 4.0.</license-p></license><license xml:lang="en" license-type="creative-commons-attribution" xlink:href="https://creativecommons.org/licenses/by/4.0/" xlink:type="simple"><license-p>This work is licensed under a Creative Commons Attribution 4.0 License.</license-p></license></permissions><self-uri xlink:href="https://www.siboncoj.ru/jour/article/view/2762">https://www.siboncoj.ru/jour/article/view/2762</self-uri><abstract><p>Цель исследования – изучить особенности экспрессии PD-L1 в клетках стромы опухоли, перитуморальных микрососудах и изолированных кластерах опухолевых клеток в ткани рака молочной железы (РМЖ) и их корреляции с клинико-морфологическими характеристиками РМЖ.</p><sec><title>Материал и методы</title><p>Материал и методы. В исследование включено 158 пациенток с впервые выявленным инвазивным РМЖ. Экспрессию PD-L1 изучали методом иммуногистохимии. Статистическую обработку результатов выполняли с использованием программы statistica 12.0.</p></sec><sec><title>Результаты</title><p>Результаты. Установлено, что экспрессия PD-L1 в перитуморальных микрососудах встречалась в 41,4 и 61,7 % случаев, при Т1–2 и Т3–4 соответственно (р=0,020) и в 39,8 и 51,7 % случаев, при N0–1 и N2–3 соответственно (р=0,008). В изолированных кластерах опухолевых клеток экспрессия маркера наблюдалась при узловой и диффузной форме РМЖ – в 28,0 и 52,5 % (р=0,005); при i–IIb, IIIa–IIIc и IV  стадии – в 25,9, 39,3 и 66,7 % (р=0,011); при Т1, Т2, Т3 и Т4 – в 30,3, 26,2, 40,0 и 52,5 % (р=0,040); при N0–1 и N2–3 – в 28,2 и 45,5 % случаев (р=0,030) соответственно. Также выявлена ядерная экспрессия в стромальных клетках, которая наблюдалась при узловой и диффузной форме РМЖ – в 28,8 и 55,0 % (р=0,003); при раннем, местнораспространенном и метастатическом РМЖ – в 17,6, 52,5 и 75,0 (р&lt;0,001); при t1, Т2, Т3 и Т4 – в 21,2, 28,7, 80,0 и 55,0 % (р=0,002); при N0, N1, N2 и N3 – в 21,7, 35,3, 51,4 и 55,0 % (р=0,005); при негативном и позитивном статусе ПР – в 49,0 и 29,0 % (р=0,014); при HER2-негативном и HER2-позитивном статусе РМЖ – в 30,3 и 52,8 % случаев (р=0,014) соответственно.</p></sec><sec><title>Заключение</title><p>Заключение. Полученные данные свидетельствуют о связи PD-L1 экспрессии с факторами прогрессирования РМЖ, и определение экспрессии PD-L1 в перитуморальных микрососудах и в изолированных кластерах опухолевых клеток, а также ядерной экспрессии маркера может быть использовано для уточнения прогноза заболевания.</p></sec></abstract><trans-abstract xml:lang="en"><sec><title>Objective</title><p>Objective: to study the features of PD-L1 expression in tumor stromal cells, peritumoral microvessels, and isolated clusters of tumor cells in breast cancer (Bc) tissue and their correlation with the clinical and morphological characteristics of Bc.</p></sec><sec><title>Material and Methods</title><p>Material and Methods. The study included 158 patients with newly diagnosed invasive BC. PD-L1 expression was studied by immunohistochemistry. statistical analysis was performed using statistica 12.0 software.</p></sec><sec><title>Results</title><p>Results. PD-L1 expression in peritumoral microvessels occurred in 41.4 and 61.7 % of cases with t1–2 and T3–4 (p=0.020), and in 39.8 and 51.7 % of cases with N0–1 and N2–3 (p=0.008), respectively. In isolated clusters of tumor cells, the marker expression was observed in 28.0 and 52.5 % of cases in nodular and diffuse forms of BC (p=0.005); in 25.9, 39.3 and 66.7 % of cases at stages I–IIb, IIIa–IIIc and IV  (p=0.011); in 30.3, 26.2, 40.0 and 52.5 % of cases in T1, T2, T3 and T4 (p=0.040); and in 28.2 and 45.5 % of cases in N0–1 and N2–3 (p=0.030), respectively. Nuclear expression of PD-L1 was also detected in stromal cells, and was observed in 28.8 and 55.0 % of cases with nodular and diffuse forms of BC (p=0.003), in 17.6, 52.5 and 75.0 % of cases in early, locally advanced and metastatic BC (p&lt;0.001), in 21.2, 28.7, 80.0 and 55.0 % of cases in T1, T2, T3 and T4 (p=0.002), in 21.7, 35.3, 51.4 and 55.0 % of cases with N0, N1, N2 and N3 (p=0.005), in 49.0 and 29.0 % of cases with negative and positive status of PR (p=0.014), in 30.3 and 52.8 % of cases with HER2-negative and HER2-positive BC status (p=0.014), respectively.</p></sec><sec><title>Conclusion</title><p>Conclusion. The data indicate the relationship between PD-L1 expression and BC progression. The determination of PD-L1 expression in peritumoral microvessels and isolated tumor cell clusters, as well as nuclear expression of the marker, can be used to clarify the prognosis of the disease.</p></sec></trans-abstract><kwd-group xml:lang="ru"><kwd>рак молочной железы</kwd><kwd>опухолевая прогрессия</kwd><kwd>лиганд рецептора программируемой клеточный гибели 1 (Pd-L1)</kwd><kwd>ядерная экспрессия Pd-L1</kwd><kwd>изолированные кластеры опухолевых клеток</kwd><kwd>перитуморальные микрососуды</kwd></kwd-group><kwd-group xml:lang="en"><kwd>breast cancer</kwd><kwd>tumor progression</kwd><kwd>programmed death-ligand 1 (Pd-L1)</kwd><kwd>PD-L1 nuclear expression</kwd><kwd>isolated clusters of tumor cells</kwd><kwd>peritumoral microvessels</kwd></kwd-group><funding-group><funding-statement xml:lang="ru">Исследование выполнено за счет гранта Российского научного фонда № 23-25-00183, https://rscf.ru/ project/23-25-00183/</funding-statement><funding-statement xml:lang="en">The study was supported by the Russian Science Foundation grant No. 23-25-00183, https://rscf.ru/project/23-25-00183/</funding-statement></funding-group></article-meta></front><back><ref-list><title>References</title><ref id="cit1"><label>1</label><citation-alternatives><mixed-citation xml:lang="ru">WHO [Internet]. Breast cancer [cited 2023 Apr 20]. URL: https://www.who.int/news-room/fact-sheets/detail/breast-cancer.</mixed-citation><mixed-citation xml:lang="en">WHO [Internet]. Breast cancer [cited 2023 Apr 20]. URL: https://www.who.int/news-room/fact-sheets/detail/breast-cancer.</mixed-citation></citation-alternatives></ref><ref id="cit2"><label>2</label><citation-alternatives><mixed-citation xml:lang="ru">Zhang J., Zhang S., Gao S., Ma Y., Tan X., Kang Y., Ren W. HIF-1α, TWIST-1 and ITGB-1, associated with Tumor Stiffness, as Novel Predictive Markers for the Pathological Response to Neoadjuvant Chemotherapy in Breast Cancer. Cancer Manag Res. 2020; 12: 2209–22. doi: 10.2147/CMAR.S246349.</mixed-citation><mixed-citation xml:lang="en">Zhang J., Zhang S., Gao S., Ma Y., Tan X., Kang Y., Ren W. HIF-1α, TWIST-1 and ITGB-1, associated with Tumor Stiffness, as Novel Predictive Markers for the Pathological Response to Neoadjuvant Chemotherapy in Breast Cancer. Cancer Manag Res. 2020; 12: 2209–22. doi: 10.2147/CMAR.S246349.</mixed-citation></citation-alternatives></ref><ref id="cit3"><label>3</label><citation-alternatives><mixed-citation xml:lang="ru">Messeha S.S., Zarmouh N.O., Soliman K.F.A. Polyphenols Modulating Effects of PD-L1/PD-1 Checkpoint and EMT-Mediated PD-L1 Overexpression in Breast Cancer. Nutrients. 2021; 13(5): 1718. doi: 10.3390/nu13051718.</mixed-citation><mixed-citation xml:lang="en">Messeha S.S., Zarmouh N.O., Soliman K.F.A. Polyphenols Modulating Effects of PD-L1/PD-1 Checkpoint and EMT-Mediated PD-L1 Overexpression in Breast Cancer. Nutrients. 2021; 13(5): 1718. doi: 10.3390/nu13051718.</mixed-citation></citation-alternatives></ref><ref id="cit4"><label>4</label><citation-alternatives><mixed-citation xml:lang="ru">Nathanson S.D., Detmar M., Padera T.P., Yates L.R., Welch D.R., Beadnell T.C., Scheid A.D., Wrenn E.D., Cheung K. Mechanisms of breast cancer metastasis. Clin Exp Metastasis. 2022; 39(1): 117–37. doi: 10.1007/s10585-021-10090-2.</mixed-citation><mixed-citation xml:lang="en">Nathanson S.D., Detmar M., Padera T.P., Yates L.R., Welch D.R., Beadnell T.C., Scheid A.D., Wrenn E.D., Cheung K. Mechanisms of breast cancer metastasis. Clin Exp Metastasis. 2022; 39(1): 117–37. doi: 10.1007/s10585-021-10090-2.</mixed-citation></citation-alternatives></ref><ref id="cit5"><label>5</label><citation-alternatives><mixed-citation xml:lang="ru">Almozyan S., Colak D., Mansour F., Alaiya A., Al-Harazi O., Qattan A., Al-Mohanna F., Al-Alwan M., Ghebeh H. PD-L1 promotes OCT4 and Nanog expression in breast cancer stem cells by sustaining PI3K/AKT pathway activation. Int J Cancer. 2017; 141(7): 1402–12. doi: 10.1002/ijc.30834.</mixed-citation><mixed-citation xml:lang="en">Almozyan S., Colak D., Mansour F., Alaiya A., Al-Harazi O., Qattan A., Al-Mohanna F., Al-Alwan M., Ghebeh H. PD-L1 promotes OCT4 and Nanog expression in breast cancer stem cells by sustaining PI3K/AKT pathway activation. Int J Cancer. 2017; 141(7): 1402–12. doi: 10.1002/ijc.30834.</mixed-citation></citation-alternatives></ref><ref id="cit6"><label>6</label><citation-alternatives><mixed-citation xml:lang="ru">Mansour F.A., Al-Mazrou A., Al-Mohanna F., Al-Alwan M., Ghebeh H. PD-L1 is overexpressed on breast cancer stem cells through notch3/mTOR axis. Oncoimmunology. 2020; 9(1). doi: 10.1080/2162402X.2020.1729299.</mixed-citation><mixed-citation xml:lang="en">Mansour F.A., Al-Mazrou A., Al-Mohanna F., Al-Alwan M., Ghebeh H. PD-L1 is overexpressed on breast cancer stem cells through notch3/mTOR axis. Oncoimmunology. 2020; 9(1). doi: 10.1080/2162402X.2020.1729299.</mixed-citation></citation-alternatives></ref><ref id="cit7"><label>7</label><citation-alternatives><mixed-citation xml:lang="ru">Wang C., Zhu H., Zhou Y., Mao F., Lin Y., Pan B., Zhang X., Xu Q., Huang X., Sun Q. Prognostic Value of PD-L1 in Breast Cancer: A MetaAnalysis. Breast J. 2017; 23(4): 436–43. doi: 10.1111/tbj.12753.</mixed-citation><mixed-citation xml:lang="en">Wang C., Zhu H., Zhou Y., Mao F., Lin Y., Pan B., Zhang X., Xu Q., Huang X., Sun Q. Prognostic Value of PD-L1 in Breast Cancer: A MetaAnalysis. Breast J. 2017; 23(4): 436–43. doi: 10.1111/tbj.12753.</mixed-citation></citation-alternatives></ref><ref id="cit8"><label>8</label><citation-alternatives><mixed-citation xml:lang="ru">Karnik T., Kimler B.F., Fan F., Tawfik O. PD-L1 in breast cancer: comparative analysis of 3 different antibodies. Hum Pathol. 2018; 72: 28–34. doi: 10.1016/j.humpath.2017.08.010.</mixed-citation><mixed-citation xml:lang="en">Karnik T., Kimler B.F., Fan F., Tawfik O. PD-L1 in breast cancer: comparative analysis of 3 different antibodies. Hum Pathol. 2018; 72: 28–34. doi: 10.1016/j.humpath.2017.08.010.</mixed-citation></citation-alternatives></ref><ref id="cit9"><label>9</label><citation-alternatives><mixed-citation xml:lang="ru">Zhou T., Xu D., Tang B., Ren Y., Han Y., Liang G., Wang J., Wang L. Expression of programmed death ligand-1 and programmed death-1 in samples of invasive ductal carcinoma of the breast and its correlation with prognosis. Anticancer Drugs. 2018; 29(9): 904–10. doi: 10.1097/CAD.0000000000000683.</mixed-citation><mixed-citation xml:lang="en">Zhou T., Xu D., Tang B., Ren Y., Han Y., Liang G., Wang J., Wang L. Expression of programmed death ligand-1 and programmed death-1 in samples of invasive ductal carcinoma of the breast and its correlation with prognosis. Anticancer Drugs. 2018; 29(9): 904–10. doi: 10.1097/CAD.0000000000000683.</mixed-citation></citation-alternatives></ref><ref id="cit10"><label>10</label><citation-alternatives><mixed-citation xml:lang="ru">Catacchio I., Silvestris N., Scarpi E., Schirosi L., Scattone A., Mangia A. Intratumoral, rather than stromal, CD8+ T cells could be a potential negative prognostic marker in invasive breast cancer patients. Transl Oncol. 2019; 12(3): 585–95. doi: 10.1016/j.tranon.2018.12.005.</mixed-citation><mixed-citation xml:lang="en">Catacchio I., Silvestris N., Scarpi E., Schirosi L., Scattone A., Mangia A. Intratumoral, rather than stromal, CD8+ T cells could be a potential negative prognostic marker in invasive breast cancer patients. Transl Oncol. 2019; 12(3): 585–95. doi: 10.1016/j.tranon.2018.12.005.</mixed-citation></citation-alternatives></ref><ref id="cit11"><label>11</label><citation-alternatives><mixed-citation xml:lang="ru">Evangelou Z., Papoudou-Bai A., Karpathiou G., Kourea H., Kamina S., Goussia A., Harissis H., Peschos D., Batistatou A. PD-L1 Expression and Tumor-infiltrating Lymphocytes in Breast Cancer: Clinicopathological Analysis in Women Younger than 40 Years Old. In Vivo. 2020; 34(2): 639–47. doi: 10.21873/invivo.11818.</mixed-citation><mixed-citation xml:lang="en">Evangelou Z., Papoudou-Bai A., Karpathiou G., Kourea H., Kamina S., Goussia A., Harissis H., Peschos D., Batistatou A. PD-L1 Expression and Tumor-infiltrating Lymphocytes in Breast Cancer: Clinicopathological Analysis in Women Younger than 40 Years Old. In Vivo. 2020; 34(2): 639–47. doi: 10.21873/invivo.11818.</mixed-citation></citation-alternatives></ref><ref id="cit12"><label>12</label><citation-alternatives><mixed-citation xml:lang="ru">Huang W., Ran R., Shao B., Li H. Prognostic and clinicopathological value of PD-L1 expression in primary breast cancer: a meta-analysis. Breast Cancer Res Treat. 2019; 178(1): 17–33. doi: 10.1007/s10549-019-05371-0.</mixed-citation><mixed-citation xml:lang="en">Huang W., Ran R., Shao B., Li H. Prognostic and clinicopathological value of PD-L1 expression in primary breast cancer: a meta-analysis. Breast Cancer Res Treat. 2019; 178(1): 17–33. doi: 10.1007/s10549-019-05371-0.</mixed-citation></citation-alternatives></ref><ref id="cit13"><label>13</label><citation-alternatives><mixed-citation xml:lang="ru">Hoffmann L.G., Sarian L.O., Vassallo J., de Paiva Silva G.R., Ramalho S.O.B., Ferracini A.C., da Silva Araujo K., Jales R.M., Figueira D.E., Derchain S. Evaluation of PD-L1 and tumor infiltrating lymphocytes in paired pretreatment biopsies and post neoadjuvant chemotherapy surgical specimens of breast carcinoma. Sci Rep. 2021; 11(1): 22478. doi: 10.1038/s41598-021-00944-w.</mixed-citation><mixed-citation xml:lang="en">Hoffmann L.G., Sarian L.O., Vassallo J., de Paiva Silva G.R., Ramalho S.O.B., Ferracini A.C., da Silva Araujo K., Jales R.M., Figueira D.E., Derchain S. Evaluation of PD-L1 and tumor infiltrating lymphocytes in paired pretreatment biopsies and post neoadjuvant chemotherapy surgical specimens of breast carcinoma. Sci Rep. 2021; 11(1): 22478. doi: 10.1038/s41598-021-00944-w.</mixed-citation></citation-alternatives></ref><ref id="cit14"><label>14</label><citation-alternatives><mixed-citation xml:lang="ru">Du Q., Che J., Jiang X., Li L., Luo X., Li Q. PD-L1 Acts as a Promising Immune Marker to Predict the Response to Neoadjuvant Chemotherapy in Breast Cancer Patients. Clin Breast Cancer. 2020; 20(1): 99–111. doi: 10.1016/j.clbc.2019.06.014.</mixed-citation><mixed-citation xml:lang="en">Du Q., Che J., Jiang X., Li L., Luo X., Li Q. PD-L1 Acts as a Promising Immune Marker to Predict the Response to Neoadjuvant Chemotherapy in Breast Cancer Patients. Clin Breast Cancer. 2020; 20(1): 99–111. doi: 10.1016/j.clbc.2019.06.014.</mixed-citation></citation-alternatives></ref><ref id="cit15"><label>15</label><citation-alternatives><mixed-citation xml:lang="ru">Cirqueira M.B., Mendonça C.R., Noll M., Soares L.R., de Paula Carneiro Cysneiros M.A., Paulinelli R.R., Moreira M.A.R., Freitas-Junior R. Prognostic Role of PD-L1 Expression in Invasive Breast Cancer: A Systematic Review and Meta-Analysis. Cancers (Basel). 2021; 13(23): 6090. doi: 10.3390/cancers13236090.</mixed-citation><mixed-citation xml:lang="en">Cirqueira M.B., Mendonça C.R., Noll M., Soares L.R., de Paula Carneiro Cysneiros M.A., Paulinelli R.R., Moreira M.A.R., Freitas-Junior R. Prognostic Role of PD-L1 Expression in Invasive Breast Cancer: A Systematic Review and Meta-Analysis. Cancers (Basel). 2021; 13(23): 6090. doi: 10.3390/cancers13236090.</mixed-citation></citation-alternatives></ref><ref id="cit16"><label>16</label><citation-alternatives><mixed-citation xml:lang="ru">Zubareva E., Senchukova M., Karmakova T. Predictive significance of HIF-1α, Snail, and PD-L1 expression in breast cancer. Clin Exp Med. 2023. doi: 10.1007/s10238-023-01026-z.</mixed-citation><mixed-citation xml:lang="en">Zubareva E., Senchukova M., Karmakova T. Predictive significance of HIF-1α, Snail, and PD-L1 expression in breast cancer. Clin Exp Med. 2023. doi: 10.1007/s10238-023-01026-z.</mixed-citation></citation-alternatives></ref><ref id="cit17"><label>17</label><citation-alternatives><mixed-citation xml:lang="ru">Chowdhury S., Veyhl J., Jessa F., Polyakova O., Alenzi A., MacMillan C., Ralhan R., Walfish P.G. Programmed death-ligand 1 overexpression is a prognostic marker for aggressive papillary thyroid cancer and its variants. Oncotarget. 2016; 7(22): 32318–28. doi: 10.18632/oncotarget.8698.</mixed-citation><mixed-citation xml:lang="en">Chowdhury S., Veyhl J., Jessa F., Polyakova O., Alenzi A., MacMillan C., Ralhan R., Walfish P.G. Programmed death-ligand 1 overexpression is a prognostic marker for aggressive papillary thyroid cancer and its variants. Oncotarget. 2016; 7(22): 32318–28. doi: 10.18632/oncotarget.8698.</mixed-citation></citation-alternatives></ref><ref id="cit18"><label>18</label><citation-alternatives><mixed-citation xml:lang="ru">Satelli A., Batth I.S., Brownlee Z., Rojas C., Meng Q.H., Kopetz S., Li S. Potential role of nuclear PD-L1 expression in cell-surface vimentin positive circulating tumor cells as a prognostic marker in cancer patients. Sci Rep. 2016; 6. doi: 10.1038/srep28910.</mixed-citation><mixed-citation xml:lang="en">Satelli A., Batth I.S., Brownlee Z., Rojas C., Meng Q.H., Kopetz S., Li S. Potential role of nuclear PD-L1 expression in cell-surface vimentin positive circulating tumor cells as a prognostic marker in cancer patients. Sci Rep. 2016; 6. doi: 10.1038/srep28910.</mixed-citation></citation-alternatives></ref><ref id="cit19"><label>19</label><citation-alternatives><mixed-citation xml:lang="ru">Wu Y., Chen W., Xu Z.P., Gu W. PD-L1 Distribution and Perspective for Cancer Immunotherapy-Blockade, Knockdown, or Inhibition. Front Immunol. 2019; 10. doi: 10.3389/fimmu.2019.02022.</mixed-citation><mixed-citation xml:lang="en">Wu Y., Chen W., Xu Z.P., Gu W. PD-L1 Distribution and Perspective for Cancer Immunotherapy-Blockade, Knockdown, or Inhibition. Front Immunol. 2019; 10. doi: 10.3389/fimmu.2019.02022.</mixed-citation></citation-alternatives></ref><ref id="cit20"><label>20</label><citation-alternatives><mixed-citation xml:lang="ru">Brierley J., Gospodarowicz M.K., Wittekind Ch. (2017). TNM Classification of Malignant Tumors (8th edition). Oxford, UK; Hoboken, NJ: John Wiley &amp; Sons, Inc., 2017.</mixed-citation><mixed-citation xml:lang="en">Brierley J., Gospodarowicz M.K., Wittekind Ch. (2017). TNM Classification of Malignant Tumors (8th edition). Oxford, UK; Hoboken, NJ: John Wiley &amp; Sons, Inc., 2017.</mixed-citation></citation-alternatives></ref><ref id="cit21"><label>21</label><citation-alternatives><mixed-citation xml:lang="ru">Kanugula A.K., Adapala R.K., Jamaiyar A., Lenkey N., Guarino B.D., Liedtke W., Yin L., Paruchuri S., Thodeti C.K. Endothelial TRPV4 channels prevent tumor growth and metastasis via modulation of tumor angiogenesis and vascular integrity. Angiogenesis. 2021; 24(3): 647–56. doi: 10.1007/s10456-021-09775-9.</mixed-citation><mixed-citation xml:lang="en">Kanugula A.K., Adapala R.K., Jamaiyar A., Lenkey N., Guarino B.D., Liedtke W., Yin L., Paruchuri S., Thodeti C.K. Endothelial TRPV4 channels prevent tumor growth and metastasis via modulation of tumor angiogenesis and vascular integrity. Angiogenesis. 2021; 24(3): 647–56. doi: 10.1007/s10456-021-09775-9.</mixed-citation></citation-alternatives></ref><ref id="cit22"><label>22</label><citation-alternatives><mixed-citation xml:lang="ru">Rodig N., Ryan T., Allen J.A., Pang H., Grabie N., Chernova T., Greenfield E.A., Liang S.C., Sharpe A.H., Lichtman A.H., Freeman G.J. Endothelial expression of PD-L1 and PD-L2 down-regulates CD8+ T cell activation and cytolysis. Eur J Immunol. 2003; 33(11): 3117–26. doi: 10.1002/eji.200324270.</mixed-citation><mixed-citation xml:lang="en">Rodig N., Ryan T., Allen J.A., Pang H., Grabie N., Chernova T., Greenfield E.A., Liang S.C., Sharpe A.H., Lichtman A.H., Freeman G.J. Endothelial expression of PD-L1 and PD-L2 down-regulates CD8+ T cell activation and cytolysis. Eur J Immunol. 2003; 33(11): 3117–26. doi: 10.1002/eji.200324270.</mixed-citation></citation-alternatives></ref><ref id="cit23"><label>23</label><citation-alternatives><mixed-citation xml:lang="ru">Gibbons Johnson R.M., Dong H. Functional Expression of Programmed Death-Ligand 1 (B7-H1) by Immune Cells and Tumor Cells. Front Immunol. 2017; 8: 961. doi: 10.3389/fimmu.2017.00961.</mixed-citation><mixed-citation xml:lang="en">Gibbons Johnson R.M., Dong H. Functional Expression of Programmed Death-Ligand 1 (B7-H1) by Immune Cells and Tumor Cells. Front Immunol. 2017; 8: 961. doi: 10.3389/fimmu.2017.00961.</mixed-citation></citation-alternatives></ref><ref id="cit24"><label>24</label><citation-alternatives><mixed-citation xml:lang="ru">Bracamonte-Baran W., Gilotra N.A., Won T., Rodriguez K.M., Talor M.V., Oh B.C., Griffin J., Wittstein I., Sharma K., Skinner J., Johns R.A., Russell S.D., Anders R.A., Zhu Q., Halushka M.K., Brandacher G., Čiháková D. Endothelial Stromal PD-L1 (Programmed Death Ligand 1) Modulates CD8+ T-Cell Infiltration After Heart Transplantation. Circ Heart Fail. 2021; 14(10). doi: 10.1161/CIRCHEARTFAILURE.120.007982.</mixed-citation><mixed-citation xml:lang="en">Bracamonte-Baran W., Gilotra N.A., Won T., Rodriguez K.M., Talor M.V., Oh B.C., Griffin J., Wittstein I., Sharma K., Skinner J., Johns R.A., Russell S.D., Anders R.A., Zhu Q., Halushka M.K., Brandacher G., Čiháková D. Endothelial Stromal PD-L1 (Programmed Death Ligand 1) Modulates CD8+ T-Cell Infiltration After Heart Transplantation. Circ Heart Fail. 2021; 14(10). doi: 10.1161/CIRCHEARTFAILURE.120.007982.</mixed-citation></citation-alternatives></ref><ref id="cit25"><label>25</label><citation-alternatives><mixed-citation xml:lang="ru">Liu S., Qin T., Liu Z., Wang J., Jia Y., Feng Y., Gao Y., Li K. Аnlotinib alters tumor immune microenvironment by downregulating PD-L1 expression on vascular endothelial cells. Cell Death Dis. 2020; 11(5): 309. doi: 10.1038/s41419-020-2511-3.</mixed-citation><mixed-citation xml:lang="en">Liu S., Qin T., Liu Z., Wang J., Jia Y., Feng Y., Gao Y., Li K. Аnlotinib alters tumor immune microenvironment by downregulating PD-L1 expression on vascular endothelial cells. Cell Death Dis. 2020; 11(5): 309. doi: 10.1038/s41419-020-2511-3.</mixed-citation></citation-alternatives></ref><ref id="cit26"><label>26</label><citation-alternatives><mixed-citation xml:lang="ru">Vanharanta S., Massagué J. Origins of metastatic traits. Cancer Cell. 2013; 24(4): 410–21. doi: 10.1016/j.ccr.2013.09.007.</mixed-citation><mixed-citation xml:lang="en">Vanharanta S., Massagué J. Origins of metastatic traits. Cancer Cell. 2013; 24(4): 410–21. doi: 10.1016/j.ccr.2013.09.007.</mixed-citation></citation-alternatives></ref><ref id="cit27"><label>27</label><citation-alternatives><mixed-citation xml:lang="ru">Celià-Terrassa T., Kang Y. Distinctive properties of metastasisinitiating cells. Genes Dev. 2016; 30(8): 892–908. doi: 10.1101/gad.277681.116.</mixed-citation><mixed-citation xml:lang="en">Celià-Terrassa T., Kang Y. Distinctive properties of metastasisinitiating cells. Genes Dev. 2016; 30(8): 892–908. doi: 10.1101/gad.277681.116.</mixed-citation></citation-alternatives></ref><ref id="cit28"><label>28</label><citation-alternatives><mixed-citation xml:lang="ru">Lambert A.W., Pattabiraman D.R., Weinberg R.A. Emerging Biological Principles of Metastasis. Cell. 2017; 168(4): 670–91. doi: 10.1016/j.cell.2016.11.037.</mixed-citation><mixed-citation xml:lang="en">Lambert A.W., Pattabiraman D.R., Weinberg R.A. Emerging Biological Principles of Metastasis. Cell. 2017; 168(4): 670–91. doi: 10.1016/j.cell.2016.11.037.</mixed-citation></citation-alternatives></ref><ref id="cit29"><label>29</label><citation-alternatives><mixed-citation xml:lang="ru">Brown C.W., Amante J.J., Mercurio A.M. Cell clustering mediated by the adhesion protein PVRL4 is necessary for α6β4 integrin-promoted ferroptosis resistance in matrix-detached cells. J Biol Chem. 2018; 293(33): 12741–8. doi: 10.1074/jbc.RA118.003017.</mixed-citation><mixed-citation xml:lang="en">Brown C.W., Amante J.J., Mercurio A.M. Cell clustering mediated by the adhesion protein PVRL4 is necessary for α6β4 integrin-promoted ferroptosis resistance in matrix-detached cells. J Biol Chem. 2018; 293(33): 12741–8. doi: 10.1074/jbc.RA118.003017.</mixed-citation></citation-alternatives></ref><ref id="cit30"><label>30</label><citation-alternatives><mixed-citation xml:lang="ru">Lo H.C., Xu Z., Kim I.S., Pingel B., Aguirre S., Kodali S., Liu J., Zhang W., Muscarella A.M., Hein S.M., Krupnick A.S., Neilson J.R., Paust S., Rosen J.M., Wang H., Zhang X.H. Resistance to natural killer cell immunosurveillance confers a selective advantage to polyclonal metastasis. Nat Cancer. 2020; 1(7): 709–22. doi: 10.1038/s43018-020-0068-9.</mixed-citation><mixed-citation xml:lang="en">Lo H.C., Xu Z., Kim I.S., Pingel B., Aguirre S., Kodali S., Liu J., Zhang W., Muscarella A.M., Hein S.M., Krupnick A.S., Neilson J.R., Paust S., Rosen J.M., Wang H., Zhang X.H. Resistance to natural killer cell immunosurveillance confers a selective advantage to polyclonal metastasis. Nat Cancer. 2020; 1(7): 709–22. doi: 10.1038/s43018-020-0068-9.</mixed-citation></citation-alternatives></ref><ref id="cit31"><label>31</label><citation-alternatives><mixed-citation xml:lang="ru">Cheung K.J., Padmanaban V., Silvestri V., Schipper K., Cohen J.D., Fairchild A.N., Gorin M.A., Verdone J.E., Pienta K.J., Bader J.S., Ewald A.J. Polyclonal breast cancer metastases arise from collective dissemination of keratin 14-expressing tumor cell clusters. Proc Natl Acad Sci USA. 2016; 113(7): 854–63. doi: 10.1073/pnas.1508541113.</mixed-citation><mixed-citation xml:lang="en">Cheung K.J., Padmanaban V., Silvestri V., Schipper K., Cohen J.D., Fairchild A.N., Gorin M.A., Verdone J.E., Pienta K.J., Bader J.S., Ewald A.J. Polyclonal breast cancer metastases arise from collective dissemination of keratin 14-expressing tumor cell clusters. Proc Natl Acad Sci USA. 2016; 113(7): 854–63. doi: 10.1073/pnas.1508541113.</mixed-citation></citation-alternatives></ref><ref id="cit32"><label>32</label><citation-alternatives><mixed-citation xml:lang="ru">Wrenn E., Huang Y., Cheung K. Collective metastasis: coordinating the multicellular voyage. Clin Exp Metastasis. 2021; 38(4): 373–99. doi: 10.1007/s10585-021-10111-0.</mixed-citation><mixed-citation xml:lang="en">Wrenn E., Huang Y., Cheung K. Collective metastasis: coordinating the multicellular voyage. Clin Exp Metastasis. 2021; 38(4): 373–99. doi: 10.1007/s10585-021-10111-0.</mixed-citation></citation-alternatives></ref><ref id="cit33"><label>33</label><citation-alternatives><mixed-citation xml:lang="ru">Pastushenko I., Blanpain C. EMT Transition States during Tumor Progression and Metastasis. Trends Cell Biol. 2019; 29(3): 212–26. doi: 10.1016/j.tcb.2018.12.001.</mixed-citation><mixed-citation xml:lang="en">Pastushenko I., Blanpain C. EMT Transition States during Tumor Progression and Metastasis. Trends Cell Biol. 2019; 29(3): 212–26. doi: 10.1016/j.tcb.2018.12.001.</mixed-citation></citation-alternatives></ref><ref id="cit34"><label>34</label><citation-alternatives><mixed-citation xml:lang="ru">Jiang Y., Zhan H. Communication between EMT and PD-L1 signaling: New insights into tumor immune evasion. Cancer Lett. 2020; 468: 72–81. doi: 10.1016/j.canlet.2019.10.013.</mixed-citation><mixed-citation xml:lang="en">Jiang Y., Zhan H. Communication between EMT and PD-L1 signaling: New insights into tumor immune evasion. Cancer Lett. 2020; 468: 72–81. doi: 10.1016/j.canlet.2019.10.013.</mixed-citation></citation-alternatives></ref><ref id="cit35"><label>35</label><citation-alternatives><mixed-citation xml:lang="ru">Sahoo S., Nayak S.P., Hari K., Purkait P., Mandal S., Kishore A., Levine H., Jolly M.K. Immunosuppressive Traits of the Hybrid Epithelial/Mesenchymal Phenotype. Front Immunol. 2021; 12. doi: 10.3389/fimmu.2021.797261.</mixed-citation><mixed-citation xml:lang="en">Sahoo S., Nayak S.P., Hari K., Purkait P., Mandal S., Kishore A., Levine H., Jolly M.K. Immunosuppressive Traits of the Hybrid Epithelial/Mesenchymal Phenotype. Front Immunol. 2021; 12. doi: 10.3389/fimmu.2021.797261.</mixed-citation></citation-alternatives></ref><ref id="cit36"><label>36</label><citation-alternatives><mixed-citation xml:lang="ru">Rom-Jurek E.M., Kirchhammer N., Ugocsai P., Ortmann O., Wege A.K., Brockhoff G. Regulation of Programmed Death Ligand 1 (PD-L1) Expression in Breast Cancer Cell Lines In Vitro and in Immunodeficient and Humanized Tumor Mice. Int J Mol Sci. 2018; 19(2): 563. doi: 10.3390/ijms19020563.</mixed-citation><mixed-citation xml:lang="en">Rom-Jurek E.M., Kirchhammer N., Ugocsai P., Ortmann O., Wege A.K., Brockhoff G. Regulation of Programmed Death Ligand 1 (PD-L1) Expression in Breast Cancer Cell Lines In Vitro and in Immunodeficient and Humanized Tumor Mice. Int J Mol Sci. 2018; 19(2): 563. doi: 10.3390/ijms19020563.</mixed-citation></citation-alternatives></ref><ref id="cit37"><label>37</label><citation-alternatives><mixed-citation xml:lang="ru">Yu J., Qin B., Moyer A.M., Nowsheen S., Tu X., Dong H., Boughey J.C., Goetz M.P., Weinshilboum R., Lou Z., Wang L. Regulation of sister chromatid cohesion by nuclear PD-L1. Cell Res. 2020; 30(7): 590–601. doi: 10.1038/s41422-020-0315-8.</mixed-citation><mixed-citation xml:lang="en">Yu J., Qin B., Moyer A.M., Nowsheen S., Tu X., Dong H., Boughey J.C., Goetz M.P., Weinshilboum R., Lou Z., Wang L. Regulation of sister chromatid cohesion by nuclear PD-L1. Cell Res. 2020; 30(7): 590–601. doi: 10.1038/s41422-020-0315-8.</mixed-citation></citation-alternatives></ref><ref id="cit38"><label>38</label><citation-alternatives><mixed-citation xml:lang="ru">Gao Y., Nihira N.T., Bu X., Chu C., Zhang J., Kolodziejczyk A., Fan Y., Chan N.T., Ma L., Liu J., Wang D., Dai X., Liu H., Ono M., Nakanishi A., Inuzuka H., North B.J., Huang Y.H., Sharma S., Geng Y., Xu W., Liu X.S., Li L., Miki Y., Sicinski P., Freeman G.J., Wei W. Acetylationdependent regulation of PD-L1 nuclear translocation dictates the efficacy of anti-PD-1 immunotherapy. Nat Cell Biol. 2020; 22(9): 1064–75. doi: 10.1038/s41556-020-0562-4.</mixed-citation><mixed-citation xml:lang="en">Gao Y., Nihira N.T., Bu X., Chu C., Zhang J., Kolodziejczyk A., Fan Y., Chan N.T., Ma L., Liu J., Wang D., Dai X., Liu H., Ono M., Nakanishi A., Inuzuka H., North B.J., Huang Y.H., Sharma S., Geng Y., Xu W., Liu X.S., Li L., Miki Y., Sicinski P., Freeman G.J., Wei W. Acetylationdependent regulation of PD-L1 nuclear translocation dictates the efficacy of anti-PD-1 immunotherapy. Nat Cell Biol. 2020; 22(9): 1064–75. doi: 10.1038/s41556-020-0562-4.</mixed-citation></citation-alternatives></ref><ref id="cit39"><label>39</label><citation-alternatives><mixed-citation xml:lang="ru">Ma R., Liu Y., Che X., Li C., Wen T., Hou K., Qu X. Nuclear PDL1 promotes cell cycle progression of BRAF-mutated colorectal cancer by inhibiting THRAP3. Cancer Lett. 2022; 527: 127–39. doi: 10.1016/j.canlet.2021.12.017.</mixed-citation><mixed-citation xml:lang="en">Ma R., Liu Y., Che X., Li C., Wen T., Hou K., Qu X. Nuclear PDL1 promotes cell cycle progression of BRAF-mutated colorectal cancer by inhibiting THRAP3. Cancer Lett. 2022; 527: 127–39. doi: 10.1016/j.canlet.2021.12.017.</mixed-citation></citation-alternatives></ref><ref id="cit40"><label>40</label><citation-alternatives><mixed-citation xml:lang="ru">Xiong W., Gao Y., Wei W., Zhang J. Extracellular and nuclear PD-L1 in modulating cancer immunotherapy. Trends Cancer. 2021; 7(9): 837–46. doi: 10.1016/j.trecan.2021.03.003.</mixed-citation><mixed-citation xml:lang="en">Xiong W., Gao Y., Wei W., Zhang J. Extracellular and nuclear PD-L1 in modulating cancer immunotherapy. Trends Cancer. 2021; 7(9): 837–46. doi: 10.1016/j.trecan.2021.03.003.</mixed-citation></citation-alternatives></ref></ref-list><fn-group><fn fn-type="conflict"><p>The authors declare that there are no conflicts of interest present.</p></fn></fn-group></back></article>
