oncotomskСибирский онкологический журналSiberian journal of oncology1814-48612312-3168Tomsk National Research Medical Сепtеr of the Russian Academy of Sciences10.21294/1814-4861-2024-23-1-87-97oncotomsk-2959Research ArticleЛАБОРАТОРНЫЕ И ЭКСПЕРИМЕНТАЛЬНЫЕ ИССЛЕДОВАНИЯLABORATORY AND EXPERIMENTAL STUDIESВизуализация контакта PD-L1-положительных и PD-1-положительных иммунных клеток в микроокружении рака молочной железыVisualization of PD-L1-positive and PD-1-positive immune cell contact in the breast cancer microenvironmenthttps://orcid.org/0000-0003-2106-3513КалинчукА. Ю.KalinchukA. Yu.

Калинчук Анна Юрьевна - младший научный сотрудник лаборатории молекулярной терапии рака.

634009, Томск, пер. Кооперативный, 5

Researcher ID (WOS): ABF-1277-2022; Author ID (Scopus): 57797359600

Anna Yu. Kalinchuk - Junior Researcher, Laboratory of Molecular Cancer Therapy, Cancer Research Institute, Тomsk National Research Medical Center, Russian Academy of Sciences.

5, Kooperativny St., Tomsk, 634009

Researcher ID (WOS): ABF-1277-2022; Author ID (Scopus): 57797359600

annakalinchuk2022@gmail.comhttps://orcid.org/0000-0002-7633-9620ПерельмутерВ. М.PerelmuterV. M.

Перельмутер Владимир Михайлович - доктор медицинских наук, профессор, главный научный сотрудник отделения общей и молекулярной патологии.

634009, Томск, пер. Кооперативный, 5

Researcher ID (WOS): C-8227-2012; Author ID (Scopus): 8091317300

Vladimir M. Perelmuter - MD, Professor, Chief Researcher, Department of General and Molecular Pathology, Cancer Research Institute, Тomsk National Research Medical Center, Russian Academy of Sciences.

5, Kooperativny St., Tomsk, 634009

Researcher ID (WOS): C-8227-2012; Author ID (Scopus): 8091317300

https://orcid.org/0000-0003-2061-8417ТаширеваЛ. А.TashirevaL. A.

Таширева Любовь Александровна - доктор медицинских наук, заведующая лабораторией молекулярной терапии рака.

634009, Томск, пер. Кооперативный, 5

Researcher ID (WOS): C-8222-2012; Author ID (Scopus): 55234960400

Lyubov A. Tashireva - MD, DSc, Head of the Laboratory of Molecular Cancer Therapy, Cancer Research Institute, Тomsk National Research Medical Center, Russian Academy of Sciences.

5, Kooperativny St., Tomsk, 634009

Researcher ID (WOS): C-8222-2012; Author ID (Scopus): 55234960400

Научно-исследовательский институт онкологии, Томский национальный исследовательский медицинский центр Российской академии наукРоссияCancer Research Institute, Tomsk National Research Medical Center, Russian Academy of SciencesRussian Federation2024210320242318797Copyright © Калинчук А.Ю., Перельмутер В.М., Таширева Л.А., 20242024Калинчук А.Ю., Перельмутер В.М., Таширева Л.А.Kalinchuk A.Y., Perelmuter V.M., Tashireva L.A.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.siboncoj.ru/jour/article/view/2959

Функционирование иммунной контрольной точки PD-1/PD-L1 в микроокружении рака молочной железы (РМЖ) может приводить к ускользанию опухоли от иммунного ответа. Однако неизвестно, как часто в ткани опухоли наблюдается контакт PD-L1 с PD-1, какие PD-L1-позитивные клетки преимущественно участвуют во взаимодействии и какую прогностическую значимость, в том числе у пациентов с иммунотерапией, оно имеет. Цель исследования – оценить частоту встречаемости ко-локализации PD-1-положительных и PD-L1-положительных клеток в микроокружении РМЖ вне проведения иммунотерапии, а также определить популяционную принадлежность данных клеток. Материал и методы. В исследование включено 25 пациентов с инвазивной карциномой молочной железы. С использованием мультиплексной TSA (tyramide signal amplifcation)-модифицированной иммуногистохимии в опухолевом микроокружении были визуализированы контакты иммунных клеток, одна из которых несет PD-1, а другая – PD-L1. Было оценено участие в таких взаимодействиях М1 макрофагов, М2 макрофагов, лимфоцитов и других иммунных клеток. Результаты. У половины больных РМЖ, включенных в исследование, в микроокружении обнаружены взаимодействия иммунных клеток, одна из которых несет PD-1, а другая – PD-L1. Наличие контактов клеток, несущих PD-1 и PD-L1, связано с уровнем TILs и соотношением количества PD-1+ и PD-L1+ клеток в микроокружении опухоли. Взаимодействие PD-1/PD-L1 было характерно в равной степени для пациенток как с положительным, так и с отрицательным PD-L1-статусом. В рассмотренных клеточных контактах в роли PD-L1+ клеток в подавляющем большинстве случаев выступали макрофаги. Лимфоциты скорее являлись PD-1-положительными клетками при контакте, чем клетками, несущими PD-L1. Кроме того, обнаружено, что безметастатическая выживаемость не сопряжена с наличием или отсутствием в опухолевом микроокружении ко-локализованных клеток, несущих PD-1 и PD-L1. Заключение. Ко-локализация иммунных клеток, несущих PD-1 и PD-L1, характерна для микроокружения РМЖ, и в таких взаимодействиях участвуют М1 и М2 макрофаги, CD3+ лимфоциты и другие иммунные клетки. Дальнейшие исследования требуются для установления прогностической значимости таких контактов.

Functioning of the PD-1/PD-L1 immune checkpoint in the microenvironment of breast cancer may lead to the tumor escape from the immune response. However, it is unknown how often PD-L1 binds to PD-1 in breast cancer patients, which PD-L1-positive cells are predominantly involved in the interaction, and what prognostic significance it has. The objective of the study was to assess the frequency of co-location of PD-1/PD-L1- positive cells in the microenvironment of breast cancer as well as to determine the population of these cells. Material and Methods. The study included 25 patients with invasive breast carcinoma. Interaction between cells carrying the PD-1 receptor and the PD-L1 ligand in the tumor microenvironment were visualized using multiplex TSA (tyramide signal amplification)-modified immunohistochemistry. Participation of M1 macrophages (CD68+CD163-CD3-CKAE1/3-), M2 macrophages (CD68+/-CD163+CD3-CKAE1/3-), lymphocytes (CD68- CD163-CD3+CKAE1/3-) and other immune cells in these interactions was assessed. Results. Half of the breast cancer patients included in the study had interactions of immune cells of the microenvironment, one of which carried PD-1, and the other carried PD-L1. The contact of cells carrying PD-1 and PD-L1 was associated with the level of TILs and the ratio of PD-1+/ PD-L1+ cells in the tumor microenvironment. The PD-1/PD-L1 interaction was found with similar frequency in PD-L1 positive and negative patients. In the cell contacts, macrophages acted as PD-L1+ cells in the vast majority of cases. Lymphocytes were PD-1-positive cells rather than PD-L1- carrying cells. In addition, it was found that metastasis-free survival was not associated with the presence or absence of co-localized cells carrying PD-1 and PD-L1 in the tumor microenvironment. Conclusion. Co-location of immune cells carrying PD-1 and PD-L1 occurs in breast cancer. M1 and M2 macrophages, CD3+ lymphocytes and other immune cells are involved in these interactions. However, further studies are needed to establish the prognostic significance of these contacts.

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The authors declare that there are no conflicts of interest present.