Immune checkpoint status and exhaustion‐related phenotypes of CD8+ T cells from the tumor‐draining regional lymph nodes in breast cancer

• Published in: Cancer medicine (Malden, MA) Vol. 12; no. 24; pp. 22196 - 22205
• Main Authors: Yilmaz, Izel, Tavukcuoglu, Ece, Horzum, Utku, Yilmaz, Kerim Bora, Akinci, Melih, Gulcelik, Mehmet Ali, Oral, Haluk Barbaros, Esendagli, Gunes
• Format: Journal Article
• Language: English
• Published: United States John Wiley & Sons, Inc 01-12-2023; John Wiley and Sons Inc; Wiley
• Subjects: Antibodies; Antigens; Breast cancer; Breast Neoplasms - genetics; Breast Neoplasms - pathology; cancer biology; CC chemokine receptors; CD25 antigen; CD3 antigen; CD4 antigen; CD56 antigen; CD8 antigen; CD8-Positive T-Lymphocytes; Cell-mediated immunity; Cells; CTLA-4 Antigen; CTLA-4 protein; CXCR5 protein; Cytokines; Cytotoxicity; Female; Hepatitis A Virus Cellular Receptor 2 - genetics; Humans; Immune checkpoint; Immunotherapy; Liver cancer; Lymph nodes; Lymph Nodes - pathology; Lymphatic system; Lymphocytes; Lymphocytes T; Memory cells; microenvironment; PD-1 protein; Peripheral blood; Phenotype; Phenotypes; Programmed Cell Death 1 Receptor - genetics; Receptors, CCR7; Software; surgical oncology; Tumors; United States > US; microenvironment; breast cancer; cancer biology; surgical oncology
• ISSN: 2045-7634; 2045-7634
• DOI: 10.1002/cam4.6802

Background
Functional status of T cells determines the responsiveness of cancer patients to immunotherapeutic interventions. Even though T cell‐mediated immunity is inaugurated in the tumor‐adjacent lymph nodes, peripheral blood has been routinely sampled for testing the immunological assays. The purpose of this study is to determine the immune checkpoint molecule expression and the exhaustion‐related phenotype of cytotoxic T cells in the regional lymph nodes from breast cancer patients.
Patients and methods
Multicolor immunophenotyping was used to determine the expression of PD‐1, TIM‐3, LAG3, CTLA‐4, CCR7, CD45RO, CD127, CD25, CXCR5, and ICOS molecules on CD3+CD4−CD56−CD8+ cytotoxic T cells freshly obtained from the lymph nodes and the peripheral blood samples of the breast cancer patients. The results were assessed together with the clinical data.
Results
A population of cytotoxic T cells was noted with high PD‐1 and CXCR5 expression in the lymph nodes of the breast cancer patients. Co‐expression of PD‐1, CXCR5, TIM‐3, and ICOS indicated a follicular helper T cell (Tfh)‐like, exhaustion‐related immunophenotype in these cytotoxic T cells. Only a minor population with CTLA‐4 and LAG3 expression was noted. The PD‐1+CXCR5+ cytotoxic T cells largely displayed CD45RO+CCR7+ central memory markers. The amount of CXCR5‐expressing PD‐1− cytotoxic T cells was elevated in the lymph nodes of the patients.
Conclusion
The regional lymph nodes of breast cancer patients harbor Tfh‐like exhausted cytotoxic T lymphocytes with high PD‐1 and TIM‐3 checkpoint molecule expression. The immunological conditions in the regional lymph nodes should be implicated for immune checkpoint immunotherapy (ICI) of cancer.
The regional lymph nodes neighboring the tumor tissue harbor a cytotoxic T lymphocyte subset with the immunophenotypic characters of Tfh‐like exhausted cells with high PD‐1 and TIM‐3 checkpoint molecule expression which may modulate the outcomes of immunotherapeutic interventions in breast cancer.