The Expression of CTLA-4 in Breast Tumors and Tumor-Infiltrating Leukocytes Affects Patients’ Systemic Inflammatory Status and Varies According to Their Molecular Subtypes

• Published in: Inflammation Vol. 46; no. 5; pp. 1639 - 1652
• Main Authors: Kern, Rodrigo, da Silva, Janaina Carla, Negretti, Fábio, Ferreira, Mariane Okamoto, Coletto, Matheus Iago Oliveira, de Oliveira, Stefania Tagliari, Alves, Fernanda Mara, Scandolara, Thalita Basso, Rech, Daniel, Panis, Carolina
• Format: Journal Article
• Language: English
• Published: New York Springer US 01-10-2023; Springer Nature B.V
• Subjects: Biomedical and Life Sciences; Biomedicine; Biopsy; Breast cancer; CTLA-4 Antigen - metabolism; CTLA-4 protein; Cytotoxicity; Enzyme-linked immunosorbent assay; Humans; Immunofluorescence; Immunology; Inflammation; Interleukin 12; Interleukin 4; Interleukin-12 - metabolism; Interleukin-4 - metabolism; Internal Medicine; Leukocytes; Lipid peroxidation; Lymphocytes; Lymphocytes T; Lymphocytes, Tumor-Infiltrating - metabolism; Lymphocytes, Tumor-Infiltrating - pathology; Nitric oxide; Nitric-oxide synthase; Oxidative stress; Pathology; Pharmacology/Toxicology; Prognosis; Rheumatology; Triple Negative Breast Neoplasms - metabolism; Triple Negative Breast Neoplasms - pathology; Tumors; breast cancer; ctla-4; inflammation; cytotoxic t lymphocyte-associated antigen 4
• ISSN: 0360-3997; 1573-2576
• DOI: 10.1007/s10753-023-01830-5

Recent evidence has pointed out that the cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) expression is a poor prognosis factor. However, the implications of CTLA-4 expression on circulating inflammatory mediators are unclear for breast cancer. Tumor biopsies and blood samples were collected from 117 breast cancer patients. Oxidative stress parameters were evaluated in plasma samples by measuring the lipoperoxidation profile and nitric oxide metabolites (NOx). Interleukins 12 (IL-12) and 4 (IL-4) were assessed by ELISA. CTLA-4 expression was determined by immunofluorescence assessed by its labeling in tumor-infiltrating leukocytes (TILs) or breast tumors. Correlations between CTLA-4 expression in breast tumors with TCD4/TCD8 infiltrating lymphocyte and inflammation-related genes were performed using data from TIMER 2.0/TCGA databases (
n
 = 2160). CTLA-4 expression in TILs significantly correlated to triple-negative breast tumors. Patients carrying CTLA-4-positive tumors exhibited lower plasmatic NOx levels, and those expressing CTLA-4 in TILs had reduced levels of IL-12 in plasma. No changes in either IL-4 or lipid peroxidation profiles were detected concerning any CTLA4 status. Compared to the Luminal A ones, oxidative stress parameters and cytokines were observed in patients bearing triple-negative tumors. CTLA-4 expression in all breast cancer subtypes positively correlated to TCD4/TCD8 lymphocyte infiltrates, as well as to the pro-inflammatory genes IL12A, IL4, NFKB1, NFKB2, NOS1, NOS2, and NOS3. CTLA-4 expression in both tumor and TILs can affect the systemic inflammatory status of breast cancer patients, especially antitumor molecules such as IL-12 and NOx that correlate to more aggressive disease.