High Expression of HLA-G in Ovarian Carcinomatosis: The Role of Interleukin-1β

• Published in: Neoplasia (New York, N.Y.) Vol. 21; no. 3; pp. 331 - 342
• Main Authors: Ullah, Matti, Azazzen, Dallel, Kaci, Rachid, Benabbou, Nadia, Pujade Lauraine, Eric, Pocard, Marc, Mirshahi, Massoud
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.03.2019; Elsevier Limited; Neoplasia Press; Elsevier
• Subjects: Ascites; Ascitic fluid; Biomarkers; Carcinoma - genetics; Carcinoma - immunology; Carcinoma - metabolism; Cell Adhesion; Cell Line, Tumor; Cell Membrane - metabolism; Cytokines; Cytokines - metabolism; Enzyme-Linked Immunosorbent Assay; Female; Gene Expression Regulation, Neoplastic; Histocompatibility antigen HLA; HLA-G Antigens - genetics; HLA-G Antigens - immunology; HLA-G Antigens - metabolism; Humans; IL-1β; Immunohistochemistry; Immunological memory; Inflammation; Interleukin-1beta - metabolism; Lymphocytes T; Lymphocytes, Tumor-Infiltrating - immunology; Lymphocytes, Tumor-Infiltrating - metabolism; Memory cells; Natural killer cells; NF-κB protein; Original article; Ovarian cancer; Ovarian Neoplasms - genetics; Ovarian Neoplasms - immunology; Ovarian Neoplasms - metabolism; Peritoneum; Protein Binding; Stromal cells; Tumor cell lines; Tumor cells; Tumor-infiltrating lymphocytes
• ISSN: 1476-5586; 1522-8002; 1476-5586
• DOI: 10.1016/j.neo.2019.01.001

The present study focuses on the influence of the tumor microenvironment on the expression of HLA-G in ovarian cancer and its impact on immune cells. We used carcinomatosis fluids (n = 16) collected from patients diagnosed with epithelial ovarian cancer, detected by an increase in CA125 levels. Our results indicate that HLA-G is expressed by 1) ascitic cell clusters, 2) stromal cells (hospicells) extracted from cancer cell clusters, and 3) cancer cell lines and tumor cells. The origin of HLA-G was linked to inflammatory cytokines present in the cancer microenvironment. In parallel, the ascitic fluid of patients with ovarian cancer contains soluble HLA-G (sHLA-G). The mesothelial cell layer and submesothelial tissues, as well as the immune cell infiltrate, do not secrete HLA-G. In contrast, sHLA-G is absorbed by peritoneal tissues along with mesothelial layers as well as immune cell infiltrates. We demonstrated that interleukin-1β along with TGF-β can be a major HLA-G–inducing factor that upregulates HLA-G expression through the NF-κB pathway. The level of HLA-G in ascites correlated positively with the expression of T regulatory (T-regs) cells, while it negatively correlated with the expression of natural killer and memory cells in tumor-infiltrating immune cells. In conclusion, the production of HLA-G is associated with the presence of inflammatory cytokines and is strongly correlated with microenvironment tolerant cells such as T-regs and diminution of NK and memory T cells.