The Tim-3-Galectin-9 Pathway and Its Regulatory Mechanisms in Human Breast Cancer

• Published in: Frontiers in immunology Vol. 10; p. 1594
• Main Authors: Yasinska, Inna M., Sakhnevych, Svetlana S., Pavlova, Ludmila, Teo Hansen Selnø, Anette, Teuscher Abeleira, Ana Maria, Benlaouer, Ouafa, Gonçalves Silva, Isabel, Mosimann, Marianne, Varani, Luca, Bardelli, Marco, Hussain, Rohanah, Siligardi, Giuliano, Cholewa, Dietmar, Berger, Steffen M., Gibbs, Bernhard F., Ushkaryov, Yuri A., Fasler-Kan, Elizaveta, Klenova, Elena, Sumbayev, Vadim V.
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Media S.A 11.07.2019
• Subjects: breast cancer; galectin-9; immune evasion; immune surveillance; Immunology; TIM-3; breast cancer; immune evasion; TIM-3; immune surveillance; galectin-9
• ISSN: 1664-3224; 1664-3224
• DOI: 10.3389/fimmu.2019.01594

Human cancer cells operate a variety of effective molecular and signaling mechanisms which allow them to escape host immune surveillance and thus progress the disease. We have recently reported that the immune receptor Tim-3 and its natural ligand galectin-9 are involved in the immune escape of human acute myeloid leukemia (AML) cells. These cells use the neuronal receptor latrophilin 1 (LPHN1) and its ligand fibronectin leucine rich transmembrane protein 3 (FLRT3, and possibly other ligands) to trigger the pathway. We hypothesized that the Tim-3-galectin-9 pathway may be involved in the immune escape of cancer cells of different origins. We found that studied breast tumors expressed significantly higher levels of both galectin-9 and Tim-3 compared to healthy breast tissues of the same patients and that these proteins were co-localized. Increased levels of LPHN2 and expressions of LPHN3 as well as FLRT3 were also detected in breast tumor cells. Activation of this pathway facilitated the translocation of galectin-9 onto the tumor cell surface, however no secretion of galectin-9 by tumor cells was observed. Surface-based galectin-9 was able to protect breast carcinoma cells against cytotoxic T cell-induced death. Furthermore, we found that cell lines from brain, colorectal, kidney, blood/mast cell, liver, prostate, lung, and skin cancers expressed detectable amounts of both Tim-3 and galectin-9 proteins. The majority of cell lines expressed one of the LPHN isoforms and FLRT3. We conclude that the Tim-3-galectin-9 pathway is operated by a wide range of human cancer cells and is possibly involved in prevention of anti-tumor immunity.