title: Tim3/Gal9 interactions between T cells and monocytes result in an immunosuppressive feedback loop that inhibits Th1 responses in osteosarcoma patients.
abstract: The Tim3/Gal9 pathway is associated with immunosuppression and worse clinical outcome in multiple cancers. To illustrate the specific mechanism of Tim3/Gal9 interaction in osteosarcoma, we examined expression, function, and regulation of Tim3/Gal9 in various cells from osteosarcoma patients. Data showed that CD4+T cells, CD8+T cells, and monocytes from both peripheral blood and tumor of osteosarcoma patients contained high frequencies of Tim3+cells, while the Gal9 expression was primarily found in regulatory T cells (Tregs) from osteosarcoma patients and was elevated compared to that in non-cancer controls. The Tim3+CD4+and CD8+T cells presented lower proliferation capacity compared to their Tim3-counterparts, which could be reverted by blocking Tim3 or Gal9. Interestingly, purified Tim3+CD4+T cells secreted more interferon gamma (IFNγ) than purified Tim3-CD4+T cells, but IFNγ production by Tim3+CD4+T cells was vulnerable to Gal9-mediated suppression. In monocytes, Tim3 expression was associated with high interleukin (IL)-10 and low IL-12 cytokine secretion profile. Exogenous recombinant Gal9, as well as CD4+CD25+Treg supernatant, further decreased IL-12 expression in monocytes. In CD4+T cell-monocyte coculture experiments, Tim3+monocytes inhibited IFNγ expression from total CD4+T cells and the development of IFNγ response in naive CD4+T cells. Blocking the Tim3/Gal9 pathway reverted these effects. Together, these results suggested that in osteosarcoma patients, Tim3 expression did not directly mediate immune suppression, but the interaction between Tim3+T cells and monocytes, naive CD4+T cells, and Gal9-expressing CD4+CD25+Tregs could resulting in progressive suppression of Th1 responses.
authors.affiliation: Department of Hand Surgery, No.401 Hospital of PLA, Qingdao 266071, Shandong, China.
authors.forename: Xiuzhong
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Hand Surgery, No.401 Hospital of PLA, Qingdao 266071, Shandong, China.
authors.forename: Yanqing
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Pharmacy, No.401 Hospital of PLA, Qingdao 266071, Shandong, China.
authors.forename: Xu
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Hand Surgery, No.401 Hospital of PLA, Qingdao 266071, Shandong, China.
authors.forename: Jin
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Hand Surgery, No.401 Hospital of PLA, Qingdao 266071, Shandong, China.
authors.forename: Xu
authors.initials: X
authors.lastname: He
authors.affiliation: Department of Hand Surgery, No.401 Hospital of PLA, Qingdao 266071, Shandong, China.
authors.forename: Guodong
authors.initials: G
authors.lastname: Teng
authors.affiliation: Department of Hand Surgery, No.401 Hospital of PLA, Qingdao 266071, Shandong, China. Electronic address: dazhiyuqd@qq.com.
authors.forename: Dazhi
authors.initials: D
authors.lastname: Yu
mesh_terms: D000293:Adolescent; D000328:Adult; D001859:Bone Neoplasms / Q000276:immunology*; D002478:Cells, Cultured; D002648:Child; D018920:Coculture Techniques; D016207:Cytokines / Q000378:metabolism; D025461:Feedback, Physiological; D005260:Female; D037161:Galectins / Q000378:metabolism*; D000072597:Hepatitis A Virus Cellular Receptor 2 / Q000378:metabolism*; D006801:Humans; D007108:Immune Tolerance; D008213:Lymphocyte Activation; D008297:Male; D009000:Monocytes / Q000276:immunology*; D012516:Osteosarcoma / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology*; D055815:Young Adult
chemical_list: D016207:Cytokines; D037161:Galectins; C448908:HAVCR2 protein, human; D000072597:Hepatitis A Virus Cellular Receptor 2; C105032:LGALS9 protein, human
keywords: Gal9; Osteosarcoma; Tim3