Tim3/Gal9 interactions between T cells and monocytes result in an immunosuppressive feedback loop that inhibits Thl responses in osteosarcoma patients

The Tim3/Gal9 pathway is associated with immunosuppression and worse clinical outcome in multiple cancers. To illustrate the specific mechanism of Tim3/Ga19 interaction in osteosarcoma, we examined expression, function, and regulation of Tim3/Ga19 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 Ga19 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 Ga19. Interestingly, purified Tim3+ CD4+ T cells secreted more interferon gamma (IFN gamma) than purified Tim3 CD4(+ T) cells, but IFN gamma production by Tim3(+) CD4(+) T cells was vulnerable to Ga19-mediated suppression. In monocytes, Tim3 expression was associated with high interleukin (IL) -10 and low IL -12 cytokine secretion profile. Exogenous recombinant Ga19, as well as CD4(+)CD25(+)Treg supernatant, further decreased IL -12 expression in monocytes. In CD4+ T cell-monocyte coculture experiments, Tim3+ monocytes inhibited IFN gamma expression from total CD4(+) T cells and the development of IFN gamma response in naive CD4+ T cells. Blocking the Tim3/Ga19 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 Ga19-expressing CINI CD25(+) Tregs could resulting in progressive suppression of Th1 responses. (C) 2017 Elsevier B.V. All rights reserved.