TIM3/CEACAM1 pathway involves in myeloid-derived suppressor cells induced CD8⁺ T cells exhaustion and bone marrow...

Myeloid-derived suppressor cells (MDSC) induced cellular immune deficiency and bone marrow inflammatory microenvironment play an important role in the pathogenesis and progression of myelodysplastic syndrome (MDS), but the underlying mechanism remains unclear. Here, we revealed that immune checkpoint protein TIM3 and CEACAM1 were highly demonstrated on MDSC and CD8⁺ T cells in MDS patients. CD8⁺ T cells were reduced in number and function and presented a exhaustion state. The levels of pro-inflammatory cytokines (IL-1β, IL-18) and CEACAM1 were raised in bone marrow supernatants and MDSC culture supernatants. Blocking or neutralizing TIM3/CEACAM1 and IL-1β/IL-18 partially reversed exhaustion of CD8⁺ T cells. Moreover, TIM3 correlated with NF-κB /NLRP3 inflammatory pathway. The levels of NF-κB/NLRP3/Caspase-1/IL-1β and IL-18 were all increased in MDSC of MDS. Co-culturing MDSC from MDS patients with rhCEACAM1 enhanced NF-κB/NLRP3/Caspase-1/IL-1β and IL-18 levels, whereas blocking TIM3 could partially reverse the above manifestations. These results indicated that TIM3/CEACAM1 pathway involved in CD8⁺ T cells exhaustion and might activate the NF-κB/NLRP3/Caspase-1 pathway in MDSC, increasing pro-inflammatory cytokines secretion in MDS bone marrow microenvironment. This study provided a basis for applying immune checkpoint inhibitors that could simultaneously modulate pro-inflammatory cytokine secretion and enhance anti-tumour immune function in the treatment of MDS.