TIM3/CEACAM1 pathway involves in myeloid‐derived suppressor cells induced CD8⁺ T cells exhaustion and bone marrow inflammatory microenvironment in myelodysplastic syndrome

Abstract

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 proinflammatory cytokine secretion and enhance anti-tumour immune function in the treatment of MDS.

Lactoferrin alleviates Western diet-induced cognitive impairment through the microbiome-gut-brain axis

“…As a result, numerous neuroin ammation processes further exacerbate the pathological processes that cause cognitive impairment [40]. The in ammatory signaling pathway NF-κB/NLRP3/caspase-1 is activated in a variety of cells [39,41]. In this study, NF-κB/NLRP3 in ammasome activation was found to be involved in neuroin ammation caused by WD feeding.…”

Bone Marrow Immune Microenvironment in Myelodysplastic Syndromes

“…Tao et al found that CD8+ T-cell exhaustion in MDS was partially dependent upon activation of the T-cell immunoglobulin and mucin-domain containing 3 (TIM3)/Galectin 9 (Gal 9) pathway [ Figure 4 ] and suggested that Gal 9 upregulation by MDSCs is responsible for this activation [ 179 ]. TIM3/Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) pathway activation may also be an alternative mechanism of MDSC involvement in T-cell exhaustion [ 180 ]. Irrespective of the specific mechanisms of MDSC-induced inhibition, MDSCs do not harbor the same mutations as the dysplastic clones [ 174 ], thus constituting an independent cellular component of the microenvironment that is actively involved in MDS pathophysiology.…”

Myeloid-Derived Suppressor Cells: New Insights into the Pathogenesis and Therapy of MDS

“…An analogous population has been identified by the unsupervised clustering of multidimensional mass cytometry data in patients with MDS [ 83 ]. The expansion of MDSCs has been mainly observed in the patients classified as high risk [ 80 , 81 , 82 , 84 ]. Although it is still an open question under investigation, there is more evidence today, mainly from preclinical models [ 78 , 85 ], that the presence of MDSCs in the BM per se can induce myelodysplastic changes and, therefore, the accumulation of MDSCs in the BM of MDS patients could be of pathogenetic significance contributing to the development and clinical course of the disease, as is discussed in detail in the next section.…”

“…In line with these data, it has also been reported that the levels of IL-10 and TGFβ1 produced by Lin − /CD33 + / DR − MDSCs are increased in high-risk MDS patients, implying their possible prognostic value in patients with MDS [ 92 ]. Moreover, MDSCs could be themselves cellular sources of proinflammatory cytokines such as IL-1β [ 84 ], contributing to the inflammatory milieu, a well characterized feature of MDS [ 93 ].…”

“…It was shown, however, that in the presence of TIM3/Gal9 inhibitors, the suppressive effect of the MDSCs on CD8+ cells was abrogated, indicating that the Gal9-TIM3 axis may play a role in the MDS MDSC-mediated T cell suppression. The possibility of MDSCs inducing T cell exhaustion in MDS has been also raised by another group, with the secretion of CEACAM1 being one of the factors proposed to mediate this action [ 84 ]. In another study, it has been proposed that the STAT3/Arg1 axis is involved in MDSCs-mediated immunosuppression in MDS, since again the pharmacological inhibition of STAT3 was able to improve the MDSC-induced changes of effector molecules on CD8+ T cells in vitro [ 81 ].…”