Co‐expression of LAG3 and TIM3 identifies a potent Treg population that suppresses macrophage functions in colorectal cancer patients

Abstract

Regulatory T (Treg) cells are critical suppressors of inflammation and are thought to exert mainly deleterious effects in cancers. In colorectal cancer (CRC), Foxp3 Treg accumulation in tumors was associated with poor prognosis. Hence, we examined the circulating Treg cells in CRC patients. Compared to controls, CRC patients presented mild upregulations in CD4 CD25 T cells and in the more canonical CD4 CD25 Foxp3 Treg cells in peripheral blood mononuclear cells. Both of these Treg populations could be roughly divided into lymphocyte activation gene 3 negative T cell immunoglobulin and mucin-domain containing-3 negative (LAG3 TIM3 ) and LAG3 TIM3 subsets. In CRC patients, the LAG3 TIM3 subset represented approximately half of CD4 CD25 T cells and greater than 60% of CD4 CD25 Foxp3 Treg cells, which was significantly more frequent than in healthy controls. Compared to the LAG3 TIM3 CD4 CD25 T cells, the LAG3 TIM3 CD4 CD25 T cells presented considerably higher transforming growth factor-β and slightly higher interleukin (IL)-10 secretion, together with higher cytotoxic T-lymphocyte associated protein 4 and Foxp3 expression levels. Notably, macrophages following incubation with LAG3 TIM3 CD4 CD25 T cells and LAG3 TIM3 CD4 CD25 T cells displayed different characteristics. Macrophages incubated with LAG3 TIM3 CD4 CD25 T cells presented lower expression of major histocompatibility complex class II, CD80, CD86, and tumor necrosis factor-α but higher expression of IL-10, than macrophages incubated with LAG3 TIM3 CD4 CD25 T cells. Together, our investigations demonstrated that CRC patients presented an enrichment of circulating Treg cells, in which the LAG3 TIM3 subset exhibited more potent expression of inhibitory molecules, and furthermore, the LAG3 TIM3 Treg cells could suppress the proinflammatory activation of macrophages more potently than the LAG3 TIM3 Treg cells.

T Regulatory Cells and Priming the Suppressive Tumor Microenvironment

“…On activated Treg, LAG-3 expression becomes upregulated facilitating robust interaction with MHC II on DCs, further promoting suppression of the anti-tumor response in the TME (94). LAG-3+CD4+CD25+ Treg isolated from colorectal cancer patients secrete high levels of immunosuppressive cytokines including TGFβ and IL-10, thereby maintaining the immunosuppressive milieu (95). Camisaschi et al describe a population of CD4+CD25+FoxP3+ T cells expressing LAG-3 with increased presence in peripheral circulation and solid tumor in advanced stage melanoma and colorectal cancers.…”

Relevance of Regulatory T Cells during Colorectal Cancer Development

“…Similarly, aiming to induce immunosuppression, Treg cells have been associated with tumor progression during CRC ( Figure 2 ) [ 49 ]. Interestingly, CRC patients display Treg cells with a higher expression of several molecules that correlate with suppression, such as Tim-3, LAG-3, TGF-β, IL-10, CD25, and CTLA-4 [ 50 ], and by the BLIMP-1 transcription factor expression in the tumor [ 51 ]. The infiltration of Treg cells into the colon is significantly higher in CRC than in a healthy colon, as well as in patients with limited disease (Union for International Cancer Control (UICC) criteria I and II) than in metastatic (UICC criteria III and IV) ones [ 52 ].…”

Netrin-1 reduces lung ischemia-reperfusion injury by increasing the proportion of regulatory T cells

“…25,26 For ischemia-reperfusion injury, Treg transplantation can significantly reduce infiltration of macrophages and lymphocytes into ischemic tissue and can inhibit apoptosis. 27,28 Our results showed that the proportion of Tregs was significantly decreased in LIRI mice, suggesting that the inflammatory response was activated in these mice. Excessive inflammation can cause further damage to lung tissues.…”