Research progress of a new immune checkpoint inhibitor T-cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain in anti-tumor immunotherapy / 中国热带医学

@#The T-cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT) is an inhibitory receptor mainly expressed on active T-cells, or natural killer cells (NK cells) that activate negative stimulus signals in immune cells by combining with multiple ligands on the surface of target cells including tumor cells and infected cells. TIGIT plays an important regulatory role in the immune pathogenesis of tumors, viral infections and various autoimmune diseases by inhibiting the over activation of cells and the over secretion of proinflammatory cytokines. Recent researches show that TIGIT is highly expressed in T cells and NK cells of cancer patients, and is related to disease progression and poor clinical prognosis. Researchers try to enhance the activity of T cells or NK cells by blocking the binding of TIGIT and its ligand for therapeutic intervention. At present, there have been many reports about the use of anti-TIGIT monoclonal antibody treatment in different mouse tumor models leading to tumor regression, TIGIT has received extensive attention in cancer immunotherapy as a promising target for next generation cancer immunotherapy. Several clinical trials are currently evaluating the efficacy of anti-TIGIT monoclonal antibodies (mAbs) in patients with several cancers. The most advanced candidate, tiragolumab, has exhibited remarkable efficacy in programmed cell death ligand 1 (PD-L1)-positive non-small cell lung carcinoma (NSCLC) patients in phase Ⅱ clinical trials, in combination with PD-L1 blockade. However, the specific mechanism of TIGIT blockade remains to be fully elucidated.

Killing effect of amplified NK cells on gastric cancer cells and its mechanism / 吉林大学学报(医学版)

Objective: To investigate the killing effect of amplified natural killer (NK) cells on the gastric cancer cells, and to elucidate its mechanism. Methods: The peripheral blood mononuclear cells (PBMCs) from 15 patients with gastric cancer were extracted and isolated. The morphology of NK cells before and after amplification was observed, the percentages of NK cells before and after amplification were detected, and the amplification time of NK cells after amplification was calculated. The killing effects of NK cells on the gastric cancer cells before and after amplification were detected. The percentages of expressions of killing activating receptors NKG2D and DNAM-1 and killing inhibitory receptors KIR2DL1 and KIR3DL1 were detected by flow cytometry. Results: Before amplification, the NK cells were round, small in size and scattered in distribution. After amplification, the NK cells were increased in size and irregular in shape. The percentage of NK cells after amplification was significantly higher than that before amplification ( P<.0. 01). and the number of the NK cells after amplification was (596 ± 152) times of before amplification. When the effective target ratio was 5 : 1. the killing activity of NK cells on the gastric cancer cells after amplification was significantly higher than that before amplification (P<0.01). After amplification, the percentages of expressions of killing activating receptors NKG2D and DNAM-1 were significantly higher than those before amplification ( P<0. 01). After amplification, the percentages of expressions of killing inhibitory receptors KIR2DL1 and KIR3DL1 were significantly lower than those before amplification (P<0.05). Conclusion: The killing effect of NK cells on the gastric cancer cells after amplification is stronger than before amplification. The mechanism may be related to increasing the expressions of activated receptors and decreasing the expressions of inhibitory receptors on the surface of NK cells after amplification.

HCMV-infected human THP-1 cells induce expression of HLA-G and its receptors / 中国病理生理杂志

[ ABSTRACT] AIM: To investigate the differential expression of human leukocyte antigen-G ( HLA-G) isoforms and its receptors in human monocyte line THP-1 after human cytomegalovirus ( HCMV) infection for exploring the role of HLA-G in HCMV escaping the immune response of the organism .METHODS: THP-1 cells were infected with HCMV Towne strain.The expression of HLA-G isoforms at mRNA and protein levels was determined by RT-PCR and Western blot, respectively.The surface expression of HLA-G and its receptors ILT2/ILT4 and the cell viability were analyzed by flow cytometry.The levels of soluble HLA-G (sHLA-G) and IL-10 were measured by ELISA.RESULTS:After infection of the THP-1 cells with HCMV , no obvious apoptosis in the cells was observed , and the viability of the cells was high .A significant up-regulation of HLA-G1,-G3,-G4 and-G5 at mRNA expression level 1 d after infection was found , while the protein expression of HLA-G1 and HLA-G5 isoforms was mainly detected .The expression of HLA-G/ILT2/ILT4 was evi-dently up-regulated 1 d after infection .The level of sHLA-G was significantly increased 1 d after infection as compared with control group (P<0.01).The expression of IL-10 was obviously up-regulated 1 d post-infection as compared with control group.CONCLUSION:The differential expression of HLA-G isoforms and secretion of the receptors ILT 2/ILT4 and IL-10 in the THP-1 cells are induced after HCMV infection .This study provides experimental evidence for evaluating the immune mechanism of HCMV infection .

Expression of leukocyte-associated immunoglobulin-like receptor-1 (LAIR-1) on osteoclasts and its potential role in rheumatoid arthritis

OBJECTIVE: Leukocyte-associated immunoglobulin-like receptor-1 is an inhibitory receptor primarily expressed by immune cells. This study was undertaken to define the role of this molecule in osteoclast differentiation and rheumatoid arthritis. METHODS: In vitro osteoclast assays were performed to characterize the role of Leukocyte-associated immunoglobulin-like receptor-1 in murine and human osteoclastogenesis. Human Leukocyte-associated immunoglobulin-like receptor-1 expression was assessed by immunohistochemistry staining in the synovium of patients with rheumatoid arthritis. The levels of soluble Human Leukocyte-associated immunoglobulin-like receptor-1 were determined by enzyme-linked immunosorbent assay. RESULTS: We found that multinucleated osteoclast formation from mouse bone marrow cells was inhibited by treatment with a monoclonal antibody against mouse Leukocyte-associated immunoglobulin-like receptor-1 in vitro. By immunohistochemistry, we found that Leukocyte-associated immunoglobulin-like receptor-1 was mainly expressed by macrophages in the inflamed synovial tissue of rheumatoid arthritis patients. In addition, serum and synovial fluid levels of soluble Leukocyte-associated immunoglobulin-like receptor-1 were higher in rheumatoid arthritis patients compared to healthy controls or osteoarthritis patients. Moreover, overexpression of Leukocyte-associated immunoglobulin-like receptor-1 in CD14+ monocytes from healthy volunteers also inhibited human osteoclastogenesis. CONCLUSION: Collectively, these data demonstrate for the first time that Leukocyte-associated immunoglobulin-like receptor-1 inhibits osteoclastogenesis. Therefore, these results may have therapeutic implications for the treatment of rheumatoid arthritis. .

Regulation of Immune Responses by the Activating and Inhibitory Myeloid-Associate Immunoglobuline-Like Receptors (MAIR) (CD300)

Activating and inhibitory cell surface receptors play important roles in regulation of immune responses. Recent progress has demonstrated that many inhibitory receptors pair with activating, as well as inhibitory, isoforms, both of whose genes are located in small clusters on a chromosome. We and others identified paired activating and inhibitory immunoglobulin-like receptors, designated myeloid-associated immunoglobulin-like receptors (MAIR) (CD300). MAIR is a multigene family consisting of nine genes on a small segment of mouse chromosome 11. MAIR family receptors are preferentially expressed on myeloid cells, including macrophages, dendritic cells, granulocytes, and bone-marrow-derived cultured mast cells, and a subset of B cells and regulate activation of these cells. Thus, MAIR plays an important role in innate immunity mediated by myeloid cells.