The immune checkpoint TIGIT is upregulated on T cells during bacterial infection and is a potential target for immunotherapy
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PROVIDER: PRJNA980088 | ENA |
REPOSITORIES: ENA
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Project description:Antibiotic resistance is a major public health threat, and alternatives to antibiotic therapy are urgently needed. Immunotherapy, particularly the blockade of inhibitory immune checkpoints, is a leading treatment option in cancer and autoimmunity. In this study, we used a murine model of Salmonella Typhimurium infection to investigate whether immune checkpoint blockade could be applied to bacterial infection. We found that the immune checkpoint T-cell immunoglobulin and ITIM domain (TIGIT) was significantly upregulated on lymphocytes during infection, particularly on CD4+ T cells, drastically limiting their proinflammatory function. Blockade of TIGIT in vivo using monoclonal antibodies was able to enhance immunity and improve bacterial clearance. The efficacy of anti-TIGIT was dependent on the capacity of the antibody to bind to Fc (fragment crystallizable) receptors, giving important insights into the mechanism of anti-TIGIT therapy. This research suggests that targeting immune checkpoints, such as TIGIT, has the potential to enhance immune responses toward bacteria and restore antibacterial treatment options in the face of antibiotic resistance. In this experiment, we investigated the effect of TIGIT on CD4+ T cells by performing bulk RNA-sequencing on WT or TIGIT-/- CD4+ T cells in the context of S. Typhimurium infection.
2024-10-31 | GSE234086 | GEO
Project description:TIGIT+ Tregs suppress Th1 and Th17 responses while sparing Th2 responses. Analysis of global gene expression of TIGIT+ vs. TIGIT- Tregs from naive mice reveled that TIGIT+ Tregs display an activated phenotype and are enriched for Treg signature genes including the Treg effector molecule Fgl2 which enables them to selectively spare Th2 responses. TIGIT+ and TIGIT- Tregs were sorted from naïve Foxp3-GFP KI mice (pooled spleen and lymph nodes) TIGIT: T cell immunoreceptor with Ig and ITIM domains
2014-12-12 | E-GEOD-56299 | biostudies-arrayexpress
Project description:Combination immunotherapy based on immune checkpoint inhibitors (ICIs) has shown great success in the treatment of many types of cancers and has become the mainstream in the comprehensive treatment of cancers. Ablation in combination with immunotherapy has achieved tremendous efficacy in some preclinical and clinical studies. To date, our team proved that ablation in combination with ICIs was a promising antitumor therapeutic strategy for the liver metastasis of colorectal cancer (CRC). Moreover, we found that the expression of T cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT) expression was up-regulated after microwave ablation (MWA), indicating that TIGIT was involved in immunosuppression, and the combination of MWA and TIGIT blockade represented a potential clinical treatment strategy. In this study, we analyzed the single-cell RNA sequencing (scRNA-seq) data from the MWA and MWA plus anti-TIGIT groups. We found that TIGIT blockade in combination with MWA significantly promoted the expansion and functions of CD8+ TILs and reshaped myeloid cells in the tumor microenvironment (TME). In conclusion, TIGIT blockade in combination with MWA was a novel treatment strategy for the liver metastasis of CRC, and this combination therapy could reprogram the TME toward an antitumor environment.
2022-03-30 | GSE194209 | GEO
Project description:Tim-1, a phosphatidylserine receptor expressed on B cells induces IL-10 production by sensing apoptotic cells. Here we show that mice with B cell-specific Tim-1 deletion developed tissue inflammation in multiple organs including spontaneous paralysis with inflammation in the central nervous system (CNS). Transcriptomic analysis demonstrated that besides IL-10, Tim-1+ B cells also differentially expressed a number of co-inhibitory “checkpoint” receptors including TIGIT. Mice with B cell-specific TIGIT deletion developed spontaneous paralysis with CNS inflammation but with limited inflammation in other organs. Our findings suggest that Tim-1+ B cells are essential for maintaining self-tolerance and restraining tissue inflammation, and that Tim-1 dependent TIGIT expression on B cells is essential for maintaining CNS-specific tolerance. A possible critical role of AhR in regulating the B cell function is discussed, as we found that AhR is a top-ranked transcription factor expressed in Tim-1+ B cells and regulates their TIGIT and IL-10 expression.
2020-08-31 | GSE150786 | GEO
Project description:Background. Although several immunotherapies against glioblastoma (GBM) have been investigated for long time, only limited effective results are acquired. Therefore, we developed immunotherapy based on genome edited NK cells knocking out the checkpoint receptor, which would overcome the immunosuppressive tumor microenvironment in GBM. Methods. We generated T cell immunoglobulin and ITIM domain (TIGIT), an inhibitory receptor expressed on lymphocytes, knockout (KO) human primary NK cells using the clustered regularly interspaced short palindromic repeats (CRISPR)/ CRISPR-associated protein9 (Cas9), each single guide RNA targeting different genome sites on TIGIT coding exons. To detect anti-tumor activity of genome edited NK cells against GBM, we utilized 2D adherent model and spheroids derived from GBM cell lines, U87, T98G, LN18, and U251. Subsequently, we performed real time cell growth assays, flow cytometry based apoptosis assays, and ELISA for investigating anti-tumor activity. Result. We established TIGIT KO human primary NK cells using CRISPR/Cas9. Flow cytometry indicated effective knockout of TIGIT and unchanged expression of immune checkpoint receptors other than TIGIT. T7 endonuclease I mutation detection assays showed that RNPs disrupted the intended genome sites. Using real time cell growth assays, we revealed enhanced anti-tumor activity of genome edited NK cells against 2D adherent GBM cells. The genome edited NK cells also exhibits enhanced anti-tumor effect against GBM spheroids derived from GBM cell lines.Conclusion. Our founding suggests that immunotherapy based on TIGIT KO NK cells using CRISPR/Cas9 is a promising therapy against GBM.
2022-09-11 | GSE212941 | GEO
Project description:IGSF8 is an Innate Immune Checkpoint and Cancer Immunotherapy Target
| PRJEB75001 | ENA
Project description:Bladder cancer is a highly metastatic tumor and one of the most common malignant tumors originating in the urinary system. Although the application of immune checkpoint, including programmed cell death-1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), achieved definite efficacy, the effect of immunotherapy for bladder cancer is still not very satisfactory. Therefore, it is very urgent to develop new targets to expand the options of immunotherapies. In this study, we utilized single cell sequencing to explore the cell composition and detected a subset of Treg cells with high expression of T cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT) and interleukin (IL)-32 molecules. Certainly, anti-tumor immune response was suppressed by this subset of Treg cells and IL-32 promoted the bladder cancer metastasis. Nevertheless, targeting TIGIT not only could reverse immunosuppression through restoring anti-tumor immune response mediated by T cells but suppressed the secretion of IL-32 and inhibited the metastasis of bladder cancer cells. Thus, our study provided a novel insight into the immunosuppression in bladder cancer and developed the TIGIT as the novel target for immunotherapy of bladder cancer. Furthermore, we also illustrated mechanism of the dual effect of targeting TIGIT in bladder cancer and revealed the metastasis-promoting effect of IL-32 in bladder cancer. Taken together, the discovery raises the possibility of TIGIT targets against bladder cancer from the bench to the bedside.
2022-01-31 | GSE186520 | GEO
Project description:CD19-targeting chimeric antigen receptor (CAR) T cell have become an important therapeutic option for patients with relapsed and refractory B cell malignancies. However, according to the recent clinical data, a significant portion of patients still do not benefit from the therapy, due various resistance mechanisms including the high expression of multiple inhibitory immune checkpoint receptors on activated CAR-T cells. Studies of checkpoint blockade immunotherapy using monoclonal antibodies have shown that simultaneously targeting inhibitory receptors that are functionally non-redundant can synergistically enhance anti-tumor responses. Here we report a lentiviral two-in-one CAR T approach in which two checkpoint receptors can be downregulated simultaneously by a dual short-hairpin RNA (shRNA) cassette integrated into a CAR vector. Using this system, we evaluated CD19-targeting CAR T cells in the context of four different checkpoint combinations, PD-1/TIM-3, PD-1/LAG-3, PD-1/CTLA-4, and PD-1/TIGIT, and found that the CAR T with PD-1/TIGIT downregulation uniquely exhibited synergistic anti-tumor effect in mouse xenograft models compared to the single PD-1 downregulation and maintained cytolytic and proliferative capacity upon repeated antigen exposure. Importantly, functional and phenotypic analysis of CAR T cells as well as analysis of transcriptomic profiles suggests that downregulation of PD-1 enhances short-term effector function while downregulation of TIGIT is primarily responsible for maintaining a less-differentiated/exhausted state, providing a potential mechanism of the synergy. The PD-1/TIGIT downregulated CAR T cells generated from DLBCL patient-derived T cells following clinically applicable manufacturing process also showed a robust anti-tumor activity and significantly improved persistence in vivo compared to conventional CD19-targeting CAR T cells. Overall, our results demonstrate that the cell-intrinsic PD-1/TIGIT dual downregulation strategy may provide an effective way to overcome the immune checkpoint-mediated resistance in CAR T therapy.
2022-09-28 | GSE158676 | GEO
Project description:TIGIT+ Tregs suppress Th1 and Th17 responses while sparing Th2 responses. Analysis of global gene expression of TIGIT+ vs. TIGIT- Tregs from naive mice reveled that TIGIT+ Tregs display an activated phenotype and are enriched for Treg signature genes including the Treg effector molecule Fgl2 which enables them to selectively spare Th2 responses.
2014-12-12 | GSE56299 | GEO
Project description:We compared the gene expression in wild type CD4+ T cells stimulated with agonistic anti-TIGIT 4D4 antibody to that of isotype and TIGIT-deficient (KO) controls.
2011-01-01 | E-MEXP-2847 | biostudies-arrayexpress