IL-21-αHSA combined with TIGIT blockade induces an effective anti-tumor immune response
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ABSTRACT:
PROVIDER: PRJNA770626 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR16297771_1.fastq.gz | Fastqsanger.gz | |||
| SRR16297771_2.fastq.gz | Fastqsanger.gz | |||
| SRR16297772_1.fastq.gz | Fastqsanger.gz | |||
| SRR16297772_2.fastq.gz | Fastqsanger.gz | |||
| SRR16297773_1.fastq.gz | Fastqsanger.gz |
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Project description:IL-21-αHSA combined with TIGIT blockade induces an effective anti-tumor immune response, indicated by the significant enrichment of pathways associated with anti-tumor immune response, as well as significantly increased expression of key genes associated with CD8+ T and NK cell cytotoxicity To further understand the mechanisms by which IL-21-αHSA enhances the benefit of TIGIT blockade, we analyzed MC38 tumor tissues 20 days after five doses of both single agent and combination treatments by RNA sequencing (RNA-seq) of 28,758 genes. Compared to isotype control treatment, combination treatment resulted in 764 genes with differential expression (defined as P < 0.05 and fold change > 2.0), while IL-21-αHSA treatment resulted in 402 DEGs and anti-mTIGIT treatment resulted in 528 DEGs (data not shown). These findings suggest that the combination treatment had a more dramatic effect on gene expression than IL-21-αHSA or anti-mTIGIT treatment alone. To evaluate the pathways underlying the synergistic anti-tumor efficacy induced by the combination treatment, we performed Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway significance enrichment analysis (defined as P adjust < 0.05). In comparison to the isotype control treatment, 41 KEGG pathways were significantly enriched in the combination treatment group (Table S1) and 31 pathways were significantly enriched in the IL-21-αHSA treatment group (Table S2), of which 28 KEGG enrichment pathways overlapped. Additionally, only 8 KEGG pathways were significantly enriched in the anti-mTIGIT treatment group (Table S3), of which 5 KEGG enrichment pathways overlapped with those of the combination treatment group. These findings suggest that IL-21-αHSA in combination with anti-mTIGIT treatment enriched more KEGG pathways with differential gene expression than for monotherapy, and most of the KEGG pathways significantly enriched by the combination treatment were also differentially enriched by IL-21-αHSA treatment alone. The top 15 pathways, ranked in order of significance, are shown in Fig. 7A. As expected, most are associated with classical anti-tumor immunity signal pathways, including the cytokine-cytokine receptor interaction pathway, the viral protein interaction with cytokine and cytokine receptor pathway, the Th1 and Th2 cell differentiation pathway, the antigen processing and presentation pathway, the T cell receptor signaling pathway, and the PD-L1 expression and PD-1 checkpoint pathway in cancer (P adjust < 0.0001). The natural killer cell mediated cytotoxicity pathway was also significantly enriched (P adjust = 0.0059) in the combination treatment group compared to isotype control treatment group, but was not among the top 15 pathways. Overall, these findings suggest that IL-21-αHSA in combination with TIGIT blockade treatment significantly affects the anti-tumor immunity signal in the tumor micro-environment. For further verification, we analyzed the gene expression levels of key effector molecules, including Interferon-γ (IFNG), Granzyme A (Gzma), Granzyme B (Gzmb), and Perforin 1 (Prf1), each of which are critical mediators of CD8+ T cell and NK cell cytotoxicity and are known to play critical roles in anti-tumor response. As shown in Fig. 7B-E, the combination treatment significantly increased the expression of all four genes (P < 0.05) relative to isotype control treatment, though only IFNG and Gzma were differentially expressed in the combination treatment group relative to the anti-mTIGIT group (P < 0.05). Collectively, these results suggest that IL-21-αHSA in combination with TIGIT blockade induces an effective anti-tumor immune response, indicated by the significant enrichment of pathways associated with anti-tumor immune response, as well as significantly increased expression of key genes associated with CD8+ T and NK cell cytotoxicity.
2021-10-14 | GSE185727 | GEO
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:Background and Aims: Chronic hepatitis B virus (HBV) infection is the leading cause of hepatocellular carcinoma (HCC) and is a serious health problem in China, East Asia, and North African countries. Effective treatment of HBV-related HCC is currently unavailable. This study evaluated the therapeutic potential of TIGIT blockade in HBV-related HCC. Approach and Results: A mouse model of spontaneous HBV-related HCC was generated by replacing wild-type hepatocytes with HBsAg+ hepatocytes (namely HBs-HepR mice). The tumors in HBs-HepR mice were inflammation-associated HCC, similar to HBV-related HCC in patients, which was distinguished from other HCC mouse models, such as diethylnitrosamine (DEN)-induced HCC, Tak1-knockout-induced HCC, HCC in stelic animal model (STAM), or nonalcoholic steatohepatitis (NASH)-induced HCC. HCC in HBs-HepR mice was characterized by an increased number of CD8+T cells whereas the production of IL-2, TNF-α, and IFN-γ by intrahepatic CD8+T cells was decreased. Increased expression of TIGIT on CD8+T cells was responsible for functional exhaustion. The therapeutic effect of TIGIT blockade was investigated at the early and middle stages of HCC progression in HBs-HepR mice. TIGIT blockade reinvigorated intrahepatic CD8+T cells with increased TNF-α and IFN-γ production and an increased number of CD8+T cells in tumors, thereby slowing the development of HCC in HBs-HepR mice. Blocking PD-L1 did not show direct therapeutic effects or synergize with TIGIT blockade. Conclusions: Blockade of TIGIT alone enhanced the anti-tumor activity of CD8+T cells during the progression of HBV-related HCC in a spontaneous HCC mouse model.
2022-12-31 | GSE209856 | 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:TIGIT Blockade Exerts Synergistic Effects on Microwave Ablation against Cancer
| PRJNA799733 | ENA
Project description:Tiragolumab, an anti-TIGIT antibody with an active IgG1κ Fc, demonstrated improved outcomes in the phase 2 CITYSCAPE trial (ClinicalTrials.gov: NCT03563716) when combined with atezolizumab (anti-PD-L1) versus atezolizumab alone. However, there remains little consensus on the mechanism(s) of response with this combination. Here we find that a high baseline of intratumoural macrophages and regulatory T cells is associated with better outcomes in patients treated with atezolizumab plus tiragolumab but not with atezolizumab alone. Serum sample analysis revealed that macrophage activation is associated with a clinical benefit in patients who received the combination treatment. In mouse tumour models, tiragolumab surrogate antibodies inflamed tumour-associated macrophages, monocytes and dendritic cells through Fcγ receptors (FcγR), in turn driving anti-tumour CD8+ T cells from an exhausted effector-like state to a more memory-like state. These results reveal a mechanism of action through which TIGIT checkpoint inhibitors can remodel immunosuppressive tumour microenvironments, and suggest that FcγR engagement is an important consideration in anti-TIGIT antibody development.
2024-03-04 | GSE260816 | 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
Project description:Regulatory B cells (Bregs) contribute to immune regulation. However, the mechanisms of action of Bregs remain elusive. Here, we report that T cell immunoreceptor with Ig and ITIM domains (TIGIT) expressed on human memory B cells especially CD19+CD24hiCD27+CD39hiIgD−IgM+CD1c+ B cells is essential for effective immune regulation. Mechanistically, TIGIT on memory B cells controls immune response by directly acting on T cells and by arresting proinflammatory function of dendritic cells, resulting in the suppression of Th1, Th2, Th17, and CXCR5+ICOS+ T cell response while promoting immune regulatory function of T cells. TIGIT+ memory B cells are also superior to other B cells at expressing additional inhibitory molecules, including IL-10, TGFβ1, granzyme B, PD-L1, CD39/CD73, and TIM-1. Lack or decrease of TIGIT+ memory B cells is associated with increased donor-specific antibody and TFH response, and decreased Treg response in renal and liver allograft patients. Therefore, TIGIT+ human memory B cells play critical roles in immune regulation.
2020-12-23 | GSE151415 | GEO
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