Tissue-resident memory T-cells in pancreatic ductal adenocarcinoma co-express PD-1 and TIGIT and inhibition is reversible by dual antibody blockade
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE210199 | GEO | 2023/01/24
REPOSITORIES: GEO
Similar Datasets
Project description:Pancreatic ductal adenocarcinoma (PDAC) has a poor clinical outlook. Responses to immune checkpoint blockade are suboptimal and a much more detailed understanding of the tumor immune microenvironment is needed if this situation is to be improved. Here, we characterized tumor-infiltrating T-cell populations in patients with PDAC using cytometry by time of flight (CyTOF) and single-cell RNA sequencing. T cells were the predominant immune cell subset observed within tumors. Over 30% of CD4+ T cells expressed a CCR6+CD161+ Th17 phenotype and 17% displayed an activated regulatory T-cell profile. Large populations of CD8+ tissue-resident memory (TRM) T cells were also present and expressed high levels of programmed cell death protein 1 (PD-1) and TIGIT. A population of putative tumor-reactive CD103+CD39+ T cells was also observed within the CD8+ tumor-infiltrating lymphocytes population. The expression of PD-1 ligands was limited largely to hemopoietic cells whilst TIGIT ligands were expressed widely within the tumor microenvironment. Programmed death-ligand 1 and CD155 were expressed within the T-cell area of ectopic lymphoid structures and colocalized with PD-1+TIGIT+ CD8+ T cells. Combinatorial anti-PD-1 and TIGIT blockade enhanced IFNγ secretion and proliferation of T cells in the presence of PD-1 and TIGIT ligands. As such, we showed that the PDAC microenvironment is characterized by the presence of substantial populations of TRM cells with an exhausted PD-1+TIGIT+ phenotype where dual checkpoint receptor blockade represents a promising avenue for future immunotherapy.
| S-EPMC10068448 | biostudies-literature
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: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:Tissue-resident memory T-cells in pancreatic ductal adenocarcinoma co-express PD-1 and TIGIT and inhibition is reversible by dual antibody blockade
| PRJNA864758 | ENA
Project description:TIGIT is an immune checkpoint receptor expressed on activated and memory T cells, immunosuppressive T regulatory cells, and natural killer (NK) cells. TIGIT has emerged as an attractive target for antitumor therapies, due to its proposed immunosuppressive effects on lymphocyte function and T cell activation. We generated an anti-TIGIT monoclonal antibody (mAb) that binds with high affinity to human, non-human primate, and murine TIGIT and through multiple experimental methodologies demonstrated that checkpoint blockade alone is insufficient for antitumor activity. Generating anti-TIGIT mAbs with various Fc backbones we show that muting the Fc-Fcγ receptor (FcγR) interaction failed to drive antitumor activity, while mAbs with Fc functional backbones demonstrate substantial antitumor activity, mediated through activation of antigen-presenting cells (APCs), T cell priming, and NK-mediated depletion of suppressive Tregs and exhausted T cells. Further, nonfucosylation of the Fc backbone resulted in enhanced immune responses and antitumor activity relative to the intact IgG1 backbone. The improved activity correlated with the biased FcγR interaction profile of the nonfucosylated anti-TIGIT mAb, which supports that FcγRIIIa binding with decreased FcγRIIb binding favorably activates APCs and enhances tumor-specific CD8+ T cell responses. The anti-TIGIT mAbs with intact FcγR interacting backbones also demonstrated synergistic enhancement of other standard antitumor treatments, including anti-PD-1 treatment and a model monomethyl auristatin E antibody–drug conjugate. These findings highlight the importance of the anti-TIGIT mAb’s Fc backbone to its antitumor activity and the extent to which this activity can be enhanced through nonfucosylation of the backbone
2023-10-18 | GSE241212 | 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: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: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: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