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TIGIT and PD-L1 co-blockade promotes clonal expansion of multipotent, non-exhausted antitumor T cells by facilitating co-stimulation

ABSTRACT: TIGIT and PD-L1 co-blockade promotes clonal expansion of multipotent, non-exhausted antitumor T cells by facilitating co-stimulation

PROVIDER: PRJNA911822 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR22719500_1.fastq.gz	Fastqsanger.gz
	SRR22719500_2.fastq.gz	Fastqsanger.gz
	SRR22719600_1.fastq.gz	Fastqsanger.gz
	SRR22719600_2.fastq.gz	Fastqsanger.gz
	SRR22719700_1.fastq.gz	Fastqsanger.gz

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TIGIT and PD-L1 co-blockade promotes clonal expansion of multipotent, non-exhausted antitumor T cells by facilitating co-stimulation

Project description:Blockade of the immune checkpoints PD-1 and TIGIT has demonstrated activity in mouse tumor models and human patients with cancer. Although these coinhibitory receptors can restrict signaling in CD8+ T cells by regulating their associated co-stimulatory receptors CD28 and CD226, the functional consequences of combining PD-1 and TIGIT blockade remain poorly characterized. In mouse tumor models, we show that combination blockade elicited CD226-driven clonal expansion of tumor antigen-specific CD8+ T cells. The expanded clones emerged from a population of stem-like cells in draining lymph nodes, entering the blood as a previously unidentified single-phenotype, multiclonal population. Upon reaching the tumor, these transiting cells expanded further and differentiated into effector or exhausted T cells, with combination blockade restricting entry into the exhaustion pathway by favoring co-stimulation. Thus, PD-1 and TIGIT inhibition helps shape the repertoire of tumor-reactive CD8+ T cells in draining lymph nodes and determines their immunological fate in the tumor to enhance therapeutic benefit. Analysis of clinical trial samples suggests a similar mechanism may also occur in patients with cancer.

2024-12-31 | GSE220901 | GEO

TIGIT and PD-L1 co-blockade promotes clonal expansion of multipotent, non-exhausted antitumor T cells by facilitating co-stimulation.

Project description:Blockade of immune checkpoints PD-1 and TIGIT has demonstrated activity in mouse tumor models and human patients with cancer. Although these coinhibitory receptors can restrict signaling in CD8+ T cells by regulating their associated co-stimulatory receptors CD28 and CD226, the functional consequences of combining PD-1 and TIGIT blockade remain poorly characterized. In mouse tumor models, we show that combination blockade elicited CD226-driven clonal expansion of tumor antigen-specific CD8+ T cells. The expanded clones emerged from a population of stem-like cells in draining lymph nodes, entering the blood as a previously unidentified single-phenotype, multiclonal population. Upon reaching the tumor, these transiting cells expanded further and differentiated into effector or exhausted T cells, with combination blockade restricting entry into the exhaustion pathway by favoring co-stimulation. Thus, PD-1 and TIGIT inhibition helps shape the repertoire of tumor-reactive CD8+ T cells in draining lymph nodes and determines their immunological fate in the tumor to enhance therapeutic benefit. Analysis of clinical trial samples suggests a similar mechanism may also occur in patients with cancer.

| S-EPMC11663793 | biostudies-literature

TIGIT+ Tregs

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

The Co-inhibitory Receptor TIGIT has T cell intrinsic functions

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

Whole genome transcriptome profiling identifies TIGIT as a regulator of T cell exhaustion in liver cancer

Project description:PD-1 checkpoint inhibition has shown promising results in patients with hepatocellular carcinoma, inducing objective responses in approximately 20% of the treated patients. The role of other co-inhibitory molecules and their individual contribution to T cell dysfunction in liver cancer, however, remain largely elusive. Here we perform for the first time a comprehensive mRNA profiling of CD8 T cells in a murine model of autochthonous liver cancer by comparing the whole genome transcriptome of naive, functional effector and exhausted, tumor-specific CD8 T cells. Our results reveal a unique transcriptome signature of exhausted T cells and demonstrate that upregulation of the inhibitory immune receptor TIGIT represents a hallmark in the process of T cell exhaustion in liver cancer. Compared to PD-1, expression of TIGIT more reliably identified exhausted, HCC-specific T cells at different stages of their differentiation. In combination with PD-1 inhibition, targeting of TIGIT with antagonistic antibodies resulted in synergistic inhibition of liver cancer growth in immunocompetent mice. Finally, we demonstrate expression of TIGIT on tumor infiltrating CD8 T cells in tissue samples of HCC patients and identify two subsets of HCC patients based on differential expression of TIGIT on HCC-specific T cells. Our transcriptome analysis therefore provides a valuable resource for the identification of key pathways involved in T cell exhaustion in patients with hepatocellular carcinoma and identifies TIGIT as a potential target in checkpoint combination therapies.

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TIGIT inhibition and lenalidomide synergistically promote anti-myeloma immune responses after stem cell transplantation in mice

Project description:TIGIT inhibition and lenalidomide promote synergistic myeloma immunity by expanding non-exhausted memory CD8 T cells

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2014-12-12 | GSE56299 | GEO

Single-cell RNA-seq of human breast tumor samples with exhausted and non-exhausted immune environments

Project description:Fresh human breast tumor tissue was dissociated into single cells and viably frozen. Patient samples were annotated as having an ""exhausted"" or ""non-exhausted"" immune environment based on CyTOF characterization of T cell phenotypes (Wagner et al, Cell 2019). 14 samples (7 exhausted, 7 non-exhausted) were selected for scRNA-seq (without prior cell type enrichment) with the goal to compare the two immune environment types and to comprehensively characterize exhaustion-associated features of the tumor microenvironment.

2023-08-25 | E-MTAB-10607 | biostudies-arrayexpress

Inhibitory TIGIT signalling is dependent on activating T cell receptor signalling

Project description:TIGIT is an immune checkpoint receptor that can signal via its intracellular inhibitory motifs to inhibit T cells, though the mechanisms remain poorly defined. To elucidate inhibitory signalling interactors of TIGIT, proximity proteomics was employed in model Jurkat T cells expressing TIGIT fused to APEX2. This identified several ligation-specific TIGIT interactors, including proteins involved in signalling (Grb2 and SOS1), cytoskeletal (CD2AP and SdcBP), and endocytic processes (IST1 and SNX3). A TIGIT mutant incapable of signalling via its inhibitory motifs prevented the recruitment of these proteins, indicating inhibitory signalling-specific engagement of these pathways. Furthermore, TIGIT engagement with these pathways, in addition to its phosphorylation and internalisation, was dependent on T cell activation as well as TIGIT ligation. Collectively, these findings demonstrate that TIGIT inhibitory signalling is restricted to activated T cells, indicating a regulatory mechanism that limits inhibition to when functionally required.

2025-05-14 | PXD063349 | Pride

Anti-TIGIT antibody improves PD-L1 blockade through myeloid and Treg cells

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

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