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PD-1 and TIGIT co-expression identifies a circulating CD8 T cell population predictive of response to anti-PD-1 therapy in melanoma and Merkel-cell carcinoma patients [RNA-seq]

ABSTRACT: Clinical benefit from PD-1 inhibitors relies on reinvigoration of endogenous anti-tumor immunity. Efforts to define cellular populations associated with PD-1 clinical efficacy have been largely restricted to analysis of tumor material and the description of subsets of relevant cellular-based biomarkers in the blood of PD-1 inhibitor treated cancer patients are yet to be characterized. Given the particular expression pattern of PD-1 and TIGIT inhibitory receptors on peripheral CD8 T-cell subsets and the reported importance of CD8 T cells co-expressing these two markers for anti-PD-1 efficacy, we sought to determine the distinct biological features of peripheral CD8 subsets delineated based on PD-1 and TIGIT expression. Our findings identify the PD-1+TIGIT+ (DPOS) CD8+ T-cell population as a subset of highly activated and proliferating T cells, enriched in tumor-specific T-cell clones and overexpressing CXCR5, a key marker of the recently described CD8 cytotoxic follicular T cell (Tfc) population. Strikingly, the frequency of DPOS T cells after 1 month of anti-PD-1 therapy was associated with clinical response in three independent cohorts of cancer patients treated with PD-1 inhibitor. Additionally, transcriptomic profiling of this subset described common features with the PD-1high CXCL13+ lymphocyte subset previously demonstrated in tumor infiltrates to be predictive of PD-1 blockade efficacy. Furthermore, TCR repertoire analysis described a cluster of emerging T-cell clonotypes in the DPOS population as a key feature of PD-1 therapeutic efficacy.

ORGANISM(S): Homo sapiens

PROVIDER: GSE141119 | GEO | 2020/11/27

REPOSITORIES: GEO

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PD-1 and TIGIT co-expression identifies a circulating CD8 T cell population predictive of response to anti-PD-1 therapy in melanoma and Merkel-cell carcinoma patients [TCR-seq]

Project description:Clinical benefit from PD-1 inhibitors relies on reinvigoration of endogenous anti-tumor immunity. Efforts to define cellular populations associated with PD-1 clinical efficacy have been largely restricted to analysis of tumor material and the description of subsets of relevant cellular-based biomarkers in the blood of PD-1 inhibitor treated cancer patients are yet to be characterized. Given the particular expression pattern of PD-1 and TIGIT inhibitory receptors on peripheral CD8 T-cell subsets and the reported importance of CD8 T cells co-expressing these two markers for anti-PD-1 efficacy, we sought to determine the distinct biological features of peripheral CD8 subsets delineated based on PD-1 and TIGIT expression. Our findings identify the PD-1+TIGIT+ (DPOS) CD8+ T-cell population as a subset of highly activated and proliferating T cells, enriched in tumor-specific T-cell clones and overexpressing CXCR5, a key marker of the recently described CD8 cytotoxic follicular T cell (Tfc) population. Strikingly, the frequency of DPOS T cells after 1 month of anti-PD-1 therapy was associated with clinical response in three independent cohorts of cancer patients treated with PD-1 inhibitor. Additionally, transcriptomic profiling of this subset described common features with the PD-1high CXCL13+ lymphocyte subset previously demonstrated in tumor infiltrates to be predictive of PD-1 blockade efficacy. Furthermore, TCR repertoire analysis described a cluster of emerging T-cell clonotypes in the DPOS population as a key feature of PD-1 therapeutic efficacy.

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Distinct cellular mechanisms underlie anti-CTLA-4 and anti-PD-1 checkpoint blockade [WES]

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Distinct cellular mechanisms underlie anti-CTLA-4 and anti-PD-1 checkpoint blockade [RNA-seq]

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2024-05-24 | PXD040266 | Pride

Batf3-dendritic cells and 4-1BB/4-1BB ligand axis are required at the effector phase within the tumor microenvironment for PD-1/PD-L1 blockade efficacy

Project description:The cellular source of positive signals that reinvigorate T cells within the tumor microenvironment (TME) for the therapeutic efficacy of PD-1/PD-L1 blockade has not been clearly defined. We now show that Batf3-lineage dendritic cells (DCs) are essential in this process. Flow cytometric analysis, gene-targeted mice, and blocking antibody studies revealed that 4-1BBL was a major positive costimulatory signal provided by these DCs within the TME, that translated to CD8+ T cell functional reinvigoration and tumor regression. Immunofluorescence and spatial transcriptomics on human tumor samples revealed clustering of Batf3+ DCs and CD8+ T cells, which correlated with anti-PD-1 efficacy. In addition, proximity to Batf3+ DCs within the TME was associated with CD8+ T cell transcriptional states linked to anti-PD-1 response. Our results demonstrate that Batf3+ DCs within the TME are critical for PD-1/PD-L1 blockade efficacy, and indicate a major role for the 4-1BB/4-1BBL axis during this process.

2024-05-13 | GSE238145 | GEO

RNA sequencing of tumor associated macrophages and T cells in clear cell renal cell carcinoma

Project description:Tumor associated macrophages and T cells were characterized in a cohort of 73 ccRCC and 5 healthy donors using mass cytometry. Macrophage and T cell subsets of interest were identified and sorted directly from samples known to contain a high frequency of these subsets. CD8+ PD-1- T cells (n=6), exhausted CD8+ PD-1+ T cells (n=6), control macrophages CD14+ HLA-DR+ CD204- CD38- CD206- (n=11) and a population of TAM characterized as CD14+ HLA-DR+ CD204+ CD38+ CD206- (n=6) were isolated using FACS sorting.

2017-05-04 | E-MTAB-5640 | biostudies-arrayexpress

Defining memory-like CD8 T cells that respond to PD-1 therapy in chronic viral infection

Project description:Chronic viral infections are characterized by a state of CD8 T cell dysfunction termed exhaustion. A better understanding of the mechanisms that regulate CD8 T cell responses during chronic infection is required to improve immunotherapies that restore function in exhausted CD8 T cells. Here we identify a novel population of virus-specific CD8 T cells with a T follicular helper (Tfh)-like signature in mice chronically infected with lymphocytic choriomeningitis virus (LCMV). These Tfh-like CD8 T cells expressed the programmed cell death-1 (PD-1) inhibitory receptor but at the same time also expressed co-stimulatory molecules and had a gene signature that was related to CD8 T cell memory precursor cells and hematopoietic stem cells (HSC). These Tfh-like CD8 T cells acted as stem cells during chronic infection undergoing self-renewal and also differentiating into the terminally exhausted CD8 T cells that were present in both lymphoid and non-lymphoid tissues. The Tfh-like CD8 T cells were found only in lymphoid tissues and resided predominantly in the T cell zones along with naÃ¯ve CD8 T cells. Interestingly, the proliferative burst after PD-1 blockade came almost exclusively from this Tfh-like CD8 T cell subset. Importantly, the transcription factor TCF1 played a cell intrinsic and essential role in the generation of Tfh-like CD8 T cells. Taken together, our study identifies Tfh-like CD8 T cells as the critical subset for maintaining the pool of virus-specific CD8 T cells during chronic infection and as the cells that proliferate after PD-1 blockade. These findings provide a better understanding of T cell exhaustion and have implications towards optimizing PD-1 directed immunotherapy. 8 samples isolated from CD8 T-cells in LCMV clone 13 GK1.5 infected mice (2 naÃ¯ve, 3 CXCR5+Tim3-, 3 CXCR5-Tim3+) cells were analyzed

2016-08-02 | E-GEOD-84105 | biostudies-arrayexpress

Epigenetic profiling of OVA-specific CD8+ TILs from mice treated with control, anti-B7S1, anti-PD-1 or anti-B7S1+anti-PD-1 antibodies

Project description:Combinational blockade of B7S1 and PD-1 exhibits stronger anti-tumor efficacy than monotherapies. In order to further understand the mechanisms whereby blockade of B7S1 or PD-1 inhibits tumor growth, we conducted ATAC-seq analysis of OVA-specific CD8+ TILs from E.G7-bearing mice treated with control antibodies, anti-B7S1, anti-PD-1 monotherapy or combinational therapy.

2018-04-03 | GSE110251 | GEO

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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