Exploration of exhausted CD8 T cell markers to predict response to immune checkpoint inhibitor therapy for hepatocellular carcinoma
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PROVIDER: PRJNA591358 | ENA |
REPOSITORIES: ENA
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Project description:This study sought to identify transcriptomic and protein markers of T cell exhaustion that may predict response to anti-program cell death-1 (anti-PD-1) / anti-PD-L1-based ICI therapy for patients with advanced/metastatic hepatocellular carcinoma (HCC).
2021-05-18 | GSE140901 | GEO
Project description:BackgroundReversal of CD8 T-cell exhaustion was considered a major antitumor mechanism of anti-programmed cell death-1 (PD-1)/ anti-programmed death ligand-1 (PD-L1)-based immune checkpoint inhibitor (ICI) therapy.ObjectivesThe aim of this study was to identify markers of T-cell exhaustion that is best associated with ICI treatment efficacy for advanced hepatocellular carcinoma (HCC).MethodsImmune cell composition of archival tumor samples was analyzed by transcriptomic analysis and multiplex immunofluorescence staining.ResultsHCC patients with objective response after anti-PD-1/anti-PD-L1-based ICI therapy (n = 42) had higher expression of genes related to T-cell exhaustion. A 9-gene signature (LAG3, CD244, CCL5, CXCL9, CXCL13, MSR1, CSF3R, CYBB, and KLRK1) was defined, whose expression was higher in patients with response to ICI therapy, correlated with density of CD8+LAG3+ cells in tumor microenvironment, and independently predicted better progression-free and overall survival. This 9-gene signature had similar predictive values for patients who received single-agent or combination ICI therapy and was not associated with prognosis in HCC patients who received surgery, suggesting that it may outperform other T-cell signatures for predicting efficacy of ICI therapy for HCC. For HCC patients who underwent surgery for both the primary liver and metastatic lung tumors (n = 31), lung metastatic HCC was associated with a higher exhausted CD8 T-cell signature, consistent with prior observation that patients with lung metastatic HCC may have higher probability of response to ICI therapy.ConclusionsCD8 T-cell exhaustion in tumor microenvironment may predict better efficacy of ICI therapy for HCC.
| S-EPMC8339511 | biostudies-literature
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
Project description:Immune checkpoint blockade can facilitate tumor clearance by T cells, resulting in long term patient survival. However, the capacity of exhausted CD8+ T cells (Tex), present during chronic antigen exposure, to form memory after antigen clearance remains unclear. Here, we performed longitudinal single cell RNA/T cell receptor sequencing and ATAC-sequencing on antigen-specific T cells after the peripheral clearance of chronic lymphocytic choriomeningitis virus infection. These data revealed the formation of a robust population of memory CD8+ T cells that transcriptionally, epigenetically, and functionally resemble central memory T cells (Tcm) that form after clearance of acute infection. To lineage trace the origin and memory recall response of Tex-derived memory clones, we utilized T cell receptor sequencing over the course of primary infection and rechallenge. We show that chronic Tcm are a clonally distinct lineage of Tex derived from progenitor exhausted cells, persist long-term in the absence of antigen, and undergo rapid clonal expansion during rechallenge. Finally, we demonstrate that αPD-L1 immune checkpoint blockade selectively expands clones which form Tcm after clearance. Together, these data support the concept that chronically stimulated T cells form bona fide functional memory T cells through an analogous differentiation pathway to acutely stimulated T cells, which may have significant implications for enhancing immune memory to cancer through checkpoint blockade and vaccination.
2025-01-27 | GSE285414 | GEO
Project description:Immune checkpoint blockade can facilitate tumor clearance by T cells, resulting in long term patient survival. However, the capacity of exhausted CD8+ T cells (Tex), present during chronic antigen exposure, to form memory after antigen clearance remains unclear. Here, we performed longitudinal single cell RNA/T cell receptor sequencing and ATAC-sequencing on antigen-specific T cells after the peripheral clearance of chronic lymphocytic choriomeningitis virus infection. These data revealed the formation of a robust population of memory CD8+ T cells that transcriptionally, epigenetically, and functionally resemble central memory T cells (Tcm) that form after clearance of acute infection. To lineage trace the origin and memory recall response of Tex-derived memory clones, we utilized T cell receptor sequencing over the course of primary infection and rechallenge. We show that chronic Tcm are a clonally distinct lineage of Tex derived from progenitor exhausted cells, persist long-term in the absence of antigen, and undergo rapid clonal expansion during rechallenge. Finally, we demonstrate that αPD-L1 immune checkpoint blockade selectively expands clones which form Tcm after clearance. Together, these data support the concept that chronically stimulated T cells form bona fide functional memory T cells through an analogous differentiation pathway to acutely stimulated T cells, which may have significant implications for enhancing immune memory to cancer through checkpoint blockade and vaccination.
2025-01-27 | GSE285412 | GEO
Project description:Immune checkpoint blockade can facilitate tumor clearance by T cells, resulting in long term patient survival. However, the capacity of exhausted CD8+ T cells (Tex), present during chronic antigen exposure, to form memory after antigen clearance remains unclear. Here, we performed longitudinal single cell RNA/T cell receptor sequencing and ATAC-sequencing on antigen-specific T cells after the peripheral clearance of chronic lymphocytic choriomeningitis virus infection. These data revealed the formation of a robust population of memory CD8+ T cells that transcriptionally, epigenetically, and functionally resemble central memory T cells (Tcm) that form after clearance of acute infection. To lineage trace the origin and memory recall response of Tex-derived memory clones, we utilized T cell receptor sequencing over the course of primary infection and rechallenge. We show that chronic Tcm are a clonally distinct lineage of Tex derived from progenitor exhausted cells, persist long-term in the absence of antigen, and undergo rapid clonal expansion during rechallenge. Finally, we demonstrate that αPD-L1 immune checkpoint blockade selectively expands clones which form Tcm after clearance. Together, these data support the concept that chronically stimulated T cells form bona fide functional memory T cells through an analogous differentiation pathway to acutely stimulated T cells, which may have significant implications for enhancing immune memory to cancer through checkpoint blockade and vaccination.
2025-01-27 | GSE285411 | GEO
Project description:Immune checkpoint blockade can facilitate tumor clearance by T cells, resulting in long term patient survival. However, the capacity of exhausted CD8+ T cells (Tex), present during chronic antigen exposure, to form memory after antigen clearance remains unclear. Here, we performed longitudinal single cell RNA/T cell receptor sequencing and ATAC-sequencing on antigen-specific T cells after the peripheral clearance of chronic lymphocytic choriomeningitis virus infection. These data revealed the formation of a robust population of memory CD8+ T cells that transcriptionally, epigenetically, and functionally resemble central memory T cells (Tcm) that form after clearance of acute infection. To lineage trace the origin and memory recall response of Tex-derived memory clones, we utilized T cell receptor sequencing over the course of primary infection and rechallenge. We show that chronic Tcm are a clonally distinct lineage of Tex derived from progenitor exhausted cells, persist long-term in the absence of antigen, and undergo rapid clonal expansion during rechallenge. Finally, we demonstrate that αPD-L1 immune checkpoint blockade selectively expands clones which form Tcm after clearance. Together, these data support the concept that chronically stimulated T cells form bona fide functional memory T cells through an analogous differentiation pathway to acutely stimulated T cells, which may have significant implications for enhancing immune memory to cancer through checkpoint blockade and vaccination.
2025-01-27 | GSE285308 | GEO
Project description:Hypoxia promotes an aggressive tumor phenotype with increased genomic instability, partially due to downregulation of DNA repair pathways. However, in addition to DNA repair, genome stability is also controlled by cell cycle checkpoints. An important issue is therefore whether hypoxia also can alter the DNA damage cell cycle checkpoints. Here, we show that hypoxia (24h 0.2% O2) alters the expression of several G2 checkpoint regulators, as examined by microarray gene expression analysis and immunoblotting of U2OS cells. While some of the changes reflected hypoxia-induced inhibition of cell cycle progression, flow cytometric bar-coding analysis of individual cells showed that the levels of several G2 checkpoint regulators were reduced in G2 phase cells after hypoxic exposure, in particular cyclin B1. These effects were accompanied by decreased Cyclin dependent kinase (CDK) activity in G2 phase cells after hypoxia. Furthermore, cells pre-exposed to hypoxia showed a longer G2 checkpoint arrest upon treatment with ionizing radiation. Similar results were found following other hypoxic conditions (~0.03 % O2 20h and 0.2% O2 72h). These results demonstrate that the DNA damage G2 checkpoint can be altered as a consequence of hypoxia, and we propose that such alterations may influence the genome stability of hypoxic tumors. We measured gene expression changes in U2OS cells after treatment with 0.2% hypoxia for 24 hours. The data were used in the exploration of hyopxia induced alterations in the G2 checkpoint.
2016-01-04 | E-GEOD-70530 | biostudies-arrayexpress
Project description:Significant heterogeneity exists within the tumor infiltrating CD8 T cell population, and exhausted T cells harbor a subpopulation that may be replicating and retain signatures of activation, with potential functional consequences in tumor progression. Dysfunctional immunity in the tumor microenvironment is associated with poor cancer outcomes, making exploration of these exhausted but activated (Tex/act) subpopulations critical to the improvement of therapeutic approaches. To investigate mechanisms associated with Tex/act cells, we sorted and performed transcriptional profiling of CD8+ tumor infiltrating lymphocytes (TIL) coexpressing the exhaustion markers PD-1 and TIM-3, from large volume melanoma tumors. We additionally performed immunologic phenotyping and functional validation, including at the single cell level, to identify potential mechanisms that underlie their dysfunctional phenotype. We identified novel dysregulated pathways in CD8+PD-1+TIM-3+ cells that have not been well studied in TIL; these include bile acid and peroxisome pathway-related metabolism, and mammalian target of rapamycin (mTOR) signaling pathways, which are highly correlated with immune checkpoint receptor expression. Through bioinformatic integration of immunophenotypic data and network analysis, we propose unexpected targets for therapies to rescue the immune response to tumors in melanoma.
2023-12-06 | GSE230864 | GEO
Project description:Functional memory T cells are derived from exhausted clones and expanded by checkpoint blockade [scRNATCR_Atlas]
| PRJNA1203596 | ENA