Primary T cells from cutaneous T-cell lymphoma skin explants display an exhausted immune checkpoint profile
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ABSTRACT:
PROVIDER: PRJNA450035 | ENA |
REPOSITORIES: ENA
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Project description:Cutaneous T-cell lymphoma (CTCL) develops from clonally expanded CD4+ T cells in a background of chronic inflammation. Dendritic cells (DCs) are potent T-cell stimulators; yet despite DCs’ extensive presence in skin, cutaneous T cells in CTCL do not respond with effective anti-tumor immunity. We evaluated primary T-cell and DC émigrés from epidermal and dermal explant cultures of skin biopsies from CTCL patients (n = 37) and healthy donors (n = 5). Compared with healthy skin, CD4+ CTCL populations contained more T cells expressing PD-1, CTLA-4, and LAG-3; and CD8+ CTCL populations comprised more T cells expressing CTLA-4 and LAG-3. CTCL populations also contained more T cells expressing the inducible T-cell costimulator (ICOS), a marker of T-cell activation. DC émigrés from healthy or CTCL skin biopsies expressed PD-L1, indicating that maturation during migration resulted in PD-L1 expression irrespective of disease. Most T cells did not express PD-L1. Using skin samples from 49 additional CTCL patients for an unsupervised analysis of genome-wide mRNA expression profiles corroborated that advanced T3/T4 stage samples expressed higher levels of checkpoint inhibition genes compared with T1/T2 stage patients or healthy controls. Exhaustion of activated T cells is therefore a hallmark of both CD4+ and CD8+ T cells directly isolated from the lesional skin of patients with CTCL, with a continuum of increasing expression in more advanced stages of disease. These results justify identification of antigens driving T-cell exhaustion and the evaluation of immune checkpoint inhibition to reverse T-cell exhaustion earlier in the treatment of CTCL.
2018-08-21 | GSE113113 | GEO
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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
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Project description:Recent development of new therapies with immune checkpoint inhibitors (ICIs) and MAPK-inhibitors (MAPKis) have significantly improved the outcome in metastatic cutaneous melanoma (CM). However, therapy response is limited to subgroups of patients and clinically useful predictive biomarkers for treatment outcome are lacking. To discover treatment-related systemic changes in plasma and potential biomarkers associated with treatment outcomes, we analysed 45 plasma samples from 24 patients with metastatic (stage IV) CM, using HiRIEF LC-MS/MS, collected before (pre-trm) and during treatment (trm). Of these, 27 samples were taken from 15 metastatic CM patients treated with ICIs (13 pre-trm and 14 trm samples; 12 matched) and 9 patients treated with MAPKis (9 matched). Matched samples were trm and pre-trm samples taken from the same individual before treatment and after the first cycle of treatment (before the second cycle). We have analysed the change in the plasma protein levels during treatment by comparing the plasma levels in the trm samples to the pre-trm samples, to detect treatment-induced alterations in the plasma proteome. We have analysed the patients treated with ICIs separately from the patients treated with MAPKis, to detect treatment-specific changes for both.
2020-07-13 | PXD017201 | Pride
Project description:CTL exhaustion is driven by chronic antigen stimulation and is characterized by specific molecular, phenotypic and functional changes. Reversing CTLs exhaustion with immune checkpoint blockade (ICB) has provided clinical benefits in different types of cancer. However, the therapeutic effects of ICB varies among patients and cancer types. Ibrutinib, a potent BTK inhibitor, is reported that it improved T cell function in ibrutinib long-term treated chronic lymphocytic leukemia patients. However, the mechanism remains unclear. We hypothesized ibrutinib can directly act on CD8+ T cells and reinvigorates exhausted CTLs. To test this, we generated in vitro exhausted OT-I cells as previously described (Zhao M et al PLoS Pathog. 16(6): e1008555) by repeatedly stimulating cells with SIINFEKL peptide. We tested the effect of ibrutinib on inhibitory receptor, exhaustion-related transcription factor expression and cytokine (IFNγ, TNFα and IL-2) production. We found that ibrutinib decreased the expression of multiple inhibitory receptors on in vitro exhausted CTL while the critical transcription factor, Tox was downregulated. The cytokine production of exhausted cells was partially improved after ibrutinib treatment. Importantly, using btk deficient mice we found the effect of ibrutinib was independent of BTK expression. To conclude, these findings suggest that ibrutinib reduces CTL exhaustion. Our study provides evidence for ibrutinib’s synergistic use with cancer immunotherapy.
2023-09-06 | GSE220433 | GEO
Project description:CD8 T cells normally differentiate from resting naïve T cells into function effector and then memory CD8 T cells following acute infections. During chronic viral infections, however, virus-specific CD8 T cells often become exhausted. We used microarrays to examine the gene expression differences between naive, effector, memory and exhausted virus-specific CD8 T cells following lymphocytic choriomeningitis virus infection. Experiment Overall Design: Three or four independent samples were sorted by flow cytometry for each cell type (naive, effector, memory and exhausted) virus-specific CD8 T cells. RNA was extracted and hybridized to Affymetrix microarrays.
2008-06-16 | E-GEOD-9650 | biostudies-arrayexpress
Project description:Terminally exhausted CD8+ T-cells, which hold certain level of anti-tumour cytotoxicity but largely reduced proliferation capacity, contribute directly to tumour growth control. However, this subpopulation do not respond to immune checkpoint blockades or most existing immunotherapies and are difficult to be reactivated. Here, we show that a half-life extended interleukin (IL)-10/Fc fusion protein directly expands the terminally exhausted CD8+ TILs and sustains their effector functions through in vivo metabolic reprogramming, leading to eradication of established solid tumours and durable cures in a majority of treated mice when combined with adoptive T-cell transfer immunotherapy. Our results provide preclinical evidence that IL-10/Fc is a safe and highly effective therapy that acts on a specific subset of CD8+ TILs distinct from those responding to immune checkpoint blockades. Thus, IL-10/Fc could complement and synergize with existing cancer immunotherapies for enhanced efficacy and response rates. We find that IL-10/Fc reprograms T-cell metabolism by promoting oxidative phosphorylation through the mitochondrial pyruvate carrier, suggesting that metabolic reprogramming is sufficient to revitalize terminally exhausted CD8+ TILs.
2021-04-01 | GSE168990 | GEO
Project description:Immune checkpoint blockade is able to achieve durable responses in a subset of patients, however we lack a satisfying comprehension of the underlying mechanisms of anti-CTLA-4 and anti-PD-1 induced tumor rejection. To address these issues we utilized mass cytometry to comprehensively profile the effects of checkpoint blockade on tumor immune infiltrates in human melanoma and murine tumor models. These analyses reveal a spectrum of tumor infiltrating T cell populations that are highly similar between tumor models and indicate that checkpoint blockade targets only specific subsets of tumor infiltrating T cell populations. Anti-PD-1 predominantly induces the expansion of specific tumor infiltrating exhausted-like CD8 T cell subsets. In contrast, anti-CTLA-4 induces the expansion of an ICOS+ Th1-like CD4 effector population in addition to engaging specific subsets of exhausted-like CD8 T cells. Thus, our findings indicate that anti-CTLA-4 and anti-PD-1 checkpoint blockade induced immune responses are driven by distinct cellular mechanisms.
2017-08-10 | GSE100808 | GEO
Project description:Immune checkpoint blockade is able to achieve durable responses in a subset of patients, however we lack a satisfying comprehension of the underlying mechanisms of anti-CTLA-4 and anti-PD-1 induced tumor rejection. To address these issues we utilized mass cytometry to comprehensively profile the effects of checkpoint blockade on tumor immune infiltrates in human melanoma and murine tumor models. These analyses reveal a spectrum of tumor infiltrating T cell populations that are highly similar between tumor models and indicate that checkpoint blockade targets only specific subsets of tumor infiltrating T cell populations. Anti-PD-1 predominantly induces the expansion of specific tumor infiltrating exhausted-like CD8 T cell subsets. In contrast, anti-CTLA-4 induces the expansion of an ICOS+ Th1-like CD4 effector population in addition to engaging specific subsets of exhausted-like CD8 T cells. Thus, our findings indicate that anti-CTLA-4 and anti-PD-1 checkpoint blockade induced immune responses are driven by distinct cellular mechanisms.
2017-08-10 | GSE100807 | GEO