Y chromosome loss in bladder cancer contributes to T cell exhaustion and sensitivity to immune checkpoint blockade [WES]
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ABSTRACT:
PROVIDER: PRJNA962610 | ENA |
REPOSITORIES: ENA
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Project description:Loss of the Y chromosome (LOY) is observed in several common cancer types, including 10-40% of bladder cancers, but the clinical and biological significance of this finding is unknown. Through genomic and transcriptomic studies, we report that low LOY gene signature scores correlate with poor prognoses in patients with bladder cancer. We then performed in-depth studies of natural occurring bladder cancer cells with LOY mutants as well as those with targeted deletion of Y chromosome by CRISPR/Cas9. Both Y+ and Y- tumors had similar growth kinetics in vitro, while Y- tumors grew faster than Y+ tumors in immune competent hosts in a T cell-dependent manner
2023-06-10 | GSE230819 | GEO
Project description:BACKGROUND. Precise stratification of patients with non–small cell lung cancer (NSCLC) is needed for appropriate application of PD-1/PD-L1 blockade therapy. METHODS. We measured soluble (s) forms of the PD-L1, PD-1, and CTLA-4 in plasma of patients with advanced NSCLC before PD-1/PD-L1 blockade. Prospective biomarker finding trial (cohort A), 50 patients with pretreated NSCLC received nivolumab. In cohort B to E, retrospective observational study, soluble immune checkpoint molecules were evaluated for patients with advanced NSCLC treated with any PD-1/PD-L1 blockade (cohort B and C), cytotoxic chemotherapy (D) or targeted therapy (E). Blood samples were obtained from all patients and soluble immune checkpoint molecules were evaluated using a highly sensitive chemiluminescence-based assay. RESULTS. Nonresponsiveness to PD-1/PD-L1 blockade therapy was associated with higher concentrations of these soluble immune factors among patients with immune-reactive (hot) tumors. Such correlation was not observed in patients treated with cytotoxic chemotherapy or targeted therapies. Integrative analysis of tumor size, PD-L1 expression in tumor tissue (tPD-L1), and gene expression in tumor tissue and peripheral CD8+ T cells revealed that high concentrations of the three soluble immune factors were associated with hyper or terminal exhaustion of antitumor immunity. The combination of sPD-L1 and sCTLA-4 efficiently discriminated responsiveness among patients with immune-reactive tumors. CONCLUSION. Combinations of soluble immune factors might be able to identify patients unlikely to respond to PD-1/PD-L1 blockade as a result of terminal exhaustion of antitumor immunity. Our data suggest such a combination might provide a biomarker complementary to tPD-L1 for NSCLC patients.
2024-03-30 | GSE242860 | 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:T-cell exhaustion occurs when T cells are chronically activated, usually in the context of cancer or chronic infection. Exhausted T cells lose effector functions, upregulate inhibitory receptors, and lose proliferation ability. Understanding the mechanisms of T-cell exhaustion is important as it has critical clinical applications, such as checkpoint blockade therapy. CD4+ T cells are understudied in the context of exhaustion, and no large-scale multiomic datasets containing proteomics, phosphoproteomics, or metabolomics exist. We therefor performed a multiomic experiment to profile this cell state using a time course analysis to also capture progression.
2024-11-28 | PXD057703 | Pride
Project description:Insufficiency of compound immune checkpoint blockade to overcome engineered T cell exhaustion in pancreatic cancer
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Project description:Despite the curative potential of checkpoint blockade immunotherapy, most patients remain unresponsive to existing treatments. Glyco-immune checkpoints – interactions of cell-surface glycans with lectin, or glycan-binding, immunoreceptors – have emerged as prominent mechanisms of immune evasion and therapeutic resistance in cancer. Here, we describe antibody-lectin chimeras (AbLecs), a modular platform for glyco-immune checkpoint blockade. AbLecs are bispecific antibody-like molecules comprising a cell-targeting antibody domain and a lectin “decoy receptor” domain that directly binds glycans and blocks their ability to engage inhibitory lectin receptors. AbLecs potentiate anticancer immune responses including phagocytosis and cytotoxicity, outperforming most existing therapies and combinations tested. By targeting a distinct axis of immunological regulation, AbLecs synergize with blockade of established immune checkpoints. AbLecs can be readily designed to target numerous tumor and immune cell subsets as well as glyco-immune checkpoints, and therefore represent a new modality for cancer immunotherapy.
2025-08-13 | PXD063934 | Pride
Project description:T cell exhaustion, a hyporesponsive state of antigen-specific CD8+ T cells exhibiting elevated expression of multiple inhibitory surface receptors, is a major obstacle for the treatment of cancer. Current immune checkpoint blockade (ICB) therapies aimed at reinvigorating exhausted CD8+ T cells have demonstrated clinical effectiveness. However, not all cancer patients achieve long-term disease control due, at least in part, to the refractory nature of terminally exhausted CD8+ T cells to be functionally reinvigorated. Besides persistent antigen stimulation, the environmental sources and mechanisms that lead to CD8+ T cell exhaustion in cancer remain to be thoroughly characterized. Here, we show that the expression of CD47 [a.k.a. integrin-associated protein (IAP) and ‘‘don’t eat me’’ signal is upregulated in tumour-associated, exhausted CD8+ T cell compartments in both human and murine tumours. Our findings reveal a novel role of the extracellular matrix protein thrombospondin-1 (TSP-1) and CD47 in promoting T cell exhaustion. Engagement of TSP-1 with CD47 drives the upregulation of TOX and inhibitory immune checkpoint molecules and compromises the effector function of CD8+ T cells during tumour progression. Mechanistically, the interaction of TSP-1 with CD47 on CD+ T cells activates the calcineurin-NFAT signaling, thereby promoting TOX expression and the T cell exhaustion program in cancer.
2025-09-17 | GSE303017 | GEO
Project description:T cell exhaustion, a hyporesponsive state of antigen-specific CD8+ T cells exhibiting elevated expression of multiple inhibitory surface receptors, is a major obstacle for the treatment of cancer. Current immune checkpoint blockade (ICB) therapies aimed at reinvigorating exhausted CD8+ T cells have demonstrated clinical effectiveness. However, not all cancer patients achieve long-term disease control due, at least in part, to the refractory nature of terminally exhausted CD8+ T cells to be functionally reinvigorated. Besides persistent antigen stimulation, the environmental sources and mechanisms that lead to CD8+ T cell exhaustion in cancer remain to be thoroughly characterized. Here, we show that the expression of CD47 [a.k.a. integrin-associated protein (IAP) and ‘‘don’t eat me’’ signal is upregulated in tumour-associated, exhausted CD8+ T cell compartments in both human and murine tumours. Our findings reveal a novel role of the extracellular matrix protein thrombospondin-1 (TSP-1) and CD47 in promoting T cell exhaustion. Engagement of TSP-1 with CD47 drives the upregulation of TOX and inhibitory immune checkpoint molecules and compromises the effector function of CD8+ T cells during tumour progression. Mechanistically, the interaction of TSP-1 with CD47 on CD+ T cells activates the calcineurin-NFAT signaling, thereby promoting TOX expression and the T cell exhaustion program in cancer.
2025-09-17 | GSE303291 | GEO
Project description:Although tumor immune microenvironment plays an important role in antitumor therapy, few studies explored the gene signatures associated with the tumor immune microenvironment of bladder cancer after neoadjuvant chemotherapy. We examined and analyzed differentially expressed genes from 9 patients with stage I-III bladder cancer by RNA immune-oncology profiling platform. After neoadjuvant chemotherapy, the expressions of 43 genes in 19 pathways and 10 genes in 5 pathways were upregulated and downregulated, respectively. Neoadjuvant chemotherapy also promoted the expression of genes related to the activation of antitumor immune responses and decreased the expression of genes related to tumor proliferation pathways. In addition, neoadjuvant chemotherapy improved tumor response to immune checkpoint blockade. Furthermore, this study also identified several genes that can be used to predict the efficacy of neoadjuvant chemotherapy and their possible molecular mechanisms. In conclusion, neoadjuvant chemotherapy may promote the activation of antitumor effects, improve the suppressive tumor immune microenvironment, and increase the sensitivity of bladder cancer to immune checkpoint blockade.
| S-EPMC9338739 | biostudies-literature
Project description:Bladder cancer remains the most immunogenic and expensive malignant tumor in the United States today. As the 4th leading cause of death from cancer in United States, Immunotherapy blocking immune checkpoints have been recently been applied to many aggressive cancers and changed interventions of urological cancers including advanced bladder cancer. The applied inhibition of PD-1-PD-L1 interactions can restore antitumor T-cell activity and enhance the cellular immune attack on antigens. The overall goals of this short review article are to introduce current cancer immunotherapy and immune checkpoint inhibitors, and to provide new insight into the underlying mechanisms that block immune checkpoints in tumor microenvironment. Furthermore, this review will address the preclinical and clinical trials to determine whether bladder cancer patients could benefit from this new cancer therapy in near future.
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