Homo sapiens
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ABSTRACT:
PROVIDER: PRJNA398304 | ENA |
REPOSITORIES: ENA
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Project description:Resistance to Checkpoint Blockade Therapy Through Inactivation of Antigen Presentation
| PRJNA398303 | ENA
Project description:Background: Checkpoint blockade immunotherapy represented by PD-1/PD-L1 or CTLA4 antibody treatment, has been of tremendous success for multiple cancers. Most patients with prostate cancer (PCa) either do not respond to CTLA4 immune checkpoint blockade or develop resistance to it, often because of low CTLA4 antigen presentation in cancer cells.
2025-04-02 | GSE234387 | GEO
Project description:Atractylenolide I enhances responsiveness to immune checkpoint blockade therapy by activating tumor antigen presentation
| PRJNA718568 | ENA
Project description:DNA mismatch repair deficient (MMR-d) cancers present an abundance of neoantigens that likely underlies their exceptional responsiveness to immune checkpoint blockade (ICB). However, MMR-d colon cancers that evade CD8+ T cells through loss of Human Leukocyte Antigen (HLA) class I-mediated antigen presentation frequently remain responsive to ICB, suggesting the involvement of other immune effector cells.
2022-11-01 | GSE216534 | GEO
Project description:Immune checkpoint blockade (ICB), notably Programmed Death-1/Programmed Death-Ligand 1 (PD-1/PD-L1) inhibition, has revolutionized the treatment of non-small cell lung cancer (NSCLC). However, durable responses are only observed in a subpopulation of patients. Defective antigen presentation and an immunosuppressive tumor microenvironment can lead to deficient T-cell recruitment and ICB resistance. We evaluated in situ vaccination with CXCL9 and CXCL10-engineered dendritic cells (CXCL9/10-DC) as a novel strategy to overcome resistance to ICB using Lkb1-null murine NSCLC model. We utilized single-cell RNA-seq to evaluate alterations of immune infiltration associated with the new therapy, which combines intratumoral CXCL9/10-DC administration and PD-1 inhibition.
2023-05-22 | GSE232730 | GEO
Project description:The anti-tumor effects of IFNγ are well-known as IFNγ binding to tumor cells increases antigen presentation and can cause cytostatic growth defects. Indeed, the inability of tumors to respond to IFNγ often renders tumors resistant to checkpoint blockade and other immunotherapies reliant on direct T cell cytotoxicity. We performed single-cell RNA-sequencing during virus therapy to get insight into the immune microenvironment of the tumor during treatment.
2023-02-03 | GSE222795 | GEO
Project description:Immune checkpoint blockade (ICB) therapy revolutionized cancer treatment, but many patients with impaired MHC-I expression remain refractory. Histone methylation was involved in anti-tumor immunity of ICB. However, the link between histone methylation and MHC-I regulation and the related mechanisms are poorly understood. Here we show that KDM5A, an H3K4 demethylase that is critical for MHC-I expression and associated antigen presentation capacity, induces robust immune response and enhances ICB efficacy. Mechanistically, KDM5A upregulates IFN-gamma/STAT1-mediated MHC-I expression via directly binding and suppressing Scos1 in tumor cells. The genes encoding the lysosomal cathepsins are recognized and up-regulated by KDM5A, resulting in enhanced antigen-presentation abilities of both tumor cells and dendritic cells. Furthermore, pharmacological enhancing KDM5A improves response to anti-PD-1 therapy. These investigations demonstrate that enhancing KDM5A triggers MHC-associated antigen presentation of both tumor cells and DCs simultaneously to boost antitumor immunity, thus represents a candidate ICB sensitizer.
2024-03-31 | GSE260912 | GEO
Project description:Suppression of antigen presentation is a mechanism employed by cancers, such small cell lung cancer (SCLC), to avoid immune surveillance and resist response to immune checkpoint blockade (ICB). A subset of SCLC with decreased neuroendocrine (NE) features have increased antigen presentation and prolonged survival with ICB but the underlying mechanism(s) are unclear and no biomarkers for patient selection are available in the SCLC clinic. Here, we discover that NOTCH1 is a key driver of intrinsic tumor immunity and anti-tumor immune response in SCLC. Mechanistically, NOTCH1-mediated NE to non-NE transdifferentiation reverses innate immune suppression and upregulates MHC Class I through epigenetic re-expression of STING and increased STING pathway sensitivity through DNA damage and release of cytosolic DNA. STING agonism synergizes with anti-PD-L1 therapy to mediate tumor eradication in a Notch-transdifferentiated syngeneic SCLC mouse model. Our results implicate Notch pathway downregulation as a mechanism of immunoevasion that may be therapeutically targeted to augment anti-tumor immune response.
2025-06-02 | GSE244944 | GEO
Project description:Suppression of antigen presentation is a mechanism employed by cancers, such small cell lung cancer (SCLC), to avoid immune surveillance and resist response to immune checkpoint blockade (ICB). A subset of SCLC with decreased neuroendocrine (NE) features have increased antigen presentation and prolonged survival with ICB but the underlying mechanism(s) are unclear and no biomarkers for patient selection are available in the SCLC clinic. Here, we discover that NOTCH1 is a key driver of intrinsic tumor immunity and anti-tumor immune response in SCLC. Mechanistically, NOTCH1-mediated NE to non-NE transdifferentiation reverses innate immune suppression and upregulates MHC Class I through epigenetic re-expression of STING and increased STING pathway sensitivity through DNA damage and release of cytosolic DNA. STING agonism synergizes with anti-PD-L1 therapy to mediate tumor eradication in a Notch-transdifferentiated syngeneic SCLC mouse model. Our results implicate Notch pathway downregulation as a mechanism of immunoevasion that may be therapeutically targeted to augment anti-tumor immune response.
2025-06-02 | GSE244945 | GEO
Project description:<p>Although immune checkpoint blockade (CPB) leads to prolonged responses in 15-40% of patients with metastatic melanoma, treatment refractory disease and progression after initial response remain major causes of mortality. While predictors of response have been reported, the common mechanisms of both primary and acquired resistance are poorly understood. To identify mechanisms of resistance and examine the evolving landscape in response to CPB, we performed whole exome sequencing (WES), immunohistochemistry (IHC), and RNA-sequencing (RNAseq) of longitudinal tumor biopsies from 17 metastatic melanoma patients treated with various CPB therapies. We found no significant changes in both mutational and neoantigen loads over time between responders and nonresponders. However, we identified abnormalities in one gene, beta-2-microglobulin (<i>B2M</i>), an essential component of MHC Class I antigen presentation, that were present in samples during disease progression but not regression. In total, we identified <i>B2M</i> aberrations in 29.4% of patients, including multiple early frameshift mutations, loss of heterozygosity (LOH) overlapping <i>B2M</i>, and absence of tumor-specific <i>B2M</i> protein expression. Additional defects in the antigen presentation and IFNγ pathways were identified but were not restricted to progressing lesions in our cohort. In two independent cohorts of 105 and 38 melanoma patients treated with ipilimumab (anti-CTLA4) and pembrolizumab (anti-PD1) respectively, we found that <i>B2M</i> LOH was enriched 3-fold in nonresponders (~30%) vs. responders (~10%) and associated with poorer overall survival (log-rank p=0.01, p=0.006). Loss of both copies of <i>B2M</i> was found only in nonresponders. We also found evidence for association of LOH overlapping <i>IFNGR1</i> with poorer overall survival exclusively in the anti-PD1 cohort. Thus, <i>B2M</i> loss is likely a common mechanism of primary and acquired resistance to therapies targeting CTLA4 or PD-1.</p>
| phs001427 | dbGaP