Impaired HLA Class 1 Antigen Processing and Presentation as a Mechanism of Acquired Resistance to Immune Checkpoint Inhibitors in Lung Cancer
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA412283 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Impaired HLA Class 1 Antigen Processing and Presentation as a Mechanism of Acquired Resistance to Immune Checkpoint Inhibitors in Lung Cancer
| PRJNA412284 | ENA
Project description:Gene expression analysis of molecules with known function in HLA class II antigen processing and presentation. Various hematopoietic cell types and (cytokine pre-treated) non-hematopoietic cells that are targeted in Graft-versus-Leukemia reactivity and Graft-versus-Host Disease were collected. Expression was compared between the different hematopoietic and non-hematopoietic cell types for the Invariant chain, HLA-DMA, HLA-DMB, HLA-DOA and HLA-DOB genes. The data show that the Invariant chain, HLA-DMA, HLA-DMB and HLA-DOA genes are expressed in all or the majority of cell types with HLA class II surface expression, whereas expression of the HLA-DOB gene is restricted to professional antigen presenting B-cells and mature dendritic cells. Total RNA was isolated from various hematopoietic cell types isolated (and cultured) from (G-CSF mobilized) peripheral blood from five different individuals and from (IFN-g pre-treated) fibroblasts cultured from skin biopsies from four different patients transplanted with allogeneic hematopoietic stem cells.
2012-06-18 | E-GEOD-38798 | biostudies-arrayexpress
Project description:Gene expression analysis of molecules with known function in HLA class II antigen processing and presentation. Various hematopoietic cell types and (cytokine pre-treated) non-hematopoietic cells that are targeted in Graft-versus-Leukemia reactivity and Graft-versus-Host Disease were collected. Expression was compared between the different hematopoietic and non-hematopoietic cell types for the Invariant chain, HLA-DMA, HLA-DMB, HLA-DOA and HLA-DOB genes. The data show that the Invariant chain, HLA-DMA, HLA-DMB and HLA-DOA genes are expressed in all or the majority of cell types with HLA class II surface expression, whereas expression of the HLA-DOB gene is restricted to professional antigen presenting B-cells and mature dendritic cells.
2012-06-19 | GSE38798 | GEO
Project description:Tumor heterogeneity results from clonal diversity and evolutionary selection, and is a major cause of therapeutic resistance. Immunotherapy may exploit alternative vulnerabilities of drug resistant cells, and tumor-specific HLA peptide ligands on the cell surface are promising leads to invoke such targeted anti-tumor responses. In this work, we investigate the variability in HLA class I peptide presentation between tumor cells of the same patient, as differential ligand presentation could impact the efficacy of immunological interventions. By organoid amplification, we modeled single-cell level heterogeneity in a MSI- colorectal cancer patient, and directly correlated clonal tumor proteomes with the respective ligandomes. With deep comparative proteome profiling and sensitive detection of >7000 peptide ligands from each tumor organoid line, we found tumor-surface peptide presentation to be largely uncoupled from the steady-state protein abundance. Within the small minority of tumor-specific ligands (~3%), source proteins needed for DNA damage sensing and repair, and tumor suppression were prominently featured, leading us to speculate that such peptides may be consistently presented, as degradative byproducts of intended silencing. While clone-specific differences in peptide presentation were observed, inter-clone variability was also highly prevalent (15-25%). Collectively, these illustrate the heterogeneous peptide presentation landscape even within one individual, and hint that a multi-peptide vaccination approach against highly conserved tumor suppressors may be a viable option in patients with low tumor-mutational burden.
2020-10-26 | PXD016582 | Pride
Project description:Mechanisms of acquired resistance to immune checkpoint inhibitors (ICI) are poorly understood. We leveraged a collection of 14 ICI-resistant lung cancer samples to investigate whether alterations in genes encoding HLA Class I antigen processing and presentation machinery (APM) components or interferon signaling play a role in acquired resistance to PD-1 or PD-L1 antagonistic antibodies. Recurrent mutations or copy-number changes were not detected in our cohort. In one case, we found acquired homozygous loss of B2M that caused lack of cell-surface HLA Class I expression in the tumor and a matched patient-derived xenograft (PDX). Downregulation of B2M was also found in two additional PDXs established from ICI-resistant tumors. CRISPR-mediated knockout of B2m in an immunocompetent lung cancer mouse model conferred resistance to PD-1 blockade in vivo, proving its role in resistance to ICIs. These results indicate that HLA Class I APM disruption can mediate escape from ICIs in lung cancer.Significance: As programmed death 1 axis inhibitors are becoming more established in standard treatment algorithms for diverse malignancies, acquired resistance to these therapies is increasingly being encountered. Here, we found that defective antigen processing and presentation can serve as a mechanism of such resistance in lung cancer. Cancer Discov; 7(12); 1420-35. ©2017 AACR.This article is highlighted in the In This Issue feature, p. 1355.
| S-EPMC5718941 | biostudies-other
Project description:C57BL/6 mouse pancreas cells were infected with a CRISPR library targeting TSGs. Total HLA and SIINFEKL presentation was measured by flow and cells were sorted for sequencing
2021-10-01 | E-MTAB-10723 | biostudies-arrayexpress
Project description:We interrogated the transcriptome from bulk-sorted T1D donor β-cells as compared to non-diabetic donors. We found β-cells also expressed mRNA for HLA Class II and Class II antigen presentation pathway components, but not a macrophage marker.
2019-03-01 | GSE121863 | GEO
Project description:The sensitivity of malignant tissues to T cell-based cancer immunotherapies is dependent on the presence of targetable HLA class I ligands on the tumor cell surface. Peptide intrinsic factors, such as HLA class I affinity, likelihood of proteasomal processing, and transport into the ER lumen have all been established as determinants of HLA ligand presentation. However, the role of sequence features at the gene and protein level as determinants of epitope presentation has not been systematically evaluated. To address this, we performed HLA ligandome mass spectrometry on patient-derived melanoma lines and used this data-set to evaluate the contribution of 7,124 gene and protein sequence features to HLA sampling. This analysis reveals that a number of predicted modifiers of mRNA and protein abundance and turn-over, including predicted mRNA methylation and protein ubiquitination sites, inform on the presence of HLA ligands. Importantly, integration of gene and protein sequence features into a machine learning approach augments HLA ligand predictions to a comparable degree as predictive models that include experimental measures of gene expression. Our study highlights the value of gene and protein features to HLA ligand predictions.
2023-01-08 | GSE210999 | GEO
Project description:The sensitivity of malignant tissues to T cell-based cancer immunotherapies is dependent on the presence of targetable HLA class I ligands on the tumor cell surface. Peptide intrinsic factors, such as HLA class I affinity, likelihood of proteasomal processing, and transport into the ER lumen have all been established as determinants of HLA ligand presentation. However, the role of sequence features at the gene and protein level as determinants of epitope presentation has not been systematically evaluated. To address this, we performed HLA ligandome mass spectrometry on patient-derived melanoma lines and used this data-set to evaluate the contribution of 7,124 gene and protein sequence features to HLA sampling. This analysis reveals that a number of predicted modifiers of mRNA and protein abundance and turn-over, including predicted mRNA methylation and protein ubiquitination sites, inform on the presence of HLA ligands. Importantly, integration of gene and protein sequence features into a machine learning approach augments HLA ligand predictions to a comparable degree as predictive models that include experimental measures of gene expression. Our study highlights the value of gene and protein features to HLA ligand predictions.
2023-01-08 | GSE210998 | GEO
Project description:Increased antigen cross-presentation but impaired cross-priming after activation of PPARγ is mediated by up-regulation of B7H1 Dendritic cells (DCs) are able to take up exogenous antigens and present antigen-derived peptides on MHC class I molecules, a process termed cross-presentation. The mannose receptor (MR), an endocytic receptor expressed on a variety of antigen-presenting cells (APCs), has been demonstrated to target soluble antigens exclusively towards cross-presentation. In this study, we investigated the role of the murine nuclear receptor peroxisome proliferator-activated receptor γ (PPARγ), a ligand-activated transcription factor with immunomodulatory properties, in MR-mediated endocytosis and cross-presentation of the model antigen ovalbumin (OVA). We could demonstrate both in vitro and in vivo that activation of PPARγ resulted in increased MR expression, which in consequence led to enhanced MR-mediated endocytosis and elevated cross-presentation of soluble OVA. Concomitantly, activation of PPARγ in DCs induced up-regulation of the co-inhibitory molecule B7H1, which, despite enhanced cross-presentation, caused an impaired activation of naive OVA-specific CD8+ T cells and the induction of T cell tolerance. These data provide a mechanistic basis for the immunomodulatory action of PPARγ which might open new possibilities in development of therapeutical approaches aimed at the control of excessive immune responses, e.g. in T cell-mediated autoimmunity. Comparison of murine mannose receptor negative versus mannose receptor positive bone marrow-derived DCs
2010-05-08 | E-GEOD-15616 | biostudies-arrayexpress