Mismatch repair deficiency is not sufficient to increase tumor immunogenicity
Ontology highlight
ABSTRACT:
PROVIDER: PRJEB56609 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| ERR11571700.fastq.gz | Fastqsanger.gz | |||
| ERR11571700_1.fastq.gz | Fastqsanger.gz | |||
| ERR11571700_2.fastq.gz | Fastqsanger.gz | |||
| ERR11572000_1.fastq.gz | Fastqsanger.gz | |||
| ERR11572000_2.fastq.gz | Fastqsanger.gz |
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Project description:Tandem mass tag spectrometry was performed on eluted peptides from 8 single cell clones derived from a DNA mismatch repair deficient (MMRd) lung cancer cell line, which was derived ex vivo from tumors induced autochthonously in the lungs of mice in the MMRd models described in Westcott, PMK, et al., Nature Genetics, 2023 (in press). Whole exome sequencing and neoantigen prediction was performed on all single cell clones, and predicted neoantigens associated with somatic mutations were provided in the inclusion list for searching spectra. Tandem mass spectra were searched with Sequest (Thermo Fisher Scientific; version IseNode in Proteome Discoverer 2.5.0.400). Sequest was set up to search a mouse uniprot database (v.July 3, 2020; 55650 entries containing common contaminants and the proteins GFP, Cas9, Puromycin, and P2A (present in the cell lines) assuming no digestion enzyme (unspecific). Sequest was searched with a fragment ion mass tolerance of 0.02 Da and a parent ion tolerance of 10.0 ppm. TMTpro was added as a fixed modification on the K and N terminus of peptides. Oxidation of methionine was specified in Sequest as a variable modification. Resulting peptides were filtered to exclude peptides with an isolation interference of greater than 30 percent and ppm error greater than plus/minus 3 ppm of the median ppm error of all peptide-spectrum matches (PSMs). Peptides were further prioritized based on concordance of relative abundance across the single cell clones with presence/absence of the associated somatic mutation.
2023-06-04 | MSV000092096 | MassIVE
Project description:Using numerous isogenic models of mismatch repair defects we sought to understand how these defects influence global transcription
2018-09-08 | GSE119667 | GEO
Project description:DNA mismatch repair deficiency (MMRd) is associated with a high tumor mutational burden (TMB) and sensitivity to immune checkpoint blockade (ICB) therapy. Nevertheless, most MMRd tumors do not durably respond to ICB and critical questions remain about immunosurveillance and TMB in these tumors. In the present study, we developed autochthonous mouse models of MMRd lung and colon cancer. Surprisingly, these models did not display increased T cell infiltration or ICB response, which we showed to be the result of substantial intratumor heterogeneity of mutations. Furthermore, we found that immunosurveillance shapes the clonal architecture but not the overall burden of neoantigens, and T cell responses against subclonal neoantigens are blunted. Finally, we showed that clonal, but not subclonal, neoantigen burden predicts ICB response in clinical trials of MMRd gastric and colorectal cancer. These results provide important context for understanding immune evasion in cancers with a high TMB and have major implications for therapies aimed at increasing TMB.
| S-EPMC10562252 | biostudies-literature
Project description:Biases of DNA repair can shape the nucleotide landscape of genomes at evolutionary timescales. However, such biases have not yet been measured in chromatin for lack of technologies. Here we develop a genome-wide assay whereby the same DNA lesion is repaired in different chromatin contexts. We insert thousands of barcoded transposons carrying a reporter of DNA mismatch repair in the genome of mouse embryonic stem cells. Upon inducing a double-strand break between tandem repeats, a mismatch is generated when the single strand annealing repair pathway is used. Surprisingly, the mismatch repair machinery favors the same strand 60-80% of the time. The location of the lesion in the genome and the type of mismatch have little influence on the repair bias in this context.
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Project description:Transcriptomic evaluation of mismatch repair defects
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Project description:The mismatch repair (MMR) family is a highly conserved group of proteins that function in correcting base-base and insertion-deletion mismatches generated during DNA replication. To systematically investigate the mismatch repair pathway, we conducted a proteomic analysis and identified MMR-associated protein complexes using a tandem-affinity purification coupled with mass spectrometry (TAP-MS) method. In total, we identified 262 high-confidence candidate interaction proteins (HCIPs).
2016-02-08 | PXD003014 | Pride
Project description:DNA mismatch repair (MMR) is an evolutionarily conserved process that corrects innate DNA polymerase infidelities during replication to maintain genomic integrity. Defects in a subset of MMR genes are associated with hereditary non-polyposis colon cancer and some other sporadic cancers, highlighting the crucial role for MMR in genome maintenance. In E. coli a helicase implicated in the MMR process is well characterized, and named UvrD, whereas in mammals it has not been identified yet, even though the eukaryotic DNA mismatch pathway is analogous to the bacterial one and uses a similar repair mechanism and key components. Here we identify MCM9 as a helicase playing a vital role in MMR in mammals. MCM9 is the last discovered member of the MCM2-9 family, and has been implicated in replication and homologous recombination processes. By an affinity-purification proteomic approach, we found that MCM9 interacts with the MMR initiation complex. Immortalized cells from MCM9 knockout mice showed clear length alterations in their microsatellites, and a dramatic MMR deficiency compared to wild-type cells. We also found that a helicase-dead form of MCM9 is totally unable to restore the MMR deficiency phenotype. Furthermore, using an siRNA approach in human cells, we demonstrated that MCM9 is regulated by MSH2, a protein responsible for mismatch recognition. Our results clearly reveal that MCM9 functions as a helicase for DNA mismatch repair in mammals, and thus is essential for the maintenance of genome stability. Proteomics analysis: FLAG-HA-tagged human MCM9 plus associated proteins were isolated by tandem affinity purification from nuclear extracts of stably-expressing HeLa S3 cells, then analysed by SDS-PAGE and silver staining. Gel lanes were cut into slices, which were processed and analysed separately. Proteins in each gel slice were digested with trypsin, extracted and analysed by LC-MS/MS on a Thermo Scientific LTQ Velos mass spectrometer, generating a series of MS RAW files. Bioinformatics: Peptide and protein identification from MS data was performed using the Sequest program, with a human IPI sequence database (v.3.60). Trypsin was defined as the protease used, a peptide mass tolerance of 2.5 was specified, and all peptide matches have a Sequest Xcorr score ≥0.5.
2015-08-19 | PXD000212 | Pride
Project description:The mismatch repair (MMR) family is a highly conserved group of proteins that function in correcting base-base and insertion-deletion mismatches generated during DNA replication. To systematically investigate the mismatch repair pathway, we conducted a proteomic analysis and identified MMR-associated protein complexes using a tandem-affinity purification coupled with mass spectrometry (TAP-MS) method. In total, we identified 262 high-confidence candidate interaction proteins (HCIPs).
2016-03-13 | MSV000079578 | MassIVE
Project description:Tumor genomic heterogeneity significantly influences the efficacy of immune checkpoint blockade (ICB) therapy. To elucidate the underlying mechanisms, we pioneered the development of an ICB response score (IRS) based on machine learning analysis of microenvironmental features. Through a pan-cancer genomic screening, we identified the nuclear receptor corepressor NCOR1 as a key regulator, the tumors with genomic deficiency of which display a tumor infiltrating lymphocyte (TIL)-inflamed microenvironment. Genetic ablation of Ncor1 delays the tumorigenesis and metastasis in syngeneic and spontaneous tumor models in immunocompetent mice. Mechanistically, NCOR1 guards DNA mismatch repair by directly interacting with MSH2 and recruiting MutSa to chromatin for mismatch recognition, independent of its transcriptional regulatory activity coupling with histone deacetylase. Ncor1 depletion in hepatocellular carcinoma and melanoma cells promotes tumor immunogenicity by increasing tumor mutation burden (TMB), neoantigen load, and TIL infiltration and activation, thereby enhancing anti-PD-1 therapy efficacy. Our findings reveal that NCOR1 loss represents a novel mechanism underlying TMB-high tumors with intact MMR components, broadening the application of ICB.
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Project description:DNA replication errors occurring in mismatch repair (MMR) deficient cells persist as mismatch mutations and predispose to a range of tumors. Here, we sequenced the first whole-genomes from MMR-deficient tumors and observed that mutation rates were drastically increased relative to MMR-proficient endometrial tumors.
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