Spontaneous mutations in the single TTN gene represent high tumor mutation burden
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PROVIDER: EGAS00001004009 | EGA |
REPOSITORIES: EGA
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Project description:While mutation-derived neoantigens are well recognized in generating anti-tumor T cell responses, increasing evidences highlight the complex association between tumor mutation burden (TMB) and tumor infiltrating lymphocytes (TILs). We examined this relationship across nine major cancer types to identify non-TMB determinants of immune responses within the tumor microenvironment. TMB overall correlated poorly with both TILs and exhausted CD8+ T cells (Tex) as an indicator of tumor-specific T cells. Computational clustering analysis performed on 4,510 tumors from The Cancer Genome Atlas revealed a group of tumors with abundant Tex but low TMB. In those tumors, we observed significantly higher expression of the stimulator of interferon genes (STING) signaling. Dendritic cells, particularly those of BATF3+ lineage, were also found to be essential for accumulation of Tex within tumors. Mechanistically, loss of genomic and cellular integrity, marked by decreased DNA damage repair, defective replication stress response, and increased apoptosis were shown to drive STING activation. These results highlight that TMB alone does not fully predict tumor immune profiles, with STING signaling compensating for low TMB in non-hypermutated tumors to enhance anti-tumor immunity. We further validated these findings using clinical samples via NanoString technology and single cell RNA-seq. Translating these results, STING agonists may benefit patients with non-hypermutated tumors. STING activation may serve as an additional biomarker to predict response to immune checkpoint blockades alongside TMB. Our research also unraveled the interplay between genomic instability and STING activation, informing potential combined chemotherapy targeting the axis of genomic integrity and immunotherapy.
2024-02-10 | GSE255107 | GEO
Project description:Tumor mutation burden (TMB) is an evolving biomarker for predicting response to immune checkpoint inhibitors (ICI’s). The goal of this study was to evaluate the use of RNA-seq for determining TMB in patients with defective DNA MMR (dMMR) due to MMR mutations or MLH1 promoter hypermethylation (HM) and tumors without dMMR. We included tumors and paired normal tissue from 58 patients for TMB analysis using RNA-seq. Forty-six tumors were MSI-H (29 with a DNA MMR germline mutation and 17 with MLH1 promoter HM) and 12 were MSS. TMB was measured using the expressed somatic nucleotide variants (eTMB). We developed a method that leverages mutational signatures to remove FFPE derived artifact from total eTMB and thereby accurately measure the eTMB. There was a significant difference in the eTMB observed between MSI-H and MSS cases; MSI-H cases had a median of 27.3 mutations/Mb compared to 6.7 mutations/Mb for MSS cases (p=3.5e-9). Among tumors with dMMR the tumors with DNA MMR mutations had a significantly higher eTMB (p=0.037) than tumors with MLH1 promoter HM: a median of 28.1 mutations/Mb vs. a median of 17.5 mutations/Mb. Furthermore, through multivariate analysis we found that MSI status, tissue type (endometrial or colorectal) and patient ages are significantly associated with eTMB. These results demonstrate that RNA-seq analysis can be used to measure eTMB in FFPE tumor specimens. Further studies are needed to determine how eTMB as determined by RNA-seq compares to TMB as determined by DNA-based NGS assays
2020-03-13 | GSE146889 | GEO
Project description:Autophagy degrades and recycles intracellular components to sustain metabolism and survival during starvation. Tumor cells upregulate and require autophagy to support their metabolism and enhance their proliferation and malignancy, and host autophagy also promotes tumor growth by providing essential tumor nutrients such as arginine in the circulation or alanine in the local tumor microenvironment. In addition to its metabolic role, autophagy regulates immune cell homeostasis and function, and suppresses inflammation, which may also play a role in cancer. Although host autophagy does not promote a T cell anti-tumor immune response in tumors with low tumor mutational burden (TMB), whether this was the case in tumors with high TMB was not known. Here we show that in contrast to low TMB tumors, host-specific deletion of the essential autophagy gene Atg7 induces a pro-inflammatory cytokine response and limits the growth of high TMB tumors, which is rescued by T-cell depletion. Expression of immune-related genes is increased in tumors from Atg7Δ/Δ hosts in a T-cell dependent manner. Tumors from Atg7Δ/Δ hosts also have decreased T regulatory cells (Tregs), and depletion of Tregs phenocopies the reduced tumor growth observed in Atg7Δ/Δ hosts. Moreover, loss of Stimulator of interferon genes (Sting) or IFNg restores growth of high TMB tumors on Atg7Δ/Δ hosts. Finally, similar to whole-body loss of autophagy, specific loss of autophagy in the liver is sufficient to limit tumor growth. Thus, autophagy, especially in the liver, promotes tumor immune tolerance by limiting STING, T cells, and IFNg, which enables tumor growth. We have designated this: Hepatic Autophagy Immune Tolerance (HAIT). Autophagy thereby promotes tumor growth through both metabolic and immune mechanisms depending on mutational load, and autophagy inhibition is an effective means to promote an anti-tumor T-cell response in high TMB tumors. Genomic DNA Profiling using Agilent SureSelect Mouse All Exon kit and sequencing using Illumina NextSeq550
2020-08-03 | GSE155556 | GEO
Project description:Autophagy degrades and recycles intracellular components to sustain metabolism and survival during starvation. Tumor cells upregulate and require autophagy to support their metabolism and enhance their proliferation and malignancy, and host autophagy also promotes tumor growth by providing essential tumor nutrients such as arginine in the circulation or alanine in the local tumor microenvironment. In addition to its metabolic role, autophagy regulates immune cell homeostasis and function, and suppresses inflammation, which may also play a role in cancer. Although host autophagy does not promote a T cell anti-tumor immune response in tumors with low tumor mutational burden (TMB), whether this was the case in tumors with high TMB was not known. Here we show that in contrast to low TMB tumors, host-specific deletion of the essential autophagy gene Atg7 induces a pro-inflammatory cytokine response and limits the growth of high TMB tumors, which is rescued by T-cell depletion. Expression of immune-related genes is increased in tumors from Atg7Δ/Δ hosts in a T-cell dependent manner. Tumors from Atg7Δ/Δ hosts also have decreased T regulatory cells (Tregs), and depletion of Tregs phenocopies the reduced tumor growth observed in Atg7Δ/Δ hosts. Moreover, loss of Stimulator of interferon genes (Sting) or IFNg restores growth of high TMB tumors on Atg7Δ/Δ hosts. Finally, similar to whole-body loss of autophagy, specific loss of autophagy in the liver is sufficient to limit tumor growth. Thus, autophagy, especially in the liver, promotes tumor immune tolerance by limiting STING, T cells, and IFNg, which enables tumor growth. We have designated this: Hepatic Autophagy Immune Tolerance (HAIT). Autophagy thereby promotes tumor growth through both metabolic and immune mechanisms depending on mutational load, and autophagy inhibition is an effective means to promote an anti-tumor T-cell response in high TMB tumors.
2020-07-27 | GSE154654 | GEO
Project description:In this manuscript, the authors had hypothesized a multi-dimensional approach modeling of both tumor and immune-related molecular mechanisms would better predict immune checkpoint blockade (ICB) response than simpler mutation-focused biomarkers, such as tumor mutational burden (TMB). The authors showed that the predictive power increases with deeper modeling of neoantigens and immune-related resistance mechanisms of ICB. The neoantigen burden score (NBS) and composite neoantigen presentation score (NEOPS) mentioned in the transcript was fully reproduced. Internally they used XGBoost algorithm to generate the results and the same is provided as dataset file. That is, the dataset provided here demonstrates that their integrative approach outperformed single-analyte biomarkers such as those found in cohort of patients with late-stage melanoma. This model is now addresses the issues in reproducing itself which was caused by version changes and deprecation of some R packages. It uses checkpoint package, which acts as a time machine for CRAN packages thereby promoting FAIReR sharing of ML models.
2024-07-23 | MODEL2407210001 | BioModels
Project description:In this manuscript, the authors had hypothesized a multi-dimensional approach modeling of both tumor and immune-related molecular mechanisms would better predict immune checkpoint blockade (ICB) response than simpler mutation-focused biomarkers, such as tumor mutational burden (TMB). The authors showed that the predictive power increases with deeper modeling of neoantigens and immune-related resistance mechanisms of ICB. The neoantigen burden score (NBS) and composite neoantigen presentation score (NEOPS) mentioned in the transcript was fully reproduced. Internally they used XGBoost algorithm to generate the results and the same is provided as dataset file. That is, the dataset provided here demonstrates that their integrative approach outperformed single-analyte biomarkers such as those found in cohort of patients with late-stage melanoma. This model is now addresses the issues in reproducing itself which was caused by version changes and deprecation of some R packages. It uses checkpoint package, which acts as a time machine for CRAN packages thereby promoting FAIReR sharing of ML models.
2024-07-23 | MODEL2407210001 | BioModels
Project description:It has been postulated that a high number of mutations resulting in the expression of neoantigens promotes T-cell-mediated inflammation and, as a consequence leads to the activation of immune checkpoints Hence, we determined if high tumor mutational burden (TMB) was associated with a distinct immune expression signature. For this analysis, 37 cases with tumor material for nanoString mRNA expression analysis were available. Overall, only minor differences in the expression levels of the immune-related genes were observed. Specific features of immune checkpoint activation such as high CD8+ T-cell scores and the IFNG signature were downregulated per trend in high compared to low TMB cases. In contrast, genes involved in neutrophil functions were found to be overexpressed in the high TMB group.
2019-05-02 | GSE122272 | GEO
Project description:Background:This study was a hypothesis generating exploration of genomic data collected at diagnosis for 19 patients, who later participated in a clinical trial. BRCA1/2 germline mutation related hereditary cancers are candidates for new immune therapeutic interventions. However, contrary to what is expected of tumors with compromised DNA repair, a prominent tumor mutation burden (TMB) in hereditary breast and ovarian cancers in this cohort, was not correlated with high global immune activity in their microenvironments. More information is needed about the relationship between genomic instability, phenotypes and immune microenvironments of BRCA1/2 related hereditary tumors in order to find appropriate markers of immune activity and the most effective anticancer immune strategies. Methods:Mining and statistical analyses of the original DNA and RNA sequencing data and data available from The Cancer Genome Atlas (TCGA) were performed using the R computing environment. To interpret the data, we have used published literature and web available resources such as Gene Ontology Tools, The Cancer immunome Atlas (TCIA) and the Cancer Research Institute iAtlas. Results: We found that BRCA1/2 germline related breast and ovarian cancers do not represent a unique phenotypic identity, but that they express a range of phenotypes similar to sporadic cancers. Importantly, BRCA2 germline mutation related breast tumors have a different profile of genomic instability compared to those related to BRCA1. However, all breast and ovarian BRCA1/2 related tumors are characterized by high homologous recombination deficiency (HRD) and low aneuploidy. Interestingly, all sporadic high grade serous ovarian cancers (HGSOC) and most of the subtypes of triple negative breast cancers (TNBC), but not other types of breast cancer, also express a high degree of HRD. Conclusion: : Tumor mutation burdon (TMB) is not associated with the magnitude of the immune response in hereditary BRCA1/2 related breast and ovarian cancers or in sporadic TNBC and sporadic HGSOC. Hereditary tumors express phenotypes as heterogenous as sporadic tumors with various degree of “BRCAness” and various characteristics of the immune microenvironments. The subtyping criteria developed for sporadic tumors can be applied for the classification of hereditary tumors and possibly also characterization of their immune microenvironment. A high HRD score may be a good candidate biomarker for response to platinum, and potentially PARP-inhibition.
2019-11-28 | GSE141142 | GEO
Project description:Tissue biomarkers for immune checkpoint inhibitor (ICI) response are limited by tumor sample heterogeneity and availability. This study identifies clinically actionable pretreatment blood biomarkers that are associated with ICI treatment response and survival in recurrent/metastatic head and neck squamous cell carcinoma. A prospective multi-center study enrolled 100 patients before standard-of-care immunotherapy. Blood immune profiles, measured by methylation cytometry, were assessed alongside tumor mutational burden (TMB) and PD-L1 combined proportion score (CPS). TMB and PD-L1 CPS were available for 56 and 91 patients, respectively. High neutrophils, monocytes, and neutrophil-to-lymphocyte ratio were associated with worse survival, while high CD4T cells, especially naïve CD4T cells, and lymphocyte-to-monocyte ratio were associated with better survival. Significant interactions between TMB and peripheral immune profiles for both progression-free and overall survival were found. Clinically relevant pretreatment peripheral immune biomarkers were identified, demonstrating the potential of DNA-based immune profiling to predict ICI response before treatment.
2024-11-15 | GSE277573 | GEO
Project description:High throughput single-cell RNA sequencing (sc-RNAseq) has become a frequently used tool to assess immune cell function and heterogeneity. Recently, the combined measurement of RNA and protein expression by sequencing was developed, which is commonly known as CITE-Seq. Acquisition of protein expression data along with transcriptome data resolves some of the limitations inherent to only assessing transcript, but also nearly doubles the sequencing read depth required per single cell. Furthermore, there is still a paucity of analysis tools to visualize combined transcript-protein datasets. Here, we describe a novel targeted transcriptomics approach that combines analysis of over 400 genes with simultaneous measurement of over 40 proteins on more than 25,000 cells. This targeted approach requires only about 1/10 of the read depth compared to a whole transcriptome approach while retaining high sensitivity for low abundance transcripts. To analyze these multi-omic transcript-protein datasets, we adapted One-SENSE for intuitive visualization of the relationship of proteins and transcripts on a single-cell level.
2020-03-30 | GSE135325 | GEO