Interference of tumor mutational burden with outcome of patients with head and neck cancer treated with definitive chemoradiation: A multicenter retrospective study of the German Cancer Consortium Radiation Oncology Group (DKTK-ROG)
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE122272 | GEO | 2019/05/02
REPOSITORIES: GEO
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Project description:Background: Most children and adolescents infected with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) develop a mild coronavirus disease 2019 (COVID-19) that usually does not require medical intervention. However, a small proportion of pediatric patients develop a severe clinical condition, Multisystem Inflammatory Syndrome in Children (MIS-C). The involvement of epigenetics in the control of the immune response and viral activity prompted us to carry out an epigenomic study to uncover target loci regulated by DNA methylation that could be altered upon the appearance of MIS-C. Methods: Peripheral blood samples were recruited from 43 confirmed MIS-C patients with a median age of 7.7 years, most of whom were of West-Eurasian origin. Four or more organ systems were involved in the majority of patients. 69 non-COVID-19 pediatric samples and 15 COVID-19 pediatric samples without MIS-C were used as controls. The cases in the two groups were mixed and divided into discovery (MIS-C = 29 and non-MIS-C = 56) and validation (MIS-C = 14 and non-MIS-C = 28) cohorts, and balanced for age, gender and ethnic background. We interrogated 850,000 CpG sites of the human genome for DNA methylation variants. Findings: The DNA methylation content of 33 CpG loci was linked with the presence of MIS-C. Of these sites, 18 (54.5%) were located in described genes. The top candidate gene was the immune T-cell mediator ZEB2; and others highly ranked candidates included the regulator of natural killer cell functional competence SH2D1B; VWA8, which contains a domain of the Von Willebrand factor A involved in the pediatric hemostasis disease; and human leukocyte antigen complex member HLA-DRB1; in addition to pro-inflammatory genes such as CUL2 and AIM2. The identified loci were used to construct a DNA methylation profile (EPIMISC) that was associated with MIS-C in both cohorts. The EPIMISC signature was also overrepresented in Kawasaki disease patients, a childhood pathology with also a possible viral trigger, that shares many of the clinical features of MIS-C. Interpretation: We have characterized DNA methylation loci that are associated with the onset of MIS-C. The identified genes are likely contributors to the characteristic exaggerated host inflammatory response observed in these patients. The described epigenetic signature could also provide new targets for more specific therapies for the disorder.
2022-06-26 | GSE193879 | 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: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:DNA Methylation profiles were generated for retrospective cases to support work into investigation of the immune environment in pediatric ependymoma. Samples were analyzed using the Illumina 450k beadchip and processed using the Heidelberg classifier (v11.2b and subsequently v12.3 for subgrouping/subtyping). The aim of the study was to better understand the immune-tumor microenvironment in pediatric ependymoma and the methylation profiles support the diagnoses of each case.
2023-10-02 | GSE190798 | GEO
Project description:Interference of tumor mutational burden with outcome of patients with head and neck cancer treated with definitive chemoradiation: A multicenter retrospective study of the German Cancer Consortium Radiation Oncology Group (DKTK-ROG)
| PRJNA504435 | ENA
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.
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Project description:By sorting receptor tyrosine kinases into endolysosomes, the endosomal sorting complexes required for transport (ESCRTs) are thought to attenuate oncogenic signaling in tumor cells. Paradoxically, ESCRT members are upregulated in tumors. Here, we show that disruption of hepatocyte growth factor-regulated tyrosine kinase substrate (HRS), a pivotal ESCRT component, inhibited tumor growth by promoting CD8+ T cell infiltration in melanoma and colon cancer mouse models. HRS ablation led to misfolded protein accumulation and triggered endoplasmic reticulum (ER) stress, resulting in the activation of the type I interferon pathway in an inositol-requiring enzyme-1α (IRE1α)/X-box binding protein 1 (XBP1)-dependent manner. HRS was upregulated in tumor cells with high tumor mutational burden (TMB). HRS expression associates with the response to PD-L1/PD-1 blockade therapy in melanoma patients with high TMB tumors. HRS ablation sensitized anti-PD-1 treatment in mouse melanoma models. Our study shows a mechanism by which tumor cells with high TMB evade immune surveillance and suggests HRS as a promising target to improve immunotherapy.
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Project description:Sex chromosomal abnormalities areare associated with multiple defects. In this study, we retrospectively analyzed the single nucleotide polymorphism (SNP) arrays of 186 early embryos with sex chromosomal abnormalities. using single nucleotide polymorphism (SNP) array. Among them, 52 cases of Turner syndrome, 21 cases of triple X syndrome, 35 cases of Klinefelter syndrome and 14 cases of XYY syndrome were detected. Moreover, 27 cases of mosaic sex chromosomal abnormalities were determined. Sex chromosomal deletions and duplications were found in 37 cases. Overall, our results presented a detailed manifestation of sex chromosomal abnormalities.
2022-07-29 | GSE208389 | GEO
Project description:Patients with prostate cancer (PC) generally do not respond favorably to immune checkpoint inhibitors, which may be due to a low abundance of tumor-infiltrating lymphocytes even when mutational load is high. Here, we identified a patient who presented with high-grade primary prostate cancer with two adjacent tumor nodules. While both nodules were mismatch repair- deficient (MMRd), exhibited pathogenic MSH2 and MSH6 alterations, had a high tumor mutational burden (TMB), and demonstrated high microsatellite instability (MSI), they had markedly distinct immune phenotypes. The first displayed a dense infiltrate of lymphocytes (“hot nodule”), while the second displayed significantly fewer infiltrating lymphocytes (“cold nodule”). Whole-exome DNA analysis found that both nodules shared many identical mutations, indicating that they were derived from a single clone. However, the cold nodule appeared to be sub-clonal relative to the hot nodule, suggesting divergent evolution of the cold nodule from the hot nodule. Whole-transcriptome RNA analysis found that the cold nodule demonstrated lower expression of genes related to antigen presentation (HLA) and, paradoxically, classical tumor immune tolerance markers such as PD-L1 (CD274) and CTLA-4. Immune cell deconvolution suggested that the hot nodule was enriched not only in CD8+ and CD4+ T lymphocytes, but also in M1 macrophages, activated NK cells, and gamma delta T cells compared to the cold nodule. This case highlights that MMRd/TMB-high PC can evolve to minimize an anti-tumor immune response, and nominates downregulation of antigen presentation machinery (HLA loss) as a potential mechanism of adaptive immune evasion in PC.
2023-10-31 | GSE246684 | GEO