scholarly journals m6A Regulators Mediated Methylation Modification Patterns and Tumor Microenvironment Infiltration Characterization In Nasopharyngeal Carcinoma

2022 ◽  
Vol 12 ◽  
Author(s):  
Zijian Liu ◽  
Jinlan He ◽  
Jiaqi Han ◽  
Jiangping Yang ◽  
Wenjun Liao ◽  
...  
Keyword(s):  
Gene Expression ◽  
Nasopharyngeal Carcinoma ◽  
Tumor Microenvironment ◽  
Lower Risk ◽  
Biological Function ◽  
Tumor Characteristics ◽  
Tumor Mutation Burden ◽  
Therapeutic Advantage ◽  
Mutation Burden

BackgroundThe role of RNA N6-methyladenosine (m6A) modification in tumor progression and metastasis has been demonstrated. Nonetheless, potential biological function of m6A modification patterns in nasopharyngeal carcinoma (NPC) remains unknown.MethodsThe m6A modification patterns were comprehensively evaluated based on 26 m6A regulators in NPC, and m6A subtype and also m6A score were identified and systematically correlated with representative tumor characteristics.ResultsTwo distinct m6A subtypes were determined and were highly consistent with immune activated and immune suppressed phenotypes, respectively. More representative m6A scores of individual tumors could predict tumor microenvironment (TME) infiltration, mRNA based stemness index (mRNAsi), EBV gene expression, genetic variation, and prognosis of NPC patients. Low m6A score, characterized by activation of immunity and suppression of mRNAsi and EBV gene, indicated an activated TME phenotype and better PFS and also lower risk of recurrence and metastasis. High m6A score, characterized by activation of Wnt and NF-κB signaling pathway and lack of effective immune infiltration, indicated an immune suppressed TME phenotype and poorer survival. Low m6A score was also correlated with increased tumor mutation burden (TMB) and better response to immunotherapy, and vice versa. A significant therapeutic advantage in patients with low m6A score was confirmed with an anti-PDL1 immunotherapy cohort.Conclusionsm6A patterns played an important role in the diversity and complexity of TME. m6A score could be used to evaluate the m6A pattern of individual tumor to enhance our understanding of TME infiltration and guide more effective immunotherapy strategies.

Role of Tumor Microenvironment on Gene Expression in Pancreatic Cancer Tumor Models

2011 ◽  
Vol 171 (1) ◽  
pp. 136-142 ◽  
Author(s):  
Soeren Torge Mees ◽  
Wolf Arif Mardin ◽  
Christina Schleicher ◽  
Mario Colombo-Benkmann ◽  
Norbert Senninger ◽  
...  
Keyword(s):  
Gene Expression ◽  
Pancreatic Cancer ◽  
Tumor Microenvironment ◽  
Tumor Models ◽  
Cancer Tumor

Tumor mutation burden and PD-L1 expression in SDH/FH mutated solid tumors.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 1524-1524
Author(s):  
Leylah Drusbosky ◽  
Christopher Szeto ◽  
Sandeep K. Reddy ◽  
Maninderjit Ghotra ◽  
Amir A. Toor ◽  
...  
Keyword(s):  
Gene Expression ◽  
Immune Checkpoint ◽  
Tumor Tissue ◽  
Fumarate Hydratase ◽  
Tumor Mutation Burden ◽  
Whole Exome ◽  
Mutation Burden ◽  
Potential Therapeutic Role ◽  
Tumor Types ◽  
First Time

1524 Background: Succinate Dehydrogenases and Fumarate Hydratase (SDH/FH) deficient tumors are characterized by succinate/fumarate accumulation and resultant pesudohypoxia that drives malignant transformation. This state of pseudohypoxia leads to dysregulation of PD-1 receptor-ligand signaling. In this study, we explored tumor mutation burden (TMB), gene expression of PD-L1, and expression of other immune checkpoint- associated genes in a diverse cohort of human tumors harboring SDH A, B, C, D and FH mutations. Methods: Retrospective analysis was performed on whole exome sequencing (WES; ~150x coverage) and whole transcriptomic RNAseq (~200x106 reads per tumor) data from NantHealth to identify tumors harboring SDHx and/or FH mutations. WES was performed on tumor tissue and matched normal for each patient to assess TMB. TMB was measured by counting all somatic-specific non-synonymous exonic mutations, with > 200 mutations qualified as TMB-high. Immune checkpoint therapy-related gene expression was evaluated for PDL1, CTLA4 , IDO, LAG3, FOXP3, PDL2, TIGIT, TIM3 and OX40 . Results: Among tumor samples from 3377 patients analyzed, 42 patients were found to harbor potentially-pathogenic & pathogenic mutations in the SDHA, B, C, D and FH genes. The most common tumor types with SDH/FH mutations were lung (n = 7), breast (n = 6), and colon cancer (n = 6). Our analysis revealed that TMB was positively correlated with the presence of SDH/FH mutations (p < 0.001). High PD-L1 expression was also significantly correlated with the presence of SDH/FH mutation (p < 0.05), while CTLA4, IDO, LAG3, FOXP3, and OX40 expression was significantly higher in SDH/FH mutated samples (p < 0.05). Conclusions: We report for the first time an association between increased TMB and increased PD-L1 expression in a variety of SDH/FH mutated tumors. These key parameters, imply that a higher TMB may drive the evolutionary pressure to select clones with a PDL1 high phenotype. This observation supports a potential therapeutic role for inhibition of PD-1/PD-L1 pathway in these tumors.

scholarly journals Molecular Characterization of the Clinical and Tumor Immune Microenvironment Signature of 5-methylcytosine-Related Regulators in non-small Cell Lung Cancer

2021 ◽  
Vol 9 ◽  
Author(s):  
Taisheng Liu ◽  
Liyi Guo ◽  
Guihong Liu ◽  
Xiaoshan Hu ◽  
Xiaoning Li ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Tumor Microenvironment ◽  
Immune Cell ◽  
Cell Infiltration ◽  
Immune Cell Infiltration ◽  
Check Point ◽  
Clinical Prognosis ◽  
Tumor Mutation Burden ◽  
Mutation Burden ◽  
Immune Check Point Inhibitor

Background: DNA methylation is an important epigenetic modification, among which 5-methylcytosine methylation (5mC) is generally associated with tumorigenesis. Nonetheless, the potential roles of 5mC regulators in the tumor microenvironment (TME) remain unclear.Methods: The 5mC modification patterns of 1,374 lung adenocarcinoma samples were analyzed systematically. The correlation between the 5mC modification and tumor microenvironment cell infiltration was further assessed. The 5mCscore was developed to evaluate tumor mutation burden, immune check-point inhibitor response, and the clinical prognosis of individual tumors.Results: Three 5mC modification patterns were established based on the clinical characteristics of 21 5mC regulators. According to the differential expression of 5mC regulators, three distinct 5mC gene cluster were also identified, which showed distinct TME immune cell infiltration patterns and clinical prognoses. The 5mCscore was constructed to evaluate the tumor mutation burden, immune check-point inhibitor response, and prognosis characteristics. We found that patients with a low 5mCscore had significant immune cell infiltration and increased clinical benefit.Conclusion: This study indicated that the 5mC modification is involved in regulating TME infiltration remodeling. Targeting 5mC modification regulators might be a novel strategy to treat lung cancer.

scholarly journals Ovarian Cancer Immunotherapy and Personalized Medicine

2021 ◽  
Vol 22 (12) ◽  
pp. 6532
Author(s):  
Susan Morand ◽  
Monika Devanaboyina ◽  
Hannah Staats ◽  
Laura Stanbery ◽  
John Nemunaitis
Keyword(s):  
Ovarian Cancer ◽  
Tumor Infiltrating Lymphocytes ◽  
Tumor Biomarkers ◽  
Future Directions ◽  
Tumor Mutation Burden ◽  
Mutation Burden ◽  
Target Treatment ◽  
Study Designs ◽  
Infiltrating Lymphocytes

Ovarian cancer response to immunotherapy is limited; however, the evaluation of sensitive/resistant target treatment subpopulations based on stratification by tumor biomarkers may improve the predictiveness of response to immunotherapy. These markers include tumor mutation burden, PD-L1, tumor-infiltrating lymphocytes, homologous recombination deficiency, and neoantigen intratumoral heterogeneity. Future directions in the treatment of ovarian cancer include the utilization of these biomarkers to select ideal candidates. This paper reviews the role of immunotherapy in ovarian cancer as well as novel therapeutics and study designs involving tumor biomarkers that increase the likelihood of success with immunotherapy in ovarian cancer.

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