Isocitrate dehydrogenase 1 mutations (mIDH1) are common in cholangiocarcinoma. (R)-2-hydroxyglutarate generated by the mIDH1 enzyme inhibits multiple α-ketoglutarate–dependent enzymes, altering epigenetics and metabolism. Here, by developing mIDH1-driven genetically engineered mouse models, we show that mIDH1 supports cholangiocarcinoma tumor maintenance through an immunoevasion program centered on dual (R)-2-hydroxyglutarate–mediated mechanisms: suppression of CD8+ T-cell activity and tumor cell–autonomous inactivation of TET2 DNA demethylase. Pharmacologic mIDH1 inhibition stimulates CD8+ T-cell recruitment and interferon γ (IFNγ) expression and promotes TET2-dependent induction of IFNγ response genes in tumor cells. CD8+ T-cell depletion or tumor cell–specific ablation of TET2 or IFNγ receptor 1 causes treatment resistance. Whereas immune-checkpoint activation limits mIDH1 inhibitor efficacy, CTLA4 blockade overcomes immunosuppression, providing therapeutic synergy. The findings in this mouse model of cholangiocarcinoma demonstrate that immune function and the IFNγ–TET2 axis are essential for response to mIDH1 inhibition and suggest a novel strategy for potentiating efficacy. Significance: Mutant IDH1 inhibition stimulates cytotoxic T-cell function and derepression of the DNA demethylating enzyme TET2, which is required for tumor cells to respond to IFNγ. The discovery of mechanisms of treatment efficacy and the identification of synergy by combined CTLA4 blockade provide the foundation for new therapeutic strategies. See related commentary by Zhu and Kwong, p. 604. This article is highlighted in the In This Issue feature, p. 587
Aberrant expression of viral-like repeat elements is a common feature of epithelial cancers, and the substantial diversity of repeat species provides a distinct view of the cancer transcriptome. Repeatome profiling across ovarian, pancreatic, and colorectal cell lines identifies distinct clustering independent of tissue origin that is seen with coding gene analysis. Deeper analysis of ovarian cancer cell lines demonstrated that human satellite II (HSATII) satellite repeat expression was highly associated with epithelial-mesenchymal transition (EMT) and anticorrelated with IFN-response genes indicative of a more aggressive phenotype. SATII expression — and its correlation with EMT and anticorrelation with IFN-response genes — was also found in ovarian cancer RNA-Seq data and was associated with significantly shorter survival in a second independent cohort of patients with ovarian cancer. Repeat RNAs were enriched in tumor-derived extracellular vesicles capable of stimulating monocyte-derived macrophages, demonstrating a mechanism that alters the tumor microenvironment with these viral-like sequences. Targeting of HSATII with antisense locked nucleic acids stimulated IFN response and induced MHC I expression in ovarian cancer cell lines, highlighting a potential strategy of modulating the repeatome to reestablish antitumor cell immune surveillance.
Objective: Our study aimed to compare the demographic characteristics of conduct disorder (CD) inpatients versus other psychiatric inpatients in children and adolescents, and assess the association between conduct disorder patients and the spectrum of substance use disorders (SUD). Methods: We included 800,614 psychiatric adolescent (12–18 years) inpatients, and this included 8885 inpatients (1.1%) primarily for conduct disorder in the Nationwide Inpatient Sample (2010–2014). ICD-9 codes were used to detect SUD, and a logistic regression model was used to evaluate the odds ratio (OR) for SUD in conduct disorder inpatients. Results: A higher proportion of conduct disorder inpatients were of 12–15 years of age (62.6%), male (64.4%), and White (45.7%). The lower median household income was correlated with a higher prevalence of conduct disorder (36.4%). Among SUD, cannabis use (23.7%) was most prevalent in conduct disorder inpatients followed by tobacco and alcohol use (10.1% each). Conduct disorder inpatients have 1.7-fold higher odds (95% confidence interval (CI) 1.52–1.82) for alcohol use and 1.4-fold higher odds (95% CI 1.31–1.49) for cannabis use compared to the non-conduct disorder inpatients. Cannabis use was seen significantly in adolescents (49.1%, 12–15 years), male (75.6%), and African Americans (45.6%). Conclusion: Conduct disorder inpatients have a higher risk of comorbid SUD compared to other psychiatric illnesses. The most common substance to be abused is cannabis followed by tobacco and alcohol. Varying pattern of substance use was seen by demographics and these predictors may help the clinicians for early diagnosis and treatment to improve overall health-related quality of life.
Background Serrated adenocarcinoma (SAC), a recognised WHO variant of colonic adenocarcinoma, is the purported end‐product of serrated neoplasia. However, the diagnosis of SAC is infrequently rendered, and little is known about its prognosis, immune microenvironment and molecular alterations. Materials and methods We assessed 903 consecutive colon carcinomas and recognised tumours with ≥ 5% (n = 77) serrated and ≥ 50% serrated patterns (n = 13). We assessed precursor polyps and synchronous polyps. We recorded demographic/clinical parameters, histological features and mismatch repair (MMR) status. We performed immunohistochemistry and quantification on tissue microarray for HLA class I/II proteins, B2MG, CD8, CD163, LAG3, FoxP3, PD‐L1 and BRAF V600E. Results We identified ≥ 5% epithelial serration prevalence in 8.5% of cases and ≥ 50% epithelial serration prevalence in 1.4% of cases. Precursor lesions were present in 21.4% of cases; these were mostly tubular adenomas with two traditional serrated adenomas identified. SAC with ≥ 5% serrations exhibited lower numbers of CD8‐positive lymphocytes (P = 0.002) and lower B2MG expression (P = 0.048), although neither value was significant at ≥ 50% serration threshold. There was no difference in HLA class I/II, or PD‐L1 expression on tumour cells and no difference in PD‐L1, LAG3, FoxP3 and CD163 expression on immune cells. There was no association with MMR status, or BRAFV600E relative to conventional adenocarcinoma. There was improved disease‐specific survival on univariate (but not multivariate) analysis between carcinomas with serrated pattern and non‐mucinous conventional colonic carcinomas at ≥ 5% epithelial serrations (P = 0.04). Conclusion SAC category shows a limited impact on survival, and this phenotype may harbour a unique immunological milieu.
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