Background: The quality and quantity of tumor neoantigens derived from tumor mutations determines the fate of the immune response in cancer. Frameshift mutations elicit better tumor neoantigens, especially when they are not targeted by nonsense-mediated mRNA decay (NMD). For tumor progression, malignant cells need to counteract the immune response including the silencing of immunodominant neoantigens (antigen immunoediting) and promoting an immunosuppressive tumor microenvironment. Although NMD inhibition has been reported to induce tumor immunity and increase the expression of cryptic neoantigens, the possibility that NMD activity could be modulated by immune forces operating in the tumor microenvironment as a new immunoediting mechanism has not been addressed.
Methods: We study the effect of SMG1 expression (main kinase that initiates NMD) in the survival and the nature of the tumor immune infiltration using TCGA RNAseq and scRNAseq datasets of breast, lung and pancreatic cancer. Different murine tumor models were used to corroborate the antitumor immune dependencies of NMD. We evaluate whether changes of SMG1 expression in malignant cells impact the immune response elicited by cancer immunotherapy. To determine how NMD fluctuates in malignant cells we generated a luciferase reporter system to track NMD activity in vivo under different immune conditions. Cytokine screening, in silico studies and functional assays were conducted to determine the regulation of SMG1 via IL-6/STAT3 signaling.
Results: IL-6/STAT3 signaling induces SMG1, which limits the expression of potent frameshift neoantigens that are under NMD control compromising the outcome of the immune response.
Conclusion: We revealed a new neoantigen immunoediting mechanism regulated by immune forces (IL-6/STAT3 signaling) responsible for silencing otherwise potent frameshift mutation-derived neoantigens.
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http://dx.doi.org/10.1186/s12943-022-01679-6 | DOI Listing |
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Department of Ophthalmology, Shanghai Ninth People's Hospital, Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, and Center for Basic Medical Research and Innovation in Visual System Diseases of Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, 200001, China.
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JHEP Rep
January 2025
State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Background & Aims: Dysregulation of one-carbon metabolism is considered an early hallmark of mitochondrial dysfunction and cancer metabolism. ALDH1L2 belongs to the aldehyde dehydrogenase family and plays an important role in tumor progression. However, little is known about the precise role and underlying mechanisms of ALDH1L2 in hepatocellular carcinoma (HCC).
View Article and Find Full Text PDFInt J Mol Sci
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Department of Gastrointestinal (GI) Oncology, Moffitt Cancer Center, Tampa, FL 33612, USA.
Intraductal papillary mucinous neoplasms (IPMN) are commonly detected pancreatic cysts that may transform into pancreatic ductal adenocarcinoma (PDAC). Predicting which IPMNs will progress to PDAC remains a clinical challenge. Moreover, identifying those clinically evident IPMNs for which a surveillance approach is best is a dire clinical need.
View Article and Find Full Text PDFInt J Clin Exp Pathol
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Shuyang Hospital of Traditional Chinese Medicine No. 28, Shanghai Middle Road, Shuyang County, Suqian, Jiangsu, China.
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View Article and Find Full Text PDFJ Clin Invest
November 2024
Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, United States of America.
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