Cancer cells restrict immunogenicity of retrotransposon expression via distinct mechanisms Journal Article
| Authors: | Sun, S.; You, E.; Hong, J.; Hoyos, D.; Del Priore, I.; Tsanov, K. M.; Mattagajasingh, O.; Di Gioacchino, A.; Marhon, S. A.; Chacon-Barahona, J.; Li, H.; Jiang, H.; Hozeifi, S.; Rosas-Bringas, O.; Xu, K. H.; Song, Y.; Lang, E. R.; Rojas, A. S.; Nieman, L. T.; Patel, B. K.; Murali, R.; Chanda, P.; Karacay, A.; Vabret, N.; De Carvalho, D. D.; Zenklusen, D.; LaCava, J.; Lowe, S. W.; Ting, D. T.; Iacobuzio-Donahue, C. A.; Solovyov, A.; Greenbaum, B. D. |
| Article Title: | Cancer cells restrict immunogenicity of retrotransposon expression via distinct mechanisms |
| Abstract: | To thrive, cancer cells must navigate acute inflammatory signaling accompanying oncogenic transformation, such as via overexpression of repeat elements. We examined the relationship between immunostimulatory repeat expression, tumor evolution, and the tumor-immune microenvironment. Integration of multimodal data from a cohort of pancreatic ductal adenocarcinoma (PDAC) patients revealed expression of specific Alu repeats predicted to form double-stranded RNAs (dsRNAs) and trigger retinoic-acid-inducible gene I (RIG-I)-like-receptor (RLR)-associated type-I interferon (IFN) signaling. Such Alu-derived dsRNAs also anti-correlated with pro-tumorigenic macrophage infiltration in late stage tumors. We defined two complementary pathways whereby PDAC may adapt to such anti-tumorigenic signaling. In mutant TP53 tumors, ORF1p from long interspersed nuclear element (LINE)-1 preferentially binds Alus and decreases their expression, whereas adenosine deaminases acting on RNA 1 (ADAR1) editing primarily reduces dsRNA formation in wild-type TP53 tumors. Depletion of either LINE-1 ORF1p or ADAR1 reduced tumor growth in vitro. The fact that tumors utilize multiple pathways to mitigate immunostimulatory repeats implies the stress from their expression is a fundamental phenomenon to which PDAC, and likely other tumors, adapt. © 2024 The Authors |
| Keywords: | immunohistochemistry; signal transduction; adult; clinical article; human tissue; protein expression; aged; primary tumor; unclassified drug; human cell; genetics; missense mutation; interferon; pancreatic neoplasms; cd8+ t lymphocyte; mouse; animal; metabolism; animals; mice; reverse transcription polymerase chain reaction; carcinoma, pancreatic ductal; cohort analysis; cell line, tumor; protein p53; mathematical model; rna binding protein; gene expression regulation; rna-binding proteins; gene expression regulation, neoplastic; immunology; microsatellite instability; immunogenicity; cancer cell; pancreas tumor; tumor cell line; tumor suppressor protein p53; innate immunity; tumor growth; macrophage; macrophages; dna binding; double stranded rna; rna, double-stranded; long terminal repeat; transcriptome sequencing; tumor microenvironment; cancer evolution; retroposon; retroelements; interferon type i; retinoic acid inducible protein i; pancreatic ductal carcinoma; tp53; long interspersed nucleotide elements; adenosine deaminase; cancer immunity; alu elements; humans; human; male; female; article; rna sequencing; immunofluorescence assay; differential expression analysis; coimmunoprecipitation; immune signaling; retrotransposons; tumor-immune microenvironment; kegg; alu repeat; multiomics; long interspersed nuclear element; m2 macrophage; type i interferon signaling; metastasis site; adar1; inverted alus; adenosine deaminases acting on rna 1; adar protein, human; short interspersed nuclear element |
| Journal Title: | Immunity |
| Volume: | 57 |
| Issue: | 12 |
| ISSN: | 1074-7613 |
| Publisher: | Cell Press |
| Date Published: | 2024-12-10 |
| Start Page: | 2879 |
| End Page: | 2894.e11 |
| Language: | English |
| DOI: | 10.1016/j.immuni.2024.10.015 |
| PUBMED: | 39577413 |
| PROVIDER: | scopus |
| PMCID: | PMC12022969 |
| DOI/URL: | |
| Notes: | Article -- MSK corresponding author is Siyu Sun -- Source: Scopus |
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