| Autor: |
Jonathan Castillo, Tianchun Xue, Samantha Joseph, Mayela Norwood, Daniel J. Mullen, Stephanie Berrellez, Sophia James, Alan L. Epstein, Troy McEachron, Crystal N. Marconett |
| Rok vydání: |
2023 |
| DOI: |
10.1101/2023.03.02.530823 |
| Popis: |
Immunotherapy has emerged as a major breakthrough that has the ability to improve survival outcomes for multiple solid tumor types, however effective response requires the combination of blocking inhibitory signals on the tumor surface and antigen presentation to the tumor surface for proper immune recognition. Several commercially available and robust methods exist for identification of tumors displaying immune-inhibitory surface receptors, including PD-L1 and CTLA-4, however it is currently difficult to predict effectiveness of antigen presentation on the cell surface. To address this, we utilized clinical and next-generation sequencing data generated by The Cancer Genome Atlas (TCGA) to identify gene signatures that are correlated to tumor mutational burden (TMB) within cancers of epithelial origins as a surrogate for neoantigen signatures. We identifiedLINC00261as a top gene correlated to mutational burden (TMB), whose expression activates DNA damage response pathwaysin vitroalong with resistance to cisplatin.LINC00261expression was also significantly correlated to MHC Class II genes involved in endogenous neoantigen presentation expression within the TCGA-LUAD cohort. This relationship was confirmedin vitrothrough ectopic reintroduction ofLINC00261for key MHC Class II presentation genes. Interferon gamma-induced MHC gene activationin vitrowas also able to induce endogenous expression ofLINC00261. Our results suggest there is a mechanistic relationship betweenLINC00261expression and functional MHC Class II neoantigen presentation in LUAD. The silencing ofLINC00261in LUAD results in compromised DNA repair, accumulation of mutations, and reduced antitumor immune response. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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