000008264 001__ 8264
000008264 005__ 20240417093535.0
000008264 0247_ $$2DOI$$a10.6083/4x51hj62j
000008264 037__ $$aIR
000008264 245__ $$aTargeting nucleic acid sensors for cancer immunotherapy
000008264 260__ $$bOregon Health and Science University
000008264 269__ $$a2020
000008264 336__ $$aAbstract
000008264 520__ $$aThe RNA sensor RIG-I (retinoic-acid inducible gene 1), also known as DDX58, recognizes cytosolic short dsRNA and plays a major role in the antiviral response. RIG-I activation triggers the type I Interferon (IFN) response and the expression of pro-inflammatory cytokines. Activation of cytosolic nucleic acid sensors has been associated with the potentiation of a robust anti-tumor immune response. In the present study, we activated RIG-I using a 5'-triphosphorilated-hpRNA in CT26, a murine colorectal carcinoma cell line. After 24h, we observed 4,474 genes that were differentially expressed between RIG-I activated and control group. According to the functional enrichment analysis, these genes are involved in the antiviral and innate immune responses. Specifically, we found Mx1 as the most differentially expressed gene, among other interferon response genes such as Mx2, Cxcl10, Ifi44l and Oas1. In vivo, injection of RIG-I stimulated CT26 cells markedly decreased tumor growth compared to their non-stimulated counterparts. Consistently, tumor weight was also decreased in RIG-I stimulated group. RNA expression analysis from the RIG-I activated tumors showed significant upregulation of IFN-I response genes which was consistent with our in vitro results. Multicolor flow cytometry analysis showed increased frequencies of Natural Killer Cells (NKs) and Dendritic Cells (DCs). Interestingly, RIG activated tumors also elicited significantly less exhausted CD8+ cells. Overall, our data highlight a critical role of tumor cell RIG-I in shaping the tumor immune microenvironment. Importantly, our work identifies several cellular and molecular immune correlates that can be exploited for combination therapies to enhance immune responses to tumors.
000008264 540__ $$fCC BY
000008264 542__ $$fIn copyright - joint owners
000008264 650__ $$aImmunotherapy$$020724
000008264 6531_ $$aCT26
000008264 6531_ $$acancer
000008264 6531_ $$aneoplasms
000008264 6531_ $$anucleic acid sensors
000008264 6531_ $$aRIG-I
000008264 6531_ $$aIFN-I response
000008264 691__ $$aSchool of Medicine$$041369
000008264 692__ $$aDepartment of Cell, Developmental and Cancer Biology$$041399
000008264 7001_ $$aBethencourt, Eugenia F.$$uOregon Health and Science University$$041354
000008264 7001_ $$aKhou, Sokchea$$uOregon Health and Science University$$041354
000008264 7001_ $$aEspinosa-Diez, Cristina$$uOregon Health and Science University$$041354
000008264 7001_ $$aRuhl, Rebecca$$uOregon Health and Science University$$041354
000008264 7001_ $$aGuan, Xiangnan$$uOregon Health and Science University$$041354
000008264 7001_ $$aXia, Zheng$$uOregon Health and Science University$$041354
000008264 7001_ $$aAnand, Sudarshan$$uOregon Health and Science University$$041354
000008264 711__ $$aResearch Week$$uOregon Health and Science University
000008264 8564_ $$957274c71-0561-4350-b298-100329db38af$$s47867$$uhttps://digitalcollections.ohsu.edu/record/8264/files/Eugenia-Fraile-Bethencourt.pdf
000008264 905__ $$a/rest/prod/4x/51/hj/62/4x51hj62j
000008264 980__ $$aResearch Week