EGFR inhibition triggers an adaptive response by co-opting antiviral signaling pathways in lung cancer

Gong, Ke; Guo, Gao; Panchani, Nishah; Bender, Matthew E.; Gerber, David E.; Minna, John D.; Fattah, Farjana J.; Gao, Boning; Peyton, Michael; Kernstine, Kemp H.; Mukherjee, Bipasha; Burma, Sandeep; Chiang, Cheng Ming; Zhang, Shanrong; Sathe, Adwait Amod; Xing, Chao; Dao, Kathryn H.; Zhao, Dawen; Akbay, Esra A.; Habib, Amyn A.

doi:10.1038/s43018-020-0048-0

Cited by 61 publications

(54 citation statements)

References 61 publications

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“…Standard of care therapy for resected NSCLC continues to evolve and recently the presence of targetable driver oncogenes are now informing adjuvant therapy approaches [26]. While the role of the immune system in targeted therapy responsiveness is unknown, preclinical and translational data suggest engagement of the immune system promotes disease control [9,27]. Whether cancer cell-specific expression of MHCII is a determinant of the TME and outcomes in patients with targetable oncogenes is unknown and remains an active area of investigation.…”

Section: Discussionmentioning

confidence: 99%

Cancer cell-specific MHCII expression as a determinant of the immune infiltrate organization and function in the non-small cell lung cancer tumor microenvironment

Wrobel

et al. 2021

Preprint

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Introduction In patients with non-small cell lung cancer (NSCLC), the prognostic significance of the tumor microenvironment (TME) immune composition has been demonstrated using single or dual-marker staining on sequential tissue sections. While these studies show that relative abundance and localization of immune cells are important parameters, deeper analyses of the NSCLC TME are necessary to refine the potential application of these findings to clinical care. Currently, the complex spatial relationships between cells of the NSCLC TME and potential drivers contributing to its immunologic composition remain unknown. Methods We employed multispectral quantitative imaging on the lung adenocarcinoma TME in 153 patients with resected tumors. On a single slide per patient, we evaluated the TME with markers for CD3, CD8, CD14, CD19, major histocompatibility complex II (MHCII), cytokeratin, and DAPI. Image analysis including tissue segmentation, phenotyping, and spatial localization were performed. Results Specimens where 5% or greater of lung cancer cells expressed MHCII (MHCIIhi TME) demonstrated increased levels of CD4+ and CD8+ T cell and CD14+ cell infiltration. In the MHCIIhi TME, the immune infiltrate was closer to cancer cells and expressed an activated phenotype. Morphologic image analysis revealed cancer cells in the MHCIIhi TME more frequently interfaced with CD4+ and CD8+ T cells. Patients with an MHCIIhi TME experienced improved overall survival (p=0.046). Conclusions Lung cancer cell-specific expression of MHCII associates with levels of immune cell infiltration, spatial localization, and activation status within the TME. This suggest cancer cell-specific expression of MHCII may represent a biomarker for the immune systems recognition and activation against the tumor.

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Section: Discussionmentioning

confidence: 99%

Cancer cell-specific MHCII expression as a determinant of the immune infiltrate organization and function in the non-small cell lung cancer tumor microenvironment

Wrobel

et al. 2021

Preprint

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“…6). The 55 ). This suggests that by promoting type I IFN signaling, the IWS1 phosphorylation pathway may promote resistance to EGFR TKI, contributing to the poor prognosis of these tumors.…”

Section: Discussionmentioning

confidence: 99%

IWS1 phosphorylation by AKT3 controls nuclear export of type I IFN mRNAs and sensitivity to oncolytic viral infection, by regulating the alternative RNA splicing of U2AF2

Laliotis

Kenney

Chavdoula

et al. 2020

Preprint

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Type I IFNs orchestrate the antiviral response. Interestingly, IFNA1 and IFNB1 genes are naturally intronless. Based on previous work, the splicing factor U2 Associated Factor 65 (U2AF65), encoded by U2AF2, and pre-mRNA Processing factor 19 (Prp19) function on the Cytoplasmic Accumulation Region Elements (CAR-E), affecting the nuclear export of intronless genes. We have previously shown that the loss of IWS1 phosphorylation by AKT3, promotes the alternative RNA splicing of U2AF2, resulting in novel transcripts lacking exon 2. This exon encodes part of the Serine-Rich (RS) domain of U2AF65, which is responsible for its binding with Prp19. Here, we show that IWS1 phosphorylation and the U2AF2 RNA splicing pattern affect the nuclear export of introless mRNAs. We also demonstrate that the same axis is required for the proper function of the CAR-Es. Mechanistically, whereas both U2AF65 isoforms bind CAR-E, the recruitment of Prp19 occurs only in cells expressing phosphorylated IWS, promoting intronless genes export. Moreover, analysis of Lung adenocarcinoma patients showed that high p-IWS1 activity correlates with the assembly of the U2AF65/Prp19 complex and export of intronless genes, in vivo. Accordingly, the expression of type I IFNs was decreased in cells deficient in IWS1 phosphorylation and the viral infection was increased. Furthermore, following infection with oncolytic virus, we observed reduced activation of p-STAT1 and expression of Interferon Stimulated Genes (ISG), in cells stimulated by shIWS1-derived supernatant, or cells treated with the pan-AKT inhibitor, MK2206. Consistently, killing curves and apoptosis assays after infection with oncolytic viruses, revealed increased susceptibility upon the loss of IWS1, with subsequent activation of Caspase-mediated death. The treatment of the lung adenocarcinoma cells with MK2206, phenocopied the loss of IWS1 phosphorylation. These data identify a novel mechanism by which the AKT/p-IWS1 axis, by hijacking the epigenetic regulation of RNA splicing and processing, contributes to the resistance to oncolytic viral infection, suggesting that combined inhibition of the splicing machinery and AKT/p-IWS1 signals would sensitize tumors to oncolytic viral treatment.

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“…The rAAV (serotype 8) vector expressing RIG-I under promoter CAG was constructed as we previously described 38,40 . For AAV8 administration, 1×10 12 vg AVV8 was injected through tail vein two weeks before the sacri ce. MS Analysis.…”

Section: Methodsmentioning

confidence: 99%

“…RIG-I is well-established to be one of the critical intracellular sensors for host recognition of RNA virus infection and subsequent induction of type I interferon (IFN) production in innate immune cells. It contains a Cterminal helicase domain to recognize cytoplasmic viral RNA and two N-terminal tandem caspase-recruiting domains (CARDs) to activate downstream type I IFN production 11,12 . Other than RIGI expression in immune cells, we previously found that RIG-I expression was mainly located in parenchymal hepatocytes in the liver, but not in mesenchymal cells 13 , suggesting the potential roles of RIG-I in liver functions and diseases.…”

Section: Introductionmentioning

confidence: 99%

JMJD4-demethylated RIG-I prevents hepatic steatosis and carcinogenesis

Zhou

Jia

et al. 2021

Preprint

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Hepatocarcinogenesis is driven by necroinflammation or metabolic disorders, and the underlying mechanisms remain largely elusive. Here, we interestingly found that DEN-induced hepatocarcinogenesis was enhanced while NASH-induced hepatocarcinogenesis was abolished by hepatocyte-specific RIG-I deficiency. Further, IL-6 decreased RIG-I expression in HCC progenitor cells (HcPCs), which then viciously promoted IL-6 effector signaling and drove HcPCs to fully established HCC. RIGI expression was increased by HFD, which then enhanced cholesterol synthesis and steatosis, and the in-turn NASH and NASH-induced hepatocarcinogenesis. Mechanistically, RIG-I was constitutively monomethylated at K18 and K146, and demethylase JMJD4-mediated RIG-I demethylation suppressed IL6STAT3 signaling. The constitutive methylated RIG-I associated with AMPKα to inhibit HMGCR phosphorylation, thus promoting HMGCR enzymatic activity and cholesterol synthesis. Together with clinical data that RIGI was decreased in hepatic precancerous dysplastic nodules while increased in NAFLD, we conclude that decreased RIGI in HcPCs promotes necroinflammationinduced hepatocarcinogenesis, while increased constitutive methylated RIG-I enhances steatosis and NASH-induced hepatocarcinogenesis.

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EGFR inhibition triggers an adaptive response by co-opting antiviral signaling pathways in lung cancer

Cited by 61 publications

References 61 publications

Cancer cell-specific MHCII expression as a determinant of the immune infiltrate organization and function in the non-small cell lung cancer tumor microenvironment

Cancer cell-specific MHCII expression as a determinant of the immune infiltrate organization and function in the non-small cell lung cancer tumor microenvironment

IWS1 phosphorylation by AKT3 controls nuclear export of type I IFN mRNAs and sensitivity to oncolytic viral infection, by regulating the alternative RNA splicing of U2AF2

JMJD4-demethylated RIG-I prevents hepatic steatosis and carcinogenesis

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