A Cancer Cell–Intrinsic GOT2–PPARδ Axis Suppresses Antitumor Immunity

Abrego, Jaime; Sanford-Crane, Hannah; Oon, Chet; Xu, Xiao; Betts, Courtney B.; Sun, Duanchen; Nagarajan, Shanthi; Diaz, Luis; Sandborg, Holly; Bhattacharyya, Sohinee; Xia, Zheng; Coussens, Lisa M.; Tontonoz, Peter; Sherman, Mara H.

doi:10.1158/2159-8290.cd-22-0661

Cited by 28 publications

(22 citation statements)

References 74 publications

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“…( 16 ). To further explore where the VANGL2-TBK1 complex is subcellular located, we separated cytosolic fractions and cytomembrane fractions as previously reported ( 23 , 24 ). Then, both lysates were generated and subjected to co-IP assay.…”

Section: Resultsmentioning

confidence: 99%

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VANGL2 inhibits antiviral IFN-I signaling by targeting TBK1 for autophagic degradation

Xie

et al. 2023

Sci. Adv.

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Stringent control of type I interferon (IFN-I) signaling is critical to potent innate immune responses against viral infection, yet the underlying molecular mechanisms are still elusive. Here, we found that Van Gogh–like 2 (VANGL2) acts as an IFN-inducible negative feedback regulator to suppress IFN-I signaling during vesicular stomatitis virus (VSV) infection. Mechanistically, VANGL2 interacted with TBK1 and promoted the selective autophagic degradation of TBK1 via K48-linked polyubiquitination at Lys 372 by the E3 ligase TRIP, which serves as a recognition signal for the cargo receptor OPTN. Furthermore, myeloid-specific deletion of VANGL2 in mice showed enhanced IFN-I production against VSV infection and improved survival. In general, these findings revealed a negative feedback loop of IFN-I signaling through the VANGL2-TRIP-TBK1-OPTN axis and highlighted the cross-talk between IFN-I and autophagy in preventing viral infection. VANGL2 could be a potential clinical therapeutic target for viral infectious diseases, including COVID-19.

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Section: Resultsmentioning

confidence: 99%

“…The Cell Fractionation Kit (no. 9038, Cell Signaling Technology) was used for cell fractionation according to the manufacturer’s protocol and the published works ( 23 , 24 ). Briefly, cells were collected by scraping, washed in PBS, and pelleted (350 g , 5 min).…”

Section: Methodsmentioning

confidence: 99%

VANGL2 inhibits antiviral IFN-I signaling by targeting TBK1 for autophagic degradation

Xie

et al. 2023

Sci. Adv.

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“…Tissues were then stained with DAPI and mounted with Vectashield mounting medium provided in the TrueVIEW quenching kit. Methods were adapted from ( 54 , 55 ).…”

Section: Methodsmentioning

confidence: 99%

Deletion of the mRNA stability factor ELAVL1 (HuR) in pancreatic cancer cells disrupts the tumor microenvironment integrity

et al. 2023

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Stromal cells promote extensive fibrosis in pancreatic ductal adenocarcinoma (PDAC), which is associated with poor prognosis and therapeutic resistance. We report here for the first time that loss of the RNA-binding protein human antigen R (HuR, ELAVL1) in PDAC cells leads to reprogramming of the tumor microenvironment. In multiple in vivo models, CRISPR deletion of ELAVL1 in PDAC cells resulted in a decrease of collagen deposition, accompanied by a decrease of stromal markers (i.e. podoplanin, α-smooth muscle actin, desmin). RNA-sequencing data showed that HuR plays a role in cell–cell communication. Accordingly, cytokine arrays identified that HuR regulates the secretion of signaling molecules involved in stromal activation and extracellular matrix organization [i.e. platelet-derived growth factor AA (PDGFAA) and pentraxin 3]. Ribonucleoprotein immunoprecipitation analysis and transcription inhibition studies validated PDGFA mRNA as a novel HuR target. These data suggest that tumor-intrinsic HuR supports extrinsic activation of the stroma to produce collagen and desmoplasia through regulating signaling molecules (e.g. PDGFAA). HuR-deficient PDAC in vivo tumors with an altered tumor microenvironment are more sensitive to the standard of care gemcitabine, as compared to HuR-proficient tumors. Taken together, we identified a novel role of tumor-intrinsic HuR in its ability to modify the surrounding tumor microenvironment and regulate PDGFAA.

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“…Mechanistically, PPARδ activation in epithelial cells induced secretion of CCL2, thereby promoting an immunosuppressive TME via the recruitment of TAMs and MDSCs ( 138 ). Moreover, it has been shown recently that the mitochondrial glutamic-oxaloacetic transaminase GOT2 directly binds to fatty acid ligands to induce PPARδ, resulting in the infiltration of ARG1 + TAMs and lack of T cells ( 139 ).…”

Section: Non–tumor Cell–autonomous Mechanisms Of Immunosuppressionmentioning

confidence: 99%

Context-Specific Determinants of the Immunosuppressive Tumor Microenvironment in Pancreatic Cancer

et al. 2023

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Immunotherapies have shown benefits across a range of human cancers, but not pancreatic ductal adenocarcinoma (PDAC). Recent evidence suggests that the immunosuppressive tumor microenvironment (TME) constitutes an important roadblock to their efficacy. The landscape of the TME differs substantially across PDAC subtypes, indicating context-specific principles of immunosuppression. In this review, we discuss how PDAC cells, the local TME, and systemic host and environmental factors drive immunosuppression in context. We argue that unraveling the mechanistic drivers of the context-specific modes of immunosuppression will open new possibilities to target PDAC more efficiently by using multimodal (immuno)therapeutic interventions. Significance: Immunosuppression is an almost universal hallmark of pancreatic cancer, although this tumor entity is highly heterogeneous across its different subtypes and phenotypes. Here, we provide evidence that the diverse TME of pancreatic cancer is a central executor of various different context-dependent modes of immunosuppression, and discuss key challenges and novel opportunities to uncover, functionalize, and target the central drivers and functional nodes of immunosuppression for therapeutic exploitation.

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A Cancer Cell–Intrinsic GOT2–PPARδ Axis Suppresses Antitumor Immunity

Cited by 28 publications

References 74 publications

VANGL2 inhibits antiviral IFN-I signaling by targeting TBK1 for autophagic degradation

VANGL2 inhibits antiviral IFN-I signaling by targeting TBK1 for autophagic degradation

Deletion of the mRNA stability factor ELAVL1 (HuR) in pancreatic cancer cells disrupts the tumor microenvironment integrity

Context-Specific Determinants of the Immunosuppressive Tumor Microenvironment in Pancreatic Cancer

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