Dataset Information

LncRNA SNHG15 Contributes to Immuno-Escape of Gastric Cancer Through Targeting miR141/PD-L1.

ABSTRACT: Introduction:Long non-coding RNAs (lncRNAs) have been demonstrated to participate in many biological processes and severs as important regulators during the progression of gastric cancer. Methods:Here, we introduced human lncRNA SNHG15 which was highly expressed in gastric cancer and cells. Interestingly, the expression of SNHG15 was correlated with programmed cell death ligand 1 (PD-L1), which promotes the resistance of gastric cancer cells to immune responses. Meanwhile, SNHG15 downregulation suppressed the expression of PD-L1 and resistance of immune responses. Results:Further, our results suggested that SNHG15 acted as a competing endogenous RNA (CeRNA) to sponge miR-141, which was downregulated in gastric cancers and negatively correlated to PD-L1. Conclusion:Our results suggested that SNHG15 improved the expression of PD-L1 by inhibiting miR-141, which in turn promoted the resistance of stomach cancer cells to the immune responses.

SUBMITTER: Dang S

PROVIDER: S-EPMC7468375 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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LncRNA SNHG15 Contributes to Immuno-Escape of Gastric Cancer Through Targeting miR141/PD-L1.

Dang Shengchun S Malik Abdul A Chen Jixiang J Qu Jianguo J Yin Kai K Cui Lei L Gu Min M

OncoTargets and therapy 20200824

<h4>Introduction</h4>Long non-coding RNAs (lncRNAs) have been demonstrated to participate in many biological processes and severs as important regulators during the progression of gastric cancer.<h4>Methods</h4>Here, we introduced human lncRNA SNHG15 which was highly expressed in gastric cancer and cells. Interestingly, the expression of SNHG15 was correlated with programmed cell death ligand 1 (PD-L1), which promotes the resistance of gastric cancer cells to immune responses. Meanwhile, SNHG15 ...[more]

PMID: 32943878

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Project description:BackgroundIn patients with microsatellite stable (MSS) metastatic colorectal cancer (mCRC), immune checkpoint blockade is ineffective, and combinatorial approaches enhancing immunogenicity need exploration.MethodsWe treated 43 patients with predominantly microsatellite stable RAS/BRAF wild-type mCRC on a phase II trial combining chemotherapy with the epidermal growth factor receptor antibody cetuximab and the programmed cell death ligand 1 (PD-L1) antibody avelumab. We performed next-generation gene panel sequencing for mutational typing of tumors and liquid biopsy monitoring as well as digital droplet PCR to confirm individual mutations. Translational analyses included tissue immunohistochemistry, multispectral imaging and repertoire sequencing of tumor-infiltrating T cells. Detected PD-L1 mutations were mechanistically validated in CRISPR/Cas9-generated cell models using qRT-PCR, immunoblotting, flow cytometry, complement-dependent cytotoxicity assay, antibody-dependent cytotoxicity by natural killer cell degranulation assay and LDH release assay as well as live cell imaging of T cell mediated tumor cell killing.ResultsCirculating tumor DNA showed rapid clearance in the majority of patients mirroring a high rate of early tumor shrinkage. In 3 of 13 patients expressing the high-affinity Fcγ receptor 3a (FcγR3a), tumor subclones with PD-L1 mutations were selected that led to loss of tumor PD-L1 by nonsense-mediated RNA decay in PD-L1 K162fs and protein degradation in PD-L1 L88S. As a consequence, avelumab binding and antibody-dependent cytotoxicity were impaired, while T cell killing of these variant clones was increased. Interestingly, PD-L1 mutant subclones showed slow selection dynamics reversing on avelumab withdrawal and patients with such subclones had above-average treatment benefit. This suggested that the PD-L1 mutations mediated resistance to direct antitumor effects of avelumab, while at the same time loss of PD-L1 reduced biological fitness by enhanced T cell killing limiting subclonal expansion.ConclusionThe addition of avelumab to standard treatment appeared feasible and safe. PD-L1 mutations mediate subclonal immune escape to avelumab in some patients with mCRC expressing high-affinity FcγR3a, which may be a subset experiencing most selective pressure. Future trials evaluating the addition of avelumab to standard treatment in MSS mCRC are warranted especially in this patient subpopulation.Trial registration numberNCT03174405.

Dataset Information

LncRNA SNHG15 Contributes to Immuno-Escape of Gastric Cancer Through Targeting miR141/PD-L1.

Publications

LncRNA SNHG15 Contributes to Immuno-Escape of Gastric Cancer Through Targeting miR141/PD-L1.

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