Exosomal lncRNA SNHG10 derived from colorectal cancer cells suppresses natural killer cell cytotoxicity by upregulating INHBC

Yiwen Huang,Wentao Ou,Yuanyuan Wang,Yuqi Luo,Dong Dong,Xiaowen Peng,Yanbo Luo

doi:10.1186/s12935-021-02221-2

Abstract

BackgroundExosome-mediated crosstalk between cancer cells and immune cells contributes to tumor growth. In this study, we investigated the mechanism underlying the exosome-mediated immune escape of colorectal cancer (CRC) cells from natural killer (NK) cells via the transfer of long noncoding RNAs (lncRNAs).MethodsAn epithelial–mesenchymal transition (EMT) model of SW480 cells was established by transforming growth factor beta (TGF-β), followed by the assessment of the effect of EMT-derived exosomes (EMT-exo) on the functions of NK cells. RNA sequencing was performed to identify exosomal lncRNAs and target genes. The function of exosomal lncRNAs in tumor growth was further verified in vivo.ResultsEMT-exo suppressed the proliferation, cytotoxicity, IFN-γ production, and perforin-1 and granzyme B secretion of NK cells. RNA sequencing revealed that SNHG10 expression was upregulated in EMT-exo compared with that in non-EMT-exo. Moreover, SNHG10 expression was upregulated in tumor tissues in CRC, which was associated with poor prognosis. Overexpression of SNHG10 in exosomes (oe-lnc-SNHG10 exo) significantly suppressed the viability and cytotoxicity of NK cells. Transcriptome sequencing of NK cells revealed that the expression levels of 114 genes were upregulated in the oe-lnc-SNHG10 exo group, including inhibin subunit beta C (INHBC), which was involved in the TGF-β signaling pathway. Si-INHBC treatment abrogated the effect of oe-lnc-SNHG10 exo on NK cells. oe-lnc-SNHG10 exo induced tumor growth and upregulated INHBC expression in mice and downregulated the expression of perforin, granzyme B, and NK1.1 in tumor tissues.ConclusionsThe CRC cell-derived exosomal lncRNA SNHG10 suppresses the function of NK cells by upregulating INHBC expression. This study provides evidence that exosomal lncRNAs contribute to immune escape by inducing NK cell inhibition and proposes a potential treatment strategy for CRC.

Highlights

Colorectal cancer (CRC) is the fourth most common human malignant tumor and the second most common cause of cancer-related mortality worldwide [1]
A significant decrease in the expression of E-cadherin and an increase in the expression of vimentin were detected using qRT-PCR following treatment with Transforming growth factor beta (TGF-β) (Fig. 1B, C). These results are consistent with the findings of previous studies [22, 23] and suggest that the epithelial–mesenchymal transition (EMT) model of SW480 colorectal cancer (CRC) cells induced by TGF-β was successfully established
We investigated whether EMT-derived exosomes (EMT-exo) affected natural killer (NK) cell function

Summary

Introduction

Colorectal cancer (CRC) is the fourth most common human malignant tumor and the second most common cause of cancer-related mortality worldwide [1]. As described by Tang et al, cancer immune escape is a major obstacle to tumor metastasis and immunotherapy [4]. It is not exactly clear how CRC cells escape immune cell monitoring to achieve metastasis and invasion. It is necessary to elucidate the molecular mechanism underlying the immune escape of CRC cells to reduce the burden on patients. We investigated the mechanism underlying the exosome-mediated immune escape of colorectal cancer (CRC) cells from natural killer (NK) cells via the transfer of long noncoding RNAs (lncRNAs)

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