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Experimental Metastasis and CTL Adoptive Transfer Immunotherapy Mouse Model
Published on: November 26, 2010
LncRNA-CTD suppresses metastasis and immune evasion by modulating snail1 and MHC-I expression in colorectal cancer
Ning Xu1, Huisi Qiu2, Yuezhang Sun1
1Guangzhou Institute of Cancer Research, the Affiliated Cancer Hospital, Guangzhou Medical University, Guangzhou, Guangdong, China.
Background:
Distant metastasis and immune evasion are the major obstacles for successful colorectal cancer (CRC) treatment. The link between metastasis and immune evasion, as well as their therapeutic significance, remains unclear.
Methods:
Long non-coding RNAs from six paired CRC and normal tissues were screened by RNA sequencing (RNA-seq). LncRNA-CTD (CTD-2568A17.8) expression levels were determined using in situ hybridization and quantitative PCR analysis. In vitro and in vivo assays were performed to confirm the function of lncRNA-CTD. Flow cytometry was used to analyze the impact of lncRNA-CTD on immune cell infiltration and T-cell function. RNA-seq combined with RNA pull-down and RNA immunoprecipitation assay was used to identify the changes in downstream molecules induced by lncRNA-CTD. The therapeutic value of the combination of lncRNA-CTD and immune checkpoint inhibitors has been evaluated.
Results:
In this study, we identified a novel long non-coding RNA, lncRNA-CTD, which is downregulated in CRC and correlates with both metastasis and immunotherapy response. Mechanistically, the interaction of lncRNA and smad2 prevented the phosphorylation and nuclear translocation of smad2, which inhibited the expression of snail1, thereby inhibiting the metastasis of CRC. LncRNA-CTD enhances major histocompatibility complex class I (MHC-I) expression on the cancer cell membrane by interacting with STUB1 to disrupt the interaction of STUB1 with the MHC-I activator NLRC5 and subsequent NLRC5 ubiquitination-mediated degradation, increasing the susceptibility of CRC cells to being killed by CD8+ T cells. TFAP4 overexpression in CRC cells caused lncRNA-CTD downregulation. Moreover, the combination of lncRNA-CTD gene delivery therapy with immune checkpoint inhibitors exerted an additive effect on tumor growth inhibition.
Conclusions:
Collectively, our study reveals the role and mechanism of lncRNA-CTD in CRC metastasis and immune evasion. Overexpression of lncRNA-CTD suppresses CRC metastasis and improves the efficacy of immune checkpoint inhibitors.Cite Now.
Insights
This study identifies a novel long non-coding RNA, lncRNA-CTD, that suppresses colorectal cancer (CRC) metastasis and immune evasion. Overexpressing lncRNA-CTD enhances immunotherapy response and inhibits tumor growth, offering new therapeutic strategies for CRC.
Area of Science:
- Oncology
- Molecular Biology
- Immunology
Background:
- Distant metastasis and immune evasion are key challenges in colorectal cancer (CRC) treatment.
- The interplay between metastasis and immune evasion in CRC and their therapeutic implications require further elucidation.
Purpose of the Study:
- To identify and characterize novel long non-coding RNAs (lncRNAs) involved in colorectal cancer (CRC) metastasis and immune evasion.
- To elucidate the underlying molecular mechanisms of lncRNA-CTD in CRC.
- To evaluate the therapeutic potential of lncRNA-CTD in combination with immune checkpoint inhibitors.
Main Methods:
- RNA sequencing (RNA-seq) to screen lncRNAs in CRC tissues.
- In situ hybridization and quantitative PCR to determine lncRNA-CTD expression.
- In vitro and in vivo assays to assess lncRNA-CTD function.
- Flow cytometry to analyze immune cell infiltration and T-cell function.
- RNA pull-down and RNA immunoprecipitation assays to identify downstream targets.
Main Results:
- A novel lncRNA, lncRNA-CTD, was identified and found to be downregulated in CRC, correlating with metastasis and immunotherapy response.
- LncRNA-CTD inhibits CRC metastasis by preventing smad2 phosphorylation and nuclear translocation, thereby suppressing snail1 expression.
- LncRNA-CTD enhances CD8+ T-cell-mediated killing of CRC cells by increasing MHC-I expression via interaction with STUB1 and NLRC5.
- TFAP4 overexpression leads to lncRNA-CTD downregulation in CRC cells.
- Combination therapy of lncRNA-CTD gene delivery and immune checkpoint inhibitors showed additive tumor growth inhibition.
Conclusions:
- LncRNA-CTD plays a crucial role in suppressing colorectal cancer (CRC) metastasis and immune evasion.
- Overexpression of lncRNA-CTD represents a promising therapeutic strategy to enhance the efficacy of immune checkpoint inhibitors in CRC treatment.
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