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Loss of NCCRP1 overcomes immune evasion in lung adenocarcinoma
Lu Liu1,2,3, Shihao Qi1,3, Liye Shao1,3
1Anhui Provincial Key Laboratory of Immunology in Chronic Diseases, Bengbu Medical University, Bengbu, Anhui, China.
Background:
The low response rate to immunotherapy in patients with lung adenocarcinoma is primarily due to tumor immune evasion. The tumor immunosuppressive microenvironment orchestrates this evasion, yet the underlying mechanisms remain elusive. Here we identify non-specific cytotoxic cell receptor protein 1 (NCCRP1) as a critical and previously uncharacterized regulator of this process.
Methods:
We first analyzed publicly accessible patient-derived single-cell RNA sequencing and RNA sequencing data to investigate the expression of NCCRP1 in lung adenocarcinoma and its impact on the tumor immune microenvironment. Subsequently, the Nccrp1 gene was knocked out in mouse lung adenocarcinoma cells using CRISPR-Cas9. The effect of NCCRP1 deletion on tumor growth was then evaluated using subcutaneous transplantation models in both NSG and C57BL/6 mice. Single-cell RNA sequencing, flow cytometry and multiple targeted in vivo interventions were employed to assess the influence of NCCRP1 on the tumor immune microenvironment. To explore the underlying mechanisms by which NCCRP1 regulates the tumor immune microenvironment, we conducted co-immunoprecipitation, RNA pull-down, ubiquitination assay, mass spectrometry, isobaric tags for relative and absolute quantitation proteomics, dual-luciferase reporter gene assay, and ELISA.
Results:
Loss of NCCRP1 inhibits lung tumor growth and prolongs survival in immunocompetent C57BL/6 mouse models. NCCRP1 deficiency upregulates CX3CL1 to recruit CX3CR1+ antitumoral macrophages. These macrophages subsequently secrete CXCL9 and CXCL10, enhancing the infiltration of CD8+ T cells and NK cells into the tumor microenvironment. Mechanistically, NCCRP1 and STAU1 competitively bind to NEDD4. NCCRP1 deficiency enhances the STAU1-NEDD4 interaction, promoting ubiquitination and proteasomal degradation of STAU1, thereby increasing CX3CL1 messenger RNA stability. Remarkably, ablating NCCRP1 synergized with anti-programmed cell death protein 1 or interferon-γ therapy, leading to complete tumor eradication.
Conclusion:
Our findings highlight NCCRP1 targeting as a promising therapeutic strategy to reprogram the immunosuppressive microenvironment and overcome the "cold tumor" phenotype in lung adenocarcinoma.
Insights
Targeting non-specific cytotoxic cell receptor protein 1 (NCCRP1) inhibits lung adenocarcinoma growth by enhancing anti-tumor immunity. This approach overcomes immune evasion and synergizes with existing therapies for complete tumor eradication.
Area of Science:
- Immunology
- Oncology
- Molecular Biology
Background:
- Lung adenocarcinoma exhibits low immunotherapy response rates due to tumor immune evasion.
- The immunosuppressive tumor microenvironment is key to immune evasion, but its regulators are not fully understood.
- Non-specific cytotoxic cell receptor protein 1 (NCCRP1) is identified as a novel regulator of this process.
Purpose of the Study:
- To investigate the role of NCCRP1 in regulating the tumor immune microenvironment in lung adenocarcinoma.
- To explore the therapeutic potential of targeting NCCRP1 to overcome immune evasion and enhance anti-tumor immunity.
Main Methods:
- Analysis of patient-derived single-cell RNA sequencing and RNA sequencing data.
- CRISPR-Cas9 knockout of Nccrp1 in mouse lung adenocarcinoma cells.
- In vivo tumor growth evaluation in mouse models, single-cell RNA sequencing, flow cytometry, and molecular mechanism studies (co-immunoprecipitation, proteomics, etc.).
Main Results:
- Loss of NCCRP1 inhibits tumor growth and improves survival in mouse models.
- NCCRP1 deficiency promotes anti-tumoral macrophage recruitment and enhances CD8+ T cell and NK cell infiltration.
- NCCRP1 deletion increases CX3CL1 mRNA stability by altering the NCCRP1-STAU1-NEDD4 interaction, leading to increased anti-tumor immunity.
- Ablating NCCRP1 synergizes with anti-PD-1 or interferon-γ therapy, resulting in complete tumor eradication.
Conclusions:
- Targeting NCCRP1 is a promising strategy to reprogram the immunosuppressive tumor microenvironment in lung adenocarcinoma.
- This approach can overcome the 'cold tumor' phenotype and enhance therapeutic efficacy.
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