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Clinical Importance of the lncRNA NEAT1 in Cancer Patients Treated with Immune Checkpoint Inhibitors
Joseph Toker1, J Bryan Iorgulescu2,3,4, Alexander L Ling1
1Harvey W. Cushing Neuro-oncology Laboratories, Department of Neurosurgery, Harvard Medical School and Brigham and Women's Hospital, Boston, Massachusetts.
Purpose:
mAbs targeting the PD-1/PD-L1 immune checkpoint are powerful tools to improve the survival of patients with cancer. Understanding the molecular basis of clinical response to these treatments is critical to identify patients who can benefit from this immunotherapy. In this study, we investigated long noncoding RNA (lncRNA) expression in patients with cancer treated with anti-PD-1/PD-L1 immunotherapy.
Experimental Design:
lncRNA expression profile was analyzed in one cohort of patients with melanoma and two independent cohorts of patients with glioblastoma (GBM) undergoing anti-PD-1/PD-L1 immunotherapy. Single-cell RNA-sequencing analyses were performed to evaluate lncRNA expression in tumor cells and tumor-infiltrating immune cells.
Results:
We identified the lncRNA NEAT1 as commonly upregulated between patients with melanoma with complete therapeutic response and patients with GBM with longer survival following anti-PD-1/PD-L1 treatment. Gene set enrichment analyses revealed that NEAT1 expression was strongly associated with the IFNγ pathways, along with downregulation of cell-cycle-related genes. Single-cell RNA-sequencing analyses revealed NEAT1 expression across multiple cell types within the GBM microenvironment, including tumor cells, macrophages, and T cells. High NEAT1 expression levels in tumor cells correlated with increased infiltrating macrophages and microglia. In these tumor-infiltrating myeloid cells, we found that NEAT1 expression was linked to enrichment in TNFα/NFκB signaling pathway genes. Silencing NEAT1 suppressed M1 macrophage polarization and reduced the expression of TNFα and other inflammatory cytokines.
Conclusions:
These findings suggest an association between NEAT1 expression and patient response to anti-PD-1/PD-L1 therapy in melanoma and GBM and have important implications for the role of lncRNAs in the tumor microenvironment.
Insights
The long noncoding RNA NEAT1 is linked to better responses in cancer patients treated with PD-1/PD-L1 immunotherapy. NEAT1 influences immune cell activity and inflammatory pathways within the tumor microenvironment.
Area of Science:
- Oncology
- Immunotherapy
- Molecular Biology
Background:
- Immune checkpoint inhibitors, such as anti-PD-1/PD-L1 monoclonal antibodies (mAbs), have improved cancer patient survival.
- Identifying biomarkers for predicting response to immunotherapy is crucial for patient selection.
- Long noncoding RNAs (lncRNAs) are increasingly recognized for their roles in cancer biology and immune regulation.
Purpose of the Study:
- To investigate the role of lncRNA expression in patients with melanoma and glioblastoma (GBM) treated with anti-PD-1/PD-L1 immunotherapy.
- To identify specific lncRNAs associated with clinical response and survival outcomes.
- To explore the functional implications of identified lncRNAs within the tumor microenvironment.
Main Methods:
- Analysis of lncRNA expression profiles in independent cohorts of melanoma and GBM patients.
- Utilizing single-cell RNA-sequencing to assess lncRNA expression in tumor and immune cells.
- Gene set enrichment analysis to understand associated molecular pathways.
- Functional studies involving silencing of NEAT1 to evaluate its impact on macrophage polarization and cytokine production.
Main Results:
- The lncRNA NEAT1 was found to be upregulated in patients with complete response (melanoma) and longer survival (GBM) treated with anti-PD-1/PD-L1 therapy.
- NEAT1 expression correlated with interferon-gamma (IFNγ) pathways and downregulation of cell-cycle genes.
- Single-cell analysis showed NEAT1 expression in tumor cells, macrophages, and T cells, with high NEAT1 in tumor cells linked to increased macrophages and microglia.
- NEAT1 in myeloid cells was associated with TNFα/NFκB signaling; NEAT1 silencing reduced M1 macrophage polarization and inflammatory cytokine production.
Conclusions:
- NEAT1 expression is associated with patient response to anti-PD-1/PD-L1 therapy in melanoma and GBM.
- NEAT1 plays a role in modulating the tumor microenvironment, particularly influencing myeloid cell function and inflammatory responses.
- These findings highlight the potential of lncRNAs as biomarkers and therapeutic targets in cancer immunotherapy.
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