Clonal Hematopoiesis Burden Correlates with Increased Inflammatory Signatures in Myeloid Cells of Non-Small Cell Lung Cancer Patients
核心概念
Metastatic non-small cell lung cancer patients with high clonal hematopoiesis burden exhibit increased inflammatory signatures, particularly in myeloid cell populations, mediated through the NF-κB pathway.
要約
This study investigated the interplay between clonal hematopoiesis (CH) and immune response in non-small cell lung cancer (NSCLC) patients undergoing immune checkpoint inhibitor (ICI) treatment. The key findings are:
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CH prevalence was significantly higher in NSCLC patients compared to controls, with a higher burden of mutations with variant allele frequency (VAF) greater than 10% observed more frequently in lung squamous cell carcinoma (LUSC) patients.
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Single-cell RNA sequencing (scRNA-seq) analysis revealed that myeloid cells from NSCLC patients with high CH burden exhibited an increased inflammatory response mediated through the NF-κB pathway. Gene set enrichment analysis and gene regulatory network analysis confirmed the activation of inflammatory pathways, particularly in the myeloid lineage.
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Further analysis of cell-cell interactions showed enhanced interactions between myeloid cells and other cell types in the high CH burden group, driven by the TNF and IL-1β pathways.
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While the impact of CH on ICI response was not significant, the authors suggest that the elevated inflammatory activity in the bloodstream of high CH burden patients may negatively impact long-term patient survival, independent of ICI treatment.
Overall, this study provides insights into the role of CH in shaping the inflammatory landscape of the tumor microenvironment in NSCLC, with potential implications for disease progression and response to immunotherapy.
Increased inflammatory signature in myeloid cells of non-small cell lung cancer patients with high clonal hematopoiesis burden
統計
Clonal hematopoiesis was detected in 44 out of 100 metastatic NSCLC patients, compared to 5 out of 42 controls (P = 0.01).
Patients with lung squamous cell carcinoma showed a higher burden of larger clones compared to lung adenocarcinoma patients (8/43 vs 2/50, P = 0.04).
引用
"Metastatic lung cancer patients showed higher CHIP prevalence (44/100 for patients vs 5/42 for controls; P = 0.01)."
"Furthermore, lung squamous cell carcinoma patients showed increased burden of larger clones compared to lung adenocarcinoma patients (8/43 for LUSC vs 2/50 for LUAD; P = 0.04)."
深掘り質問
How might the inflammatory signatures observed in myeloid cells of high clonal hematopoiesis burden patients influence the tumor microenvironment and disease progression in NSCLC?
The inflammatory signatures observed in myeloid cells of NSCLC patients with high clonal hematopoiesis burden can have significant implications for the tumor microenvironment and disease progression. These inflammatory signatures, particularly mediated by the NF-κB pathway, can lead to a pro-inflammatory state within the tumor microenvironment. This inflammatory milieu can promote tumor growth, invasion, and metastasis by creating a favorable environment for cancer cell proliferation and survival. Additionally, the activation of inflammatory pathways in myeloid cells can contribute to immune evasion mechanisms employed by the tumor, leading to resistance to immunotherapy and other treatment modalities. Furthermore, the chronic inflammation induced by high clonal hematopoiesis burden may also contribute to the development of a more aggressive and treatment-resistant phenotype in NSCLC, ultimately impacting disease progression and patient outcomes.
What are the potential therapeutic implications of targeting the NF-κB pathway or other inflammatory mediators in NSCLC patients with high clonal hematopoiesis burden?
Targeting the NF-κB pathway or other inflammatory mediators in NSCLC patients with high clonal hematopoiesis burden holds significant therapeutic potential. By inhibiting the NF-κB pathway or modulating other inflammatory mediators, it may be possible to disrupt the pro-inflammatory environment within the tumor microenvironment. This could potentially enhance the efficacy of existing treatments, such as immune checkpoint inhibitors, by reducing immune suppression and enhancing anti-tumor immune responses. Additionally, targeting inflammatory pathways could help overcome resistance to therapy and improve patient outcomes. Furthermore, by dampening the inflammatory response associated with high clonal hematopoiesis burden, it may be possible to mitigate the aggressive nature of the disease and slow down disease progression. Overall, targeting the NF-κB pathway and other inflammatory mediators represents a promising therapeutic strategy for NSCLC patients with high clonal hematopoiesis burden.
Could the insights from this study on the interplay between clonal hematopoiesis and inflammation be extended to other solid tumor types or chronic diseases beyond cancer?
The insights gained from this study on the interplay between clonal hematopoiesis and inflammation in NSCLC may indeed be extended to other solid tumor types and chronic diseases beyond cancer. Clonal hematopoiesis and the associated inflammatory signatures have been implicated in various malignancies and non-malignant conditions, suggesting a broader relevance of these findings. In other solid tumor types, such as colorectal cancer, breast cancer, and melanoma, clonal hematopoiesis and inflammation have been shown to impact disease progression, treatment response, and patient outcomes. Similarly, in chronic diseases like cardiovascular disease, diabetes, and autoimmune disorders, the presence of clonal hematopoiesis and inflammatory activation have been linked to disease pathogenesis and complications. Therefore, the therapeutic implications of targeting inflammatory pathways in the context of clonal hematopoiesis burden may have broader applications across different disease settings, highlighting the potential for personalized and targeted interventions to modulate the immune response and improve patient outcomes.
