Macrophage NLRP3 activation and IL-1β release drive osimertinib-induced antitumor immunity
Haiyang Yu1, Xin Sun2, Yan Li1,3
1Department of Medical Oncology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China.
Background:
Despite the clinical efficacy of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in non-small cell lung cancer (NSCLC), patient outcomes vary even among those with identical EGFR mutations. This study investigates whether osimertinib, a third-generation EGFR-TKI, activates the nucleotide-binding oligomerization domain-like receptor protein-3 (NLRP3) inflammasome in macrophages to drive antitumor immunity and explores its mechanistic basis.
Methods:
Using bone marrow-derived macrophages from wild-type and gene-deficient mice, human peripheral blood mononuclear cells, and a Lewis lung cancer murine model, we assessed osimertinib-induced NLRP3 inflammasome activation, interleukin (IL)-1β secretion, pyroptosis, and tumor microenvironment (TME) remodeling. Mechanistic studies evaluated lysosomal dysfunction, calcium overload, mitochondrial damage, and reactive oxygen species (ROS) production. Clinical correlations were analyzed in patients with NSCLC treated with EGFR-TKIs.
Results:
Osimertinib triggered NLRP3 inflammasome activation in macrophages via lysosomal dysfunction-induced calcium overload, leading to mitochondrial damage and ROS production, which acted as damage-associated molecular patterns to activate NLRP3. This process promoted IL-1β release, pyroptosis, and CD8+ T-cell activation while suppressing regulatory T cells in the TME. In murine models, osimertinib's antitumor effects were abrogated by NLRP3 inhibition (MCC950) and enhanced by recombinant IL-1β (rIL-1β) co-administration (p<0.01). Clinically, high NLRP3 and IL-1β expression in tumor-associated macrophages (TAMs) correlated with prolonged progression-free survival (p<0.01) and overall survival (p<0.01) in EGFR-TKI-treated patients with NSCLC.
Conclusions:
Osimertinib exerts off-target immunomodulatory effects by activating the tumor-extrinsic NLRP3 inflammasome, linking mitochondrial-lysosomal crosstalk to antitumor immunity. NLRP3 and IL-1β in TAMs emerge as predictive biomarkers for EGFR-TKI efficacy, while rIL-1β combination therapy represents a novel strategy to enhance clinical outcomes.
Insights
Osimertinib activates the NLRP3 inflammasome in macrophages, enhancing antitumor immunity in non-small cell lung cancer (NSCLC). This finding suggests NLRP3 inflammasome activation and IL-1β in tumor-associated macrophages (TAMs) are predictive biomarkers for EGFR-TKI efficacy.
Area of Science:
- Immunology
- Oncology
- Cell Biology
Background:
- Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) show clinical efficacy in non-small cell lung cancer (NSCLC), but patient outcomes vary.
- The precise mechanisms driving these variable responses, even in patients with identical EGFR mutations, remain incompletely understood.
Purpose of the Study:
- To investigate whether osimertinib, a third-generation EGFR-TKI, activates the nucleotide-binding oligomerization domain-like receptor protein-3 (NLRP3) inflammasome in macrophages.
- To explore the mechanistic basis of osimertinib-induced NLRP3 inflammasome activation and its role in driving antitumor immunity.
- To assess the clinical relevance of NLRP3 inflammasome activation and IL-1β in NSCLC patients treated with EGFR-TKIs.
Main Methods:
- Utilized bone marrow-derived macrophages, human peripheral blood mononuclear cells, and a Lewis lung cancer murine model to assess osimertinib-induced NLRP3 inflammasome activation, IL-1β secretion, and pyroptosis.
- Investigated mechanistic pathways including lysosomal dysfunction, calcium overload, mitochondrial damage, and reactive oxygen species (ROS) production.
- Correlated findings with clinical data from NSCLC patients undergoing EGFR-TKI treatment.
Main Results:
- Osimertinib activated the NLRP3 inflammasome in macrophages through lysosomal dysfunction, leading to calcium overload, mitochondrial damage, and ROS production.
- This activation promoted IL-1β release, pyroptosis, and CD8+ T-cell activation, while suppressing regulatory T cells in the tumor microenvironment.
- In vivo, osimertinib's antitumor effects were dependent on NLRP3 inflammasome activation and enhanced by IL-1β co-administration; high NLRP3 and IL-1β expression in tumor-associated macrophages (TAMs) correlated with improved progression-free and overall survival in EGFR-TKI-treated NSCLC patients.
Conclusions:
- Osimertinib exhibits off-target immunomodulatory effects by activating the NLRP3 inflammasome, linking mitochondrial-lysosomal crosstalk to enhanced antitumor immunity.
- NLRP3 inflammasome and IL-1β within TAMs serve as predictive biomarkers for EGFR-TKI efficacy.
- Combination therapy with IL-1β may represent a novel strategy to improve clinical outcomes in NSCLC.
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