Denfivontinib Activates Effector T Cells Through the NLRP3 Inflammasome, Yielding Potent Anticancer Effects by
Dong Kwon Kim1,2, Chun-Bong Synn1, Wongeun Lee1
1Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, Republic of Korea.
Abstract:
Various combination therapies have been investigated to overcome the limitations of using immune checkpoint inhibitors. However, determining the optimal combination therapy remains challenging. To overcome the therapeutic limitation, we conducted a translational research to elucidate the mechanisms by which AXL inhibition enhances antitumor effects when combined with anti-PD-1 antibody therapy. Herein, we demonstrated improved antitumor effects through combination treatment with denfivontinib and pembrolizumab which resulted in enhanced differentiation into effector CD4+ and CD8+ memory T cells, accompanied by an increase in IFN-γ expression in the YHIM-2004 xenograft model derived from patients with non-small cell lung cancer. Concurrently, a reduction in the number of immunosuppressive M2 macrophages and myeloid-derived suppressor cells was observed. Mechanistically, denfivontinib potentiated the NOD-like receptor pathway, thereby facilitating NLRP3 inflammasome formation. This leads to macrophage activation via NF-κB signaling pathway activation. We have confirmed that the positive interaction between macrophages and T cells arises from the enhanced antigen-presenting machinery of activated macrophages. Furthermore, the observed tumor effects in AXL knockout mice confirmed that AXL inhibition by denfivontinib enhances the antitumor effects, thus opening new avenues for therapeutic interventions aimed at overcoming limitations in immunotherapy. To demonstrate the extent to which our findings reflect clinical results, we analyzed bulk RNA sequencing data from 21 patients with non-small cell lung cancer undergoing anti-PD-1 immunotherapy. The NLRP3 inflammasome score influenced enhanced immune responses in patient data undergoing anti-PD-1 immunotherapy, suggesting a role for the NLRP3 inflammasome in activating immune responses during treatment.
Insights
Combining AXL inhibition with anti-PD-1 therapy enhances anti-tumor immune responses. This approach boosts effector T cells and activates macrophages, showing promise for non-small cell lung cancer treatment.
Area of Science:
- Immunology
- Oncology
- Pharmacology
Background:
- Immune checkpoint inhibitors (ICIs) like anti-PD-1 therapy show promise but face limitations.
- Optimizing combination therapies is crucial for overcoming resistance and improving patient outcomes.
- AXL receptor tyrosine kinase is implicated in tumor progression and immune evasion.
Purpose of the Study:
- To investigate the synergistic anti-tumor effects of combining AXL inhibition with anti-PD-1 antibody therapy.
- To elucidate the underlying mechanisms of enhanced anti-tumor immunity.
- To validate findings in preclinical models and correlate with clinical data in non-small cell lung cancer (NSCLC).
Main Methods:
- Utilized a xenograft model (YHIM-2004) derived from NSCLC patients.
- Administered combination therapy with denfivontinib (AXL inhibitor) and pembrolizumab (anti-PD-1 antibody).
- Analyzed immune cell populations, cytokine expression (IFN-γ), and signaling pathways (NLRP3 inflammasome, NF-κB).
- Conducted experiments in AXL knockout mice and analyzed bulk RNA sequencing data from NSCLC patients.
Main Results:
- Combination therapy significantly improved anti-tumor effects, enhancing effector CD4+ and CD8+ T cell differentiation and IFN-γ production.
- Observed a reduction in immunosuppressive M2 macrophages and myeloid-derived suppressor cells.
- Denfivontinib treatment potentiated the NLRP3 inflammasome pathway, leading to macrophage activation and enhanced antigen presentation.
- AXL inhibition was confirmed to enhance anti-tumor effects, with clinical data suggesting a role for NLRP3 inflammasome in anti-PD-1 immunotherapy response.
Conclusions:
- Combination of AXL inhibition (denfivontinib) and anti-PD-1 therapy (pembrolizumab) demonstrates significant anti-tumor efficacy in NSCLC.
- The mechanism involves enhanced T cell responses, M2 macrophage and MDSC reduction, and NLRP3 inflammasome activation.
- AXL inhibition represents a promising strategy to overcome immunotherapy limitations, with NLRP3 inflammasome activation being a key factor in treatment response.
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