GEO series
Denfivontinib activates effector T-cells through NLRP3-inflammasome, yielding potent anticancer effects by combination with pembrolizumab
GSE276724
Homo sapiens; Mus musculus
Expression profiling by high throughput sequencing
15 samples
Submitted 2025/03/12
Platform GPL25526
Summary
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 therapeutical limitation, we conducted a translational research to elucidate the mechanisms by which AXL inhibition enhances the anti-tumor 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 NSCLC. 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 the NLRP3 inflammasome formation. This leads to macrophage activation via the NF-kB 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 knock-out mice confirmed that AXL inhibition by denfivontinib enhances the anti-tumor 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 NSCLC patients 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 NLRP3 inflammasome in activating immune responses during treatment.
Published in
Kim DK, Synn CB, Lee W et al.
· Molecular cancer therapeutics 2025
· PMID 39632711
· doi:10.1158/1535-7163.MCT-24-0501
This dataset
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Direct links to NCBI, no account and no request form: the whole study as GSE276724_RAW.tar, processed values as the series matrix, the supplementary file directory, and per-sample supplementary files for any of the 15 samples. Raw sequencing reads are also available from ENA.
Also filed as BioProject PRJNA1158761 and SRA study SRP532913. Searching any of these in the dataset finder brings you back here.
Study design
15 conditions, each sampled once — no replicated groups
Read from 15 sample titles: 15 distinct titles with little repetition. Check it against the sample list below before relying on it.
Samples in this study
0 selected
- GSM8504569 YHIM-2004 (1)
- GSM8504570 YHIM-2004 (2)
- GSM8504571 YHIM- 2004 (3)
- GSM8504572 YHIM-1062 (1)
- GSM8504573 YHIM-1062 (2)
- GSM8504574 YHIM-1062 (3)
- GSM8504575 YHIM-1018 (1)
- GSM8504576 YHIM-1018 (2)
- GSM8504577 YHIM-1018 (3)
- GSM8504578 YHIM-1013 (1)
- GSM8504579 YHIM-1013 (2)
- GSM8504580 YHIM-1013 (3)
- GSM8504581 YHIM-2018 (1)
- GSM8504582 YHIM-2018 (2)
- GSM8504583 YHIM-2018 (3)
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