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Inhibiting KRAS with CD47 and immune checkpoint overcomes intrinsic resistance to combined KRAS and immune checkpoint
Kentaro Hirade1, Noritaka Tanaka2, Taisuke Kajino2
1Division of Molecular Therapeutics, Aichi Cancer Center Research Institute, Nagoya 464-8681, Japan; Department of Hematology and Oncology, Nagoya City University Institute of Medical and Pharmaceutical Sciences, Nagoya 467-8601, Japan.
Abstract:
Although Kirsten rat sarcoma virus (KRAS) G12C inhibitors alter the treatment strategy for patients with KRAS G12C-mutant lung cancer, their efficacy remains insufficient to eliminate tumors. Here, we identify that inhibition of mutant KRAS promotes escape from macrophage phagocytosis by upregulating the expression of cluster of differentiation 47 (CD47) and CD24. These proteins are induced by the binding of FOXA1 to the super-enhancer of CD47 and grainyhead-like transcription factor 2 (GRHL2) to the promoter of CD24, respectively. Whereas the addition of an anti-CD47 antibody restores macrophage phagocytosis, phagocytic macrophages induce programmed death-ligand 1 (PD-L1) expression, resulting in the suppression of CD8 T cell activation. Combination of a KRAS inhibitor with anti-CD47 and anti-PD-L1 antibodies achieves long-term survival in an orthotopic murine model recalcitrant to KRAS inhibition with immune checkpoint therapy. These results suggest that targeting KRAS with an anti-CD47 antibody and immune checkpoint blockade is a promising strategy, especially in immune-cold lung tumors.
Insights
KRAS G12C inhibitors for lung cancer can be improved. Blocking CD47 and PD-L1 with KRAS inhibitors enhances anti-tumor immunity and survival in preclinical models.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- KRAS G12C inhibitors offer new treatment avenues for lung cancer but have limited efficacy.
- Tumor cells can evade immune responses, hindering treatment effectiveness.
Purpose of the Study:
- To investigate mechanisms by which KRAS inhibition affects anti-tumor immunity.
- To explore combination therapies involving KRAS inhibition, CD47 blockade, and immune checkpoint inhibitors.
Main Methods:
- Analysis of CD47 and CD24 expression following KRAS inhibition in lung cancer models.
- Investigated the roles of FOXA1 and GRHL2 in regulating CD47 and CD24.
- Evaluated the efficacy of combining KRAS inhibitors with anti-CD47 and anti-PD-L1 antibodies in murine models.
Main Results:
- KRAS G12C inhibition upregulates CD47 and CD24, promoting immune escape from macrophage phagocytosis.
- Anti-CD47 antibody restores phagocytosis, but induces PD-L1 expression, suppressing CD8 T cell activation.
- Combination therapy (KRAS inhibitor, anti-CD47, anti-PD-L1) achieved long-term survival in resistant models.
Conclusions:
- Targeting KRAS, CD47, and PD-L1 simultaneously is a promising strategy for KRAS G12C-mutant lung cancer.
- This combination therapy may be particularly effective in immune-cold tumors, overcoming resistance to KRAS inhibition and immunotherapy.
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