CRISPR-Cas9 Screening Identifies KRAS-Induced COX2 as a Driver of Immunotherapy Resistance in Lung Cancer.
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Embargo End Date
ICR Authors
Authors
Boumelha, J
de Castro, A
Bah, N
Cha, H
de Carné Trécesson, S
Rana, S
Tomaschko, M
Anastasiou, P
Mugarza, E
Moore, C
Goldstone, R
East, P
Litchfield, K
Lee, S-H
Molina-Arcas, M
Downward, J
de Castro, A
Bah, N
Cha, H
de Carné Trécesson, S
Rana, S
Tomaschko, M
Anastasiou, P
Mugarza, E
Moore, C
Goldstone, R
East, P
Litchfield, K
Lee, S-H
Molina-Arcas, M
Downward, J
Document Type
Journal Article
Date
2024-07-15
Date Accepted
2024-04-08
Abstract
Oncogenic KRAS impairs antitumor immune responses. As effective strategies to combine KRAS inhibitors and immunotherapies have so far proven elusive, a better understanding of the mechanisms by which oncogenic KRAS drives immune evasion is needed to identify approaches that could sensitize KRAS-mutant lung cancer to immunotherapy. In vivo CRISPR-Cas9 screening in an immunogenic murine lung cancer model identified mechanisms by which oncogenic KRAS promotes immune evasion, most notably via upregulation of immunosuppressive COX2 in cancer cells. Oncogenic KRAS potently induced COX2 in both mouse and human lung cancer, which was suppressed using KRAS inhibitors. COX2 acted via prostaglandin E2 (PGE2) to promote resistance to immune checkpoint blockade (ICB) in lung adenocarcinoma. Targeting COX2/PGE2 remodeled the tumor microenvironment by inducing proinflammatory polarization of myeloid cells and influx of activated cytotoxic CD8+ T cells, which increased the efficacy of ICB. Restoration of COX2 expression contributed to tumor relapse after prolonged KRAS inhibition. These results provide the rationale for testing COX2/PGE2 pathway inhibitors in combination with KRASG12C inhibition or ICB in patients with KRAS-mutant lung cancer. Significance: COX2 signaling via prostaglandin E2 is a major mediator of immune evasion driven by oncogenic KRAS that promotes immunotherapy and KRAS-targeted therapy resistance, suggesting effective combination treatments for KRAS-mutant lung cancer.
Citation
Cancer Research, 2024,
Source Title
Cancer Research
Publisher
AMER ASSOC CANCER RESEARCH
ISSN
0008-5472
eISSN
1538-7445
1538-7445
1538-7445
Collections
Research Team
Lung Cancer Group