Therapeutic KRASG12C inhibition drives effective interferon-mediated antitumor immunity in immunogenic lung cancers.
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Date
2022-07-22ICR Author
Author
Mugarza, E
van Maldegem, F
Boumelha, J
Moore, C
Rana, S
Llorian Sopena, M
East, P
Ambler, R
Anastasiou, P
Romero-Clavijo, P
Valand, K
Cole, M
Molina-Arcas, M
Downward, J
Type
Journal Article
Metadata
Show full item recordAbstract
Recently developed KRASG12C inhibitory drugs are beneficial to lung cancer patients harboring KRASG12C mutations, but drug resistance frequently develops. Because of the immunosuppressive nature of the signaling network controlled by oncogenic KRAS, these drugs can indirectly affect antitumor immunity, providing a rationale for their combination with immune checkpoint blockade. In this study, we have characterized how KRASG12C inhibition reverses immunosuppression driven by oncogenic KRAS in a number of preclinical lung cancer models with varying levels of immunogenicity. Mechanistically, KRASG12C inhibition up-regulates interferon signaling via Myc inhibition, leading to reduced tumor infiltration by immunosuppressive cells, enhanced infiltration and activation of cytotoxic T cells, and increased antigen presentation. However, the combination of KRASG12C inhibitors with immune checkpoint blockade only provides synergistic benefit in the most immunogenic tumor model. KRASG12C inhibition fails to sensitize cold tumors to immunotherapy, with implications for the design of clinical trials combining KRASG12C inhibitors with anti-PD1 drugs.
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Subject
Humans
Immune Checkpoint Inhibitors
Interferons
Lung Neoplasms
Mutation
Proto-Oncogene Proteins p21(ras)
Research team
Lung Cancer Group
Language
eng
Date accepted
2022-06-07
License start date
2022-07-22
Citation
Science Advances, 2022, 8 (29), pp. eabm8780 -
Publisher
AMER ASSOC ADVANCEMENT SCIENCE