Therapeutic KRASG12C inhibition drives effective interferon-mediated antitumor immunity in immunogenic lung cancers.
Loading...
Embargo End Date
ICR Authors
Authors
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
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
Document Type
Journal Article
Date
2022-07-22
Date Accepted
2022-06-07
Abstract
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.
Citation
Science Advances, 2022, 8 (29), pp. eabm8780 -
Source Title
Science Advances
Publisher
AMER ASSOC ADVANCEMENT SCIENCE
ISSN
2375-2548
eISSN
2375-2548
2375-2548
2375-2548
Collections
Research Team
Lung Cancer Group