Therapeutic KRAS G12C inhibition drives effective interferon-mediated antitumor immunity in immunogenic lung cancers

作者：Edurne Mugarza, Febe van Maldegem, Jesse Boumelha, Christopher E. G. Moore, Sareena Rana, Miriam Llorian, Philip East, Rachel Ambler, Panayiotis Anastasiou, Pablo Romero-Clavijo, Karishma Valand, Megan Cole, Miriam Gómez Molina, Julian Downward · 发表于：Science Advances · 年份：2022 · DOI：10.1126/sciadv.abm8780 · 被引用次数：148 · 研究领域：Cancer Immunotherapy and Biomarkers、Monoclonal and Polyclonal Antibodies Research、Immunotherapy and Immune Responses

Recently developed KRAS G12C inhibitory drugs are beneficial to lung cancer patients harboring KRAS G12C 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 KRAS G12C inhibition reverses immunosuppression driven by oncogenic KRAS in a number of preclinical lung cancer models with varying levels of immunogenicity. Mechanistically, KRAS G12C 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 KRAS G12C inhibitors with immune checkpoint blockade only provides synergistic benefit in the most immunogenic tumor model. KRAS G12C inhibition fails to sensitize cold tumors to immunotherapy, with implications for the design of clinical trials combining KRAS G12C inhibitors with anti-PD1 drugs.