Therapeutic KRAS^G12C inhibition drives effective interferon-mediated anti-tumour immunity in immunogenic lung cancers

Abstract Recently developed KRAS G12C inhibitory drugs are beneficial to lung cancer patients harbouring KRAS G12C mutations, but drug resistance frequently develops. Due to the immunosuppressive nature of the signaling network controlled by oncogenic KRAS, these drugs can indirectly affect anti-tumour immunity, providing a rationale for their combination with immune checkpoint blockade. In this study, we have characterised how KRAS G12C inhibition reverses immune suppression driven by oncogenic KRAS in a number of pre-clinical lung cancer models with varying levels of immunogenicity. Mechanistically, KRAS G12C inhibition upregulates interferon signaling via Myc inhibition, leading to reduced tumour 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 tumour model. KRAS G12C inhibition fails to sensitize cold tumours to immunotherapy, with implications for the design of clinical trials combining KRAS G12C inhibitors with anti-PD1 drugs. One sentence summary KRAS inhibition mobilizes anti-tumour immunity in immunogenic lung cancer models through derepressing interferon signaling via repression of Myc.