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

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.