Therapeutic KRASG12C inhibition drives effective interferon-mediated anti-tumour immunity in immunogenic lung cancers

Abstract

The recent development and approval of KRASG12C inhibitors promises to change profoundly the clinical management of lung cancer patients harbouring KRASG12C mutations. However, early clinical data indicate that acquired drug resistance can frequently develop after the initial response. Due to the immunosuppressive nature of the signaling network controlled by oncogenic KRAS, targeted KRASG12C inhibition can indirectly affect anti-tumour immunity. This has served as a rationale for combination with immune checkpoint blockade, showing therapeutic benefit in certain immunogenic pre-clinical tumour models. In this study, we characterised how KRASG12C inhibition reverses immune suppression driven by oncogenic KRAS in a number of pre-clinical lung cancer models with varying levels of immunogenicity. Mechanistically, KRASG12C inhibition upregulates interferon pathway gene expression via inhibition of Myc and, in tumours, leads to reduced infiltration of immunosuppressive cells, increased interferon responses and antigen presentation, and also enhanced infiltration and activation of cytotoxic T cells. However, the combination of KRASG12C inhibitors with immune checkpoint blockade only provides synergistic benefit in the most immunogenic tumour model, with KRASG12C inhibition failing to sensitize cold tumours to immunotherapy. In immunogenic tumours, complete responses to KRASG12C inhibition requires tumour cell autonomous interferon gamma signaling. Our data have important implications for the design of clinical trials combining KRASG12C inhibitors with anti-PD-1 drugs and suggest that additional combination strategies will be needed for immunotherapy refractory patients.

Competing Interest Statement

J.D. has acted as a consultant for AstraZeneca, Bayer, Jubilant, Theras, BridgeBio, Vividion and Novartis, and has funded research agreements with BMS and Revolution Medicines. None of the other authors of this manuscript have a financial interest related to this work.