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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 γ 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. One sentence summary KRASG12C inhibition mobilizes anti-tumour immunity in immunogenic lung cancer models through derepressing interferon signaling via repression of Myc.

Oncogenic KRAS mutations drive tumourigenesis in 30% of non-small cell lung cancer (NSCLC). Despite much effort, targeted therapies that aim to directly inhibit signalling pathways downstream of KRAS have limited clinical benefits for NSCLC patients, but the recent approval of PD-1/PD-L1 antibodies has led to striking durable responses. However, only a fraction of patients respond and therefore a deeper understanding of the mechanisms that drive immune evasion are required in order to broaden the clinical efficacy of immunotherapy. Increasing evidence suggests that oncogenic signalling pathways greatly influence the tumour immune landscape to impair anti-tumour immune responses. We therefore aim to understand the mechanisms by which KRAS signalling mediates immune evasion in lung cancer. Current mouse models of KRAS-mutant lung cancer are poorly immunogenic, limiting investigations into tumour-immune interactions. To overcome this, we generated a novel transplantable KRAS-mutant lung cancer model, KPAR1.3, which triggers spontaneous anti-tumour immune responses and is sensitive to immune checkpoint blockade. To identify mechanisms of immune evasion we carried out an in vivo pooled CRISPR-Cas9 screen targeting 240 KRAS-regulated genes using this novel immunogenic model. This identified a number of genes that increased sensitivity or caused resistance to anti-tumour immune responses. As an alternative approach we utilised the recently developed class of mutant-specific KRAS-G12C inhibitors to assess the impact of inhibiting KRAS signalling on anti-tumour immune responses in KPAR1.3 tumours. KRAS-inhibition stimulated adaptive immunity in vivo, which contributed to the response of KPAR1.3 tumours in immune-competent mice. Together these data suggest that targeting KRAS, or KRAS-driven mechanisms of immune evasion, could broaden the clinical efficacy of immunotherapy in KRAS-mutant NSCLC. Citation Format: Jesse Boumelha, Sophie de Carné, Edurne Mugarza, Pablo Romero-Clavijo, Miriam Molina-Arcas, Julian Downward. Uncovering mechanisms of immune evasion in a novel immunogenic model of KRAS-mutant lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1820.