Boumelha, Jesse; (2022) Mechanisms of immune evasion in a novel immunogenic model of KRAS-mutant lung cancer. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

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 impairing 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 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. Among these, KRAS-driven COX-2 expression was identified as a major mediator of immune evasion which could be therapeutically targeted in vivo. The screen also highlighted the role of tumour-intrinsic IFNγ signalling for sensitivity to anti-tumour immune responses. By using pharmacological KRAS pathway inhibitors we demonstrated that oncogenic KRAS suppresses tumour-intrinsic IFN signalling which can be restored in vivo by the recently developed class of mutant-specific KRASG12C inhibitors. In line with this, we show that the efficacy of KRASG12C inhibition is partially dependent on adaptive immunity. 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.

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