Abstract P026: Uncovering mechanisms of immune evasion in a novel immunogenic model of KRAS-mutant lung cancer

Abstract

Abstract Oncogenic KRAS mutations drive tumorigenesis in 30% of non-small cell lung cancer (NSCLC). Despite much effort, targeted therapies that aim to directly inhibit signaling 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 signaling pathways greatly influence the tumor immune landscape to impair anti-tumor immune responses. We therefore aim to understand the mechanisms by which KRAS signaling mediates immune evasion in lung cancer. Current mouse models of KRAS-mutant lung cancer are poorly immunogenic, limiting investigations into tumor-immune interactions. To overcome this, we generated a novel transplantable KRAS-mutant lung cancer model, KPAR1.3, which triggers spontaneous anti-tumor 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-tumor immune responses. As an alternative approach we utilized the recently developed class of mutant-specific KRAS-G12C inhibitors to assess the impact of inhibiting KRAS signaling on anti-tumor immune responses in KPAR1.3 tumors. KRAS-inhibition stimulated adaptive immunity in vivo, which contributed to the response of KPAR1.3 tumors 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, Pablo Romero, Miriam Moliona, Julian Downward. Uncovering mechanisms of immune evasion in a novel immunogenic model of KRAS-mutant lung cancer [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2021 Oct 5-6. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(1 Suppl):Abstract nr P026.