Targeting immunosuppressive mechanisms in KRAS mutant lung cancer

Abstract

Clinical trials with single agent immune checkpoint inhibitors, mainly the anti-PD-1 antibody, have achieved noteworthy benefit with an objective response rate in 17% of non-small cell lung cancer (NSCLC) patients. However, minimal or no response in a large proportion of patients suggest that additional immune suppression pathways need to be identified in the tumor microenvironment to define combination immune therapies for future therapeutic intervention. We have focused our studies on the KRAS mutant subset, as it accounts for >30% of NSCLC patients with high mortality rates due to a conspicuous lack of effective FDA approved targeted therapies. To enable selection of appropriate immunotherapies, we have performed comprehensive analysis of immune microenvironments in a mouse model of KRAS driven NSCLC, to identify various potential mechanisms that may lead to effector T cell suppression. Validation of key findings in human KRAS adenocarcinomas identified several dominant immunosuppressive mechanisms employed by KRAS tumors. These mechanisms include spatiotemporal organization of immune cells (T cell exclusion/inclusion, MDSCs, Macrophages), expression of specific co-inhibitory checkpoints (PD1-PD-L1, LAG-3, TIM-3, TIGIT), and additional components of T cell suppression (IDO, Arginase, Tregs). Identification of concurrent dominant immune suppressive mechanisms employed by KRAS tumors has allowed us to employ rationally guided effective combination therapeutics, which are being tested in exploratory trials in preclinical models, together with immunomodulatory action of conventional standard of care chemotherapy and radiation therapy. Our approach is in line with recent success of combination immunotherapies in melanoma and colon cancer, and could impact the selection of immunotherapies for treating mutant KRAS NSCLC patients in the clinic.