Elucidating the Role of the Tumor Suppressor KEAP1 in Antitumor Immunity - Project Summary - Elucidating the role of the tumor suppressor KEAP1 in antitumor immunity Lung cancer is the leading cause of cancer-related deaths worldwide, with non-small cell lung cancer (NSCLC) being the most common subtype, representing approximately 85% of all diagnoses. Among the major drivers of lung cancer, about 20% of NSCLC patients exhibit loss-of-function mutations in the tumor suppressor and E3 ubiquitin ligase KEAP1. Although immune checkpoint blockade (ICB) inhibitors represent the most recent breakthrough in treating advanced NSCLC, a significant portion of patients experiences primary resistance, especially those harboring KEAP1 mutations. Our recent work describes how the loss of KEAP1 leads to the suppression of the type I interferon response, promoting lung cancer immune evasion (Marzio et al., Cell 2022). Through multi-omic profiling of NSCLC human and mouse samples, we confirmed that KEAP1-mutant NSCLCs exhibit immune-evasive features, including reduced T cell infiltration and resistance to immune checkpoint inhibitors. This analysis also identified a set of novel potential KEAP1 substrates that are overexpressed in KEAP1-mutant tumors. Among these substrates, we identified several oncoproteins that play a crucial role in the activation of the pro-inflammatory transcription factor NF-B. The goal of the proposed research is to investigate the hypothesis that the newly identified upregulated oncoproteins are bona fide KEAP1 substrates. We will employ biochemistry, molecular/cell biology, and somatic cell genetic approaches to functionally and mechanistically interrogate the contribution of these putative novel substrates in the immune-evasive phenotype observed in KEAP1-mutant NSCLCs (Aim 1). A natural corollary of this goal is to test the premise that therapeutic targeting of the validated substrate can improve the efficacy of immunotherapy for NSCLC (Aim 2). Understanding how the loss of KEAP1, along with the concomitant accumulation of its substrates, promotes immune evasion in cancer has the potential to profoundly impact our comprehension of the immune response to NSCLC and enhance the success of therapy for this tumor type. Additionally, since KEAP1 loss-of-function mutations are recurrent features in several malignancies, the significance of this proposal is evident. We anticipate that our results will present a promising opportunity to treat patients with KEAP1 alterations using novel and alternative therapeutic approaches. Completion of this work will also unveil the molecular mechanisms underlying the physiological role of KEAP1 in regulating inflammation and immunological responses during cancer development and progression, offering therapeutic opportunities for a substantial number of patients whose tumors are driven by its loss. Shaped by our longstanding dedication to the field of DNA damage response and cancer biology, this project is part of our ongoing efforts to uncover novel molecular mechanisms that contribute to malignant transformation.
