Hi-jacking the kynurenine pathway: A new therapeutic approach used to treat cisplatin resistant lung cancer that evades immune surveillance and proliferates with increased ROS levels

Miami Va Health Care System, Miami FL

Investigators

Linked publications & trials

Abstract

Background: Lung cancer poses a significant threat to veterans, representing one of the most fatal malignancies in the Veterans Health Administration (VHA). In 2023, the FDA approved anti-PD1 immune checkpoint inhibitors (ICI) with platinum-containing chemotherapy as a neoadjuvant/adjuvant treatment for non- small cell lung cancer (NSCLC), but efficacy remains limited to patients whose tumors express high programmed death-ligand 1 (PD-L1) and mutation burden. Long-term survival is rare, with inevitable relapse. We believe that a subset of NSCLC is intrinsically shielded from immune surveillance. We reported that some treatment-resistant NSCLCs have heightened indoleamine 2,3-dioxygenase-1 (IDO1) activity, enhancing tryptophan catabolism and elevating kynurenine (KYN) production. This process is pivotal in establishing peripheral tolerance and evading immune surveillance. Notably, our pilot study revealed elevated KYN levels in serum from patients with treatment-resistant vs. those with sensitive tumors. In this proposal, we preliminary discovered that elevated expression of Yes-associated protein-1 (YAP1) may correlate with a shorter duration of response (DOR) to ICI. We hypothesize that the interaction between the YAP1&IDO1 networks promotes immune evasion and tumor growth. YAP1&IDO1 form a complex system to heighten an immunosuppressive tumor microenvironment (TME) in resistant cancer cells. We will test this hypothesis and begin assessing clinical relevance in NSCLC models mimicking immune evasive (IE) tumors to: (i) elucidate the impact of YAP1&IDO1 interplay on NSCLC survival and immune evasion, (ii) disrupting YAP1&IDO1 interplay and evaluate effects on NSCLC survival and immune evasion in vivo, and (iii) explore correlations between YAP1&KYN expression and ICI responsiveness in NSCLC patients retrospectively and prospectively using PDOT-3D microfluidic (patient-derived organoid tissue) system. Innovation: Conceptual: The understanding of the KYN pathway remains limited. Our lab was the first to show that blocking IDO1 alone leads to TDO2 upregulation. Additionally, we identified the crucial role of reactive oxygen species in driving IDO1 activity, thereby increasing KYN levels. We believe increased oxidative metabolism caused by YAP1 perpetuates IDO1 activity, promoting IE tumors. Disrupting IDO1&YAP1 could reverse IE, promoting immune control and improving outcomes; Technical: To investigate our new-in-class IDO1/TDO2 inhibitor (AT-0174) using our cisplatin-resistant NSCLC cell lines that replicate IE tumor phenotypes, developed a safe method to induce a solitary primary tumor in a mouse's left lung via a surgical chest wall opening and injection, and developed a novel PDOT-3D system using patients own blood. This system mimics tissue architecture and TME, yielding clinically relevant data for drug discovery. Significance and Impact: Addressing lung cancer, the most prevalent cancer at the VHA, is urgent among Veterans due to higher incidents and lower survival rates compared to civilians. This is compounded by increased toxin exposure during military service, with recent legislation priority addressing fatal lung diseases like NSCLC by the VHA. This proposal aims to deeper understanding of factors limiting the DOR to current ICI, identify crucial prognostic and predictive markers for ICI therapy besides PD-L1 and tumor mutation burden, to improve response rate, and DOR among Veterans, their families, and the general population. Path to translation/implementation: We will investigate how metabolic alterations in NSCLC impact evasion and explore therapeutic strategies to restore immune control and enhance existing ICI. We will assess the effects of FDA-approved drugs and AT-0174 on NSCLC tumor model growth and survival. These data could improve treatments, survival, and treatment choices in future translational pathways. Exploring correlations between YAP1 and KYN, and ICI responsiveness in NSCLC patients has a direct translational impact in providing a more conclusive determination of poor prognosis and treatment outcome. This correlation of molecular expression to treatment outcomes can provide the basis for future studies of prognostic/diagnostic markers.