Abstract 3065: Targeting of metabolic reprogramming in lung cancer by utilizing patient-derived organoid tissue for precision medicine

Abstract

Abstract In a preliminary pilot study, we reported elevated activity of indoleamine 2,3-dioxygenase 1 (IDO1) in serum from cisplatin-resistant (CR) lung cancer patients compared to cisplatin-sensitive (CS) patients. This heightened IDO1 activity was associated with increased tryptophan (TRP) catabolism, resulting in the upregulation of kynurenine (KYN) production. The detection of KYN can now be readily achieved through immunohistochemistry (IHC). We demonstrated that this upregulation contributed to increased Treg (regulatory T cell) and MDSC (myeloid-derived suppressor cell) populations resulting in an immunosuppressive tumor microenvironment. To investigate this effect, we used dual inhibition of IDO1/TDO2 (tryptophan2,3-dioxygenase 2) in an orthotopic mouse model of CR-Lewis lung carcinoma. This resulted in a significant reduction in tumor volume compared to LLC-CS (n=7, p<0.01), confirming the role of TRP catabolism in CR tumorigenesis. To determine the relevance of the data derived from this mouse model to clinical settings, we established 50 patient-derived organoid tissues (PDOT) from patients with NSCLC. PDOT is an experimental ex vivo tissue model developed to recapitulate the intricate features of lung architecture, including the lung acinus. Upon optimizing our collection and growth protocols, each PDOT successfully developed into a spherical body within 14 days. Furthermore, through bulk RNA-seq analysis, we showed that PDOT closely mirrors the expression of key molecular markers (PD-L1 and mutations), as observed in the original tumor tissues. PDOT from patients possessing high levels of PD-L1 and KYN were exquisitely sensitive to dual inhibition with 2-3-fold greater sensitivity compared to patients with undetectable KYN expression in growth inhibition assays (GI50=20±5.5μM vs. 65±7.5μM). Increased lipid peroxidation was detected via flow cytometry by accumulation of the C11-BODIPY reporter dye in the dual inhibition treatment group. Moreover, we integrated PDOT with a novel 3D microfluidic culture that can be supplied with patient-matched peripheral blood mononuclear cells (PBMC) to assess immune response. Using CyTOF, we showed that dual inhibitors with Atezolizumab (anti-PD-L1) enhanced immune effector (CD8+, NK) and suppressed immunosuppressive (Treg, MDSC) populations. We believe that our swift progress in PDOT development may bridge the divide between cancer biomarker expression and patient trials by timely complementing conventional drug studies based on cell lines and xenografts to facilitate the design of personalized therapies. As a result, the extensive reporting that we have contributed for KYN expression profiling in CR has the potential to serve as a valuable companion diagnostic tool in the future. This can assist in applying precision oncology by finding the most appropriate patients for immunotherapies. Citation Format: Chunjing Wu, Jonathan D. Nguyen, George Theodore, Estelamari Rodriguez, Sydney Spector, Emily Kim, Taranatee Khan, Pablo Puente, Yujie Wang, Dao M. Nguyen, Cheng-Bang Chen, Diane Lim, Lynn G. Feun, Niramol Savaraj, Medhi Wangpaichitr. Targeting of metabolic reprogramming in lung cancer by utilizing patient-derived organoid tissue for precision medicine [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3065.