이새봄 (H. Lee Moffitt Cancer Center & Research Institute) | 한빛사논문 > 한빛사

한빛사논문

조회124

H. Lee Moffitt Cancer Center & Research Institute

CV File

Nat. Commun., 31 August 2026 | https://doi.org/10.1038/s41467-026-76972-9 IFN-γ-driven iNOS induction in macrophages mediates CAR T cell resistance in B cell lymphoma

Sae Bom Lee^1,2, Allan Pavy³, Nolan Beatty^1,2, Justin C. Boucher¹, Jay K. Mandula^1,2, Emiliano Roselli⁴, Darwin C. Chang^1,2, Rachel V. Jimenez¹, Hiroshi Kotani⁵, Kayla Reid⁴, Julio Vazquez-Martinez¹, Payal Goala^1,2, Max Ilecki³, Cooper J. Sailer³, Shannon L. McSain³, Showkat Hamid³, Muhammad Junaid Tariq³, Rosa A. Sierra-Mondragon¹, Min Liu⁶,
John M. Koomen⁶, Jonathan Nguyen⁶, Mohammad Hussaini⁷, Timothy I. Shaw⁸, Xuefeng Wang⁸, Jianmin Wang⁹, Julieta Abraham-Miranda¹⁰, Rawan Faramand¹⁰, Michael D. Jain¹⁰, Meredith L. Stone³, Frederick L. Locke¹¹, Paulo C. Rodriguez¹, Yun Pyo Kang¹¹ & MarcoL. Davila⁴

¹Department of Immunology, H. Lee Moffitt Cancer Center, Tampa, FL, USA.
²Cancer Biology PhD Program, University of South Florida, Tampa, FL, USA.
³Department of Medicine, Roswell Park Cancer Center, Buffalo, NY, USA.
⁴Department of Clinical Science, H. Lee Moffitt Cancer Center, Tampa, FL, USA.
⁵Division of Medical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa, Japan.
⁶Proteomics and Metabolomics Core, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
⁷Department of Pathology, H. Lee Moffitt Cancer Center, Tampa, FL, USA.
⁸Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center, Tampa, FL, USA.
⁹Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.
¹⁰Department of Blood and Marrow Transplant and Cellular Immunotherapy, H. Lee Moffitt Cancer Center, Tampa, FL, USA.
¹¹College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea.

Corresponding author
Correspondence to Marco L. Davila.

Abstract

Chimeric antigen receptor (CAR) T cell therapies have revolutionized B cell malignancy treatment, but many patients with large B cell lymphoma (LBCL) experience primary resistance or relapse. To uncover resistance mechanisms, here we examine pre-infusion tumor biopsies and observe that increased immunoregulatory macrophages correlate with poor clinical responses. In murine models, CAR T cell-produced interferon-gamma (IFN-γ) upregulates inducible nitric oxide synthase (iNOS, NOS2) in immunoregulatory macrophages, impairing CAR T cell function. Proteomic profiling reveals that iNOS-expressing macrophages promote apoptosis and cell cycle arrest while downregulating protein synthesis machinery in CAR T cells. Metabolically, CAR T cells exhibit reduced glycolytic intermediates and altered tricarboxylic acid (TCA) cycle activity. Pharmacological inhibition of iNOS enhances CAR T cell treatment efficacy in vivo. Elevated levels of iNOS+CD14+ monocytes in leukaphereses are associated with non-durable responses to CAR T cells. Targeting iNOS in immunoregulatory macrophages, potentially by modulating CAR T-produced IFN-γ, could improve LBCL outcomes.

논문정보