Nature communications · 2026
IFN-γ-driven iNOS induction in macrophages mediates CAR T cell resistance in B cell lymphoma.
СтатьяПоддержка NIH: внешняя программаПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
Обработка статьи · этапы, ошибки и управление
Загрузка состояния…
Ошибки и ограничения
История · было → стало
Состояние обновляется каждые 5 секунд, пока блок открыт. Процент показывается только там, где известен объём работы. Пауза останавливает продолжение этапа; текущий запрос к источнику может завершиться.
Lee Sae Bom, Pavy Allan, Beatty Nolan, Boucher Justin C, Mandula Jay K, Roselli Emiliano, Chang Darwin C, Jimenez Rachel V, Kotani Hiroshi, Reid Kayla, Vazquez-Martinez Julio, Goala Payal, Ilecki Max, Sailer Cooper J, McSain Shannon L, Hamid Showkat, Tariq Muhammad Junaid, Sierra-Mondragon Rosa A, Liu Min, Koomen John M, Nguyen Jonathan, Hussaini Mohammad, Shaw Timothy I, Wang Xuefeng, Wang Jianmin, Abraham-Miranda Julieta, Faramand Rawan, Jain Michael D, Stone Meredith L, Locke Frederick L, Rodriguez Paulo C, Kang Yun Pyo, Davila Marco L
Аннотация
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.