Overcoming CD226-related immune evasion in acute myeloid leukemia with CD38 CAR-engineered NK cells.

IF 6.9 1区生物学 Q1 CELL BIOLOGY Cell reports Pub Date : 2025-01-28 Epub Date: 2025-01-03 DOI:10.1016/j.celrep.2024.115122

Luciana Melo Garcia, Achintyan Gangadharan, Pinaki Banerjee, Ye Li, Andy G X Zeng, Hind Rafei, Paul Lin, Bijender Kumar, Sunil Acharya, May Daher, Luis Muniz-Feliciano, Gary M Deyter, Gabriel Dominguez, Jeong Min Park, Francia Reyes Silva, Ana Karen Nunez Cortes, Rafet Basar, Nadima Uprety, Mayra Shanley, Mecit Kaplan, Enli Liu, Elizabeth J Shpall, Katayoun Rezvani

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Abstract

CD226 plays a vital role in natural killer (NK) cell cytotoxicity, interacting with its ligands CD112 and CD155 to initiate immune synapse formation, primarily through leukocyte function-associated-1 (LFA-1). Our study examined the role of CD226 in NK cell surveillance of acute myeloid leukemia (AML). NK cells in patients with AML had lower expression of CD226. CRISPR-Cas9 deletion of CD226 led to reduced LFA-1 recruitment, poor synapse formation, and decreased NK cell anti-leukemic activity. Engineering NK cells to express a chimeric antigen receptor targeting the AML antigen CD38 (CAR38) could overcome the need for CD226 to establish strong immune synapses. LFA-1 blockade reduced CAR38 NK cell activity, and this depended on the CD38 expression levels of AML cells. This suggests parallel but potentially cooperative roles for LFA-1 and CAR38 in synapse formation. Our findings suggest that CAR38 NK cells could be an effective therapeutic strategy to overcome CD226-mediated immune evasion in AML.

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CD38 car修饰NK细胞克服急性髓系白血病cd226相关免疫逃避

CD226在自然杀伤（NK）细胞毒性中起着至关重要的作用，它与配体CD112和CD155相互作用，主要通过白细胞功能相关-1 （LFA-1）启动免疫突触的形成。我们的研究检测了CD226在急性髓性白血病（AML） NK细胞监测中的作用。AML患者NK细胞中CD226的表达较低。CRISPR-Cas9缺失CD226导致LFA-1募集减少，突触形成不良，NK细胞抗白血病活性降低。工程NK细胞表达靶向AML抗原CD38 （CAR38）的嵌合抗原受体可以克服CD226建立强免疫突触的需要。LFA-1阻断降低了CAR38 NK细胞活性，这取决于AML细胞的CD38表达水平。这表明LFA-1和CAR38在突触形成中具有平行但潜在的合作作用。我们的研究结果表明，CAR38 NK细胞可能是克服cd226介导的AML免疫逃避的有效治疗策略。

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来源期刊

Cell reports CELL BIOLOGY-

CiteScore

13.80

自引率

1.10%

发文量

1305

审稿时长

77 days

期刊介绍： Cell Reports publishes high-quality research across the life sciences and focuses on new biological insight as its primary criterion for publication. The journal offers three primary article types: Reports, which are shorter single-point articles, research articles, which are longer and provide deeper mechanistic insights, and resources, which highlight significant technical advances or major informational datasets that contribute to biological advances. Reviews covering recent literature in emerging and active fields are also accepted. The Cell Reports Portfolio includes gold open-access journals that cover life, medical, and physical sciences, and its mission is to make cutting-edge research and methodologies available to a wide readership. The journal's professional in-house editors work closely with authors, reviewers, and the scientific advisory board, which consists of current and future leaders in their respective fields. The advisory board guides the scope, content, and quality of the journal, but editorial decisions are independently made by the in-house scientific editors of Cell Reports.