Pre-TCR-targeted immunotherapy for T cell acute lymphoblastic leukemia

IF 27.6 1区 医学 Q1 IMMUNOLOGY
Patricia Fuentes, Marina García-Peydró, Juan Alcain, Marta Mosquera, Carmela Cela, Claudia Cifuentes, Montserrat Torrebadell, Ignacio Isola, Mireia Camós, Manuel Ramírez, Balbino Alarcón, María L. Toribio
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Abstract

Targeted immunotherapy for T cell acute lymphoblastic leukemia (T-ALL), an aggressive tumor of developing T cell progenitors, is an urgent unmet need, especially for relapsed/refractory disease. Selective T-ALL targeting is challenging due to the shared antigen expression between leukemic and normal T cells. Here we identify the pre-T cell receptor (pre-TCR), a surface receptor essential for T cell development, as a biomarker of leukemia-initiating cells (LICs) in human T-ALL. Loss-of-function genetic approaches demonstrate that pre-TCR signaling is necessary for LIC activity and tumor progression in pre-TCR+ T-ALL patient xenografts in mice. Furthermore, we demonstrate the specific therapeutic targeting of the pre-TCR with a monoclonal antibody against the invariant pTα subunit of the human pre-TCR, and validate an anti-pTα antibody–drug conjugate in vivo treatment as a potent immunotherapy for inhibiting LIC activity and tumor progression of T-ALL in mice. These findings reveal the suitability of pre-TCR targeting as a promising therapy for the treatment of individuals with relapsed/refractory T-ALL expressing the pre-TCR. The authors identify pre-TCR as a key biomarker and therapeutic target in T-ALL. Targeting it with an anti-pTα antibody–drug conjugate inhibits leukemia-initiating cells and tumor growth in mice, offering promise for relapsed/refractory T-ALL treatment.

Abstract Image

Abstract Image

T细胞急性淋巴细胞白血病的tcr前靶向免疫治疗
T细胞急性淋巴细胞白血病(T- all)是一种发展中的T细胞祖细胞的侵袭性肿瘤,靶向免疫治疗是一个迫切的未满足的需求,特别是对于复发/难治性疾病。选择性T- all靶向是具有挑战性的,因为白血病和正常T细胞之间有共同的抗原表达。在这里,我们确定了T细胞前受体(pre-TCR),一种T细胞发育所必需的表面受体,作为人类T- all中白血病起始细胞(lic)的生物标志物。功能丧失遗传学方法表明,tcr前信号传导对于小鼠tcr前+ T-ALL异种移植患者的LIC活性和肿瘤进展是必要的。此外,我们证明了针对人tcr前的不变pTα亚基的单克隆抗体对tcr前的特异性治疗靶向性,并验证了抗pTα抗体-药物偶联物在体内治疗作为抑制小鼠T-ALL的LIC活性和肿瘤进展的有效免疫疗法。这些研究结果表明,靶向治疗tcr前基因表达的复发/难治性T-ALL是一种有希望的治疗方法。
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来源期刊
Nature Immunology
Nature Immunology 医学-免疫学
CiteScore
40.00
自引率
2.30%
发文量
248
审稿时长
4-8 weeks
期刊介绍: Nature Immunology is a monthly journal that publishes the highest quality research in all areas of immunology. The editorial decisions are made by a team of full-time professional editors. The journal prioritizes work that provides translational and/or fundamental insight into the workings of the immune system. It covers a wide range of topics including innate immunity and inflammation, development, immune receptors, signaling and apoptosis, antigen presentation, gene regulation and recombination, cellular and systemic immunity, vaccines, immune tolerance, autoimmunity, tumor immunology, and microbial immunopathology. In addition to publishing significant original research, Nature Immunology also includes comments, News and Views, research highlights, matters arising from readers, and reviews of the literature. The journal serves as a major conduit of top-quality information for the immunology community.
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