pd -1靶向顺式递送IL-2变体在人肺癌中诱导了多方面的抗肿瘤T细胞反应

IF 14.6 1区医学 Q1 CELL BIOLOGY

Science Translational Medicine Pub Date : 2025-09-17 DOI:10.1126/scitranslmed.adr3718

Irene Fusi, Clara Serger, Petra Herzig, Markus Germann, Michael T. Sandholzer1, Nicole Oelgarth1, Petra C. Schwalie, Leyla Don, Viola K. Vetter, Viktor H. Koelzer, Didier Lardinois, Henry Kao, Laura Codarri Deak, Pablo Umaña, Christian Klein, Aljaz Hojski, Marina Natoli, Alfred Zippelius

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引用次数: 0

摘要

抗体-细胞因子融合蛋白正被开发为下一代癌症免疫疗法，旨在向目标免疫人群传递激活信号。其中，pd1 - il2v是一种缺乏CD25结合的工程化白细胞介素-2变体（IL-2v），与高亲和力的程序性细胞死亡蛋白1 （PD-1）阻断抗体融合，在小鼠肿瘤模型中显示出有希望的结果。在这里，使用人类模型系统，我们表明PD1-IL2v通过靶向CD8 +和常规CD4 + T （T conv）细胞引发多方面的抗肿瘤T细胞反应。肺癌患者源性肿瘤片段（PDTF）平台上的单细胞RNA测序（scRNAseq）显示，PD1-IL2v驱动增殖性、细胞毒性CD8 + T细胞的扩张，表现出肿瘤反应性的特征。这同时伴随着CXCR6的上调，增强了它们的迁移能力。在T转换细胞中，PD1-IL2v上调CXCL13的表达，并促进与抗pd1反应性相关的T滤泡辅助/T辅助1 （T FH /T h1）样转录程序。我们的研究结果为il -2v靶向递送到人类肿瘤内PD-1 +细胞的作用提供了机制见解，支持了下一代免疫细胞因子的临床开发。

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PD-1–targeted cis-delivery of an IL-2 variant induces a multifaceted antitumoral T cell response in human lung cancer

Antibody-cytokine fusion proteins are being developed as next-generation cancer immunotherapies, aiming to deliver activation signals to targeted immune populations. Among these, PD1-IL2v—an engineered interleukin-2 variant (IL-2v) lacking CD25 binding, fused to a high-affinity programmed cell death protein 1 (PD-1) blocking antibody—has shown promising results in murine tumor models. Here, using human model systems, we show that PD1-IL2v elicits a multifaceted antitumor T cell response by targeting both CD8⁺ and conventional CD4⁺ T (T_conv) cells. Single-cell RNA sequencing (scRNAseq) on a lung cancer patient–derived tumor fragment (PDTF) platform revealed that PD1-IL2v drives the expansion of proliferative, cytotoxic CD8⁺ T cells exhibiting features of tumor reactivity. This was accompanied by up-regulation of CXCR6, enhancing their migratory capacity. In T_conv cells, PD1-IL2v up-regulated CXCL13 expression and promoted a T follicular helper/T helper 1 (T_FH/T_H1)–like transcriptional program associated with anti-PD1 responsiveness. Our findings provide mechanistic insights into the effects of IL-2v–targeted delivery to PD-1⁺ cells within human tumors, supporting the clinical development of next-generation immunocytokines.

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来源期刊

Science Translational Medicine CELL BIOLOGY-MEDICINE, RESEARCH & EXPERIMENTAL

CiteScore

26.70

自引率

1.20%

发文量

309

审稿时长

1.7 months

期刊介绍： Science Translational Medicine is an online journal that focuses on publishing research at the intersection of science, engineering, and medicine. The goal of the journal is to promote human health by providing a platform for researchers from various disciplines to communicate their latest advancements in biomedical, translational, and clinical research. The journal aims to address the slow translation of scientific knowledge into effective treatments and health measures. It publishes articles that fill the knowledge gaps between preclinical research and medical applications, with a focus on accelerating the translation of knowledge into new ways of preventing, diagnosing, and treating human diseases. The scope of Science Translational Medicine includes various areas such as cardiovascular disease, immunology/vaccines, metabolism/diabetes/obesity, neuroscience/neurology/psychiatry, cancer, infectious diseases, policy, behavior, bioengineering, chemical genomics/drug discovery, imaging, applied physical sciences, medical nanotechnology, drug delivery, biomarkers, gene therapy/regenerative medicine, toxicology and pharmacokinetics, data mining, cell culture, animal and human studies, medical informatics, and other interdisciplinary approaches to medicine. The target audience of the journal includes researchers and management in academia, government, and the biotechnology and pharmaceutical industries. It is also relevant to physician scientists, regulators, policy makers, investors, business developers, and funding agencies.