类有机物
主要组织相容性复合体
CD8型
外周血单个核细胞
T细胞
抗原
生物
免疫系统
T细胞受体
人类白细胞抗原
癌症免疫疗法
抗体
细胞毒性T细胞
癌症研究
CD3型
表位
免疫疗法
细胞生物学
免疫学
生物化学
体外
作者
Katharina Kroll,Mariana Mata,Kimberly A. Homan,Virginie Micallef,Alejandro Carpy,Ken Hiratsuka,Ryuji Morizane,Annie Moisan,Marcel Gubler,Antje-Christine Walz,Estelle Marrer-Berger,Jennifer A. Lewis
标识
DOI:10.1073/pnas.2305322120
摘要
T cell bispecific antibodies (TCBs) are the focus of intense development for cancer immunotherapy. Recently, peptide-MHC (major histocompatibility complex)-targeted TCBs have emerged as a new class of biotherapeutics with improved specificity. These TCBs simultaneously bind to target peptides presented by the polymorphic, species-specific MHC encoded by the human leukocyte antigen (HLA) allele present on target cells and to the CD3 coreceptor expressed by human T lymphocytes. Unfortunately, traditional models for assessing their effects on human tissues often lack predictive capability, particularly for “on-target, off-tumor” interactions. Here, we report an immune-infiltrated, kidney organoid-on-chip model in which peripheral blood mononuclear cells (PBMCs) along with nontargeting (control) or targeting TCB-based tool compounds are circulated under flow. The target consists of the RMF peptide derived from the intracellular tumor antigen Wilms’ tumor 1 (WT1) presented on HLA-A2 via a bivalent T cell receptor-like binding domain. Using our model, we measured TCB-mediated CD8 + T cell activation and killing of RMF-HLA-A2-presenting cells in the presence of PBMCs and multiple tool compounds. DP47, a non-pMHC-targeting TCB that only binds to CD3 (negative control), does not promote T cell activation and killing. Conversely, the nonspecific ESK1-like TCB (positive control) promotes CD8 + T cell expansion accompanied by dose-dependent T cell–mediated killing of multiple cell types, while WT1-TCB* recognizing the RMF-HLA-A2 complex with high specificity, leads solely to selective killing of WT1-expressing cells within kidney organoids under flow. Our 3D kidney organoid model offers a platform for preclinical testing of cancer immunotherapies and investigating tissue-immune system interactions.
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