PD-1阻断后肿瘤浸润浆细胞特征分析揭示肿瘤特异性抗体

Tumor-infiltrating plasma cell profiling after PD-1 blockade reveals tumor-specific antibodies.

期刊: Cancer Cell
PMID: 42508408
原文: PubMed ↗
发布日期: 2026-07-28

作者

R Ryan Meyerhoff — Division of Interventional Radiology, Department of Radiology, Duke University School of Medicine, Durham, NC 27710, USA. Electronic address: meyerhr@mskcc.org.
Alan Chen — Division of Medical Oncology, Department of Medicine, Duke University School of Medicine, Durham, NC 27710, USA.
Jenny O'Brien — Division of Medical Oncology, Department of Medicine, Duke University School of Medicine, Durham, NC 27710, USA.
Carmen M Anadon — Department of Integrative Immunobiology, Duke University School of Medicine, Durham, NC 27710, USA.
Luis Uriel Lopez Bailon — Division of Medical Oncology, Department of Medicine, Duke University School of Medicine, Durham, NC 27710, USA.
Dayan Carrion-Estrada — Division of Medical Oncology, Department of Medicine, Duke University School of Medicine, Durham, NC 27710, USA.
Koravit Poysungnoen — Department of Biomedical Engineering, Duke University, Durham, NC 27710, USA.
Jared Lindenberger — Department of Surgery, Duke University School of Medicine, Durham, NC 27710, USA.
Gabor Kemeny — Division of Medical Oncology, Department of Medicine, Duke University School of Medicine, Durham, NC 27710, USA.
Liliana Lyniv — Division of Medical Oncology, Department of Medicine, Duke University School of Medicine, Durham, NC 27710, USA.
Vaibjav Jain — Duke Molecular Physiology Institute, Duke University School of Medicine, Durham, NC 27710, USA.
Ricardo Chaurio — Department of Integrative Immunobiology, Duke University School of Medicine, Durham, NC 27710, USA.
Noah Plappert — Department of Integrative Immunobiology, Duke University School of Medicine, Durham, NC 27710, USA.
Tyler Evangelous — Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC 27710, USA.
Chan Soo Park — Department of Surgery, Duke University School of Medicine, Durham, NC 27710, USA.
Alok Sinha — Department of Chemistry, Duke University, Durham, NC 27710, USA; Department of Computer Science, Duke University, Durham, NC 27710, USA.
Eziafa Oduah — Division of Medical Oncology, Department of Medicine, Duke University School of Medicine, Durham, NC 27710, USA.
Carolyn Glass — Department of Pathology, Duke University School of Medicine, Durham, NC 27710, USA.
Kent Weinhold — Department of Surgery, Duke University School of Medicine, Durham, NC 27710, USA.
Simon Gregory — Duke Molecular Physiology Institute, Duke University School of Medicine, Durham, NC 27710, USA.
John W Hickey — Duke Molecular Physiology Institute, Duke University School of Medicine, Durham, NC 27710, USA.
Priyamvada Acharya — Department of Surgery, Duke University School of Medicine, Durham, NC 27710, USA; Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC 27710, USA.
Neal Ready — Division of Medical Oncology, Department of Medicine, Duke University School of Medicine, Durham, NC 27710, USA.
Jose R Conejo-Garcia — Department of Integrative Immunobiology, Duke University School of Medicine, Durham, NC 27710, USA.
Wilton B Williams — Department of Integrative Immunobiology, Duke University School of Medicine, Durham, NC 27710, USA; Department of Surgery, Duke University School of Medicine, Durham, NC 27710, USA; Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC 27710, USA. Electronic address: wilton.williams@duke.edu.
Scott J Antonia — Division of Medical Oncology, Department of Medicine, Duke University School of Medicine, Durham, NC 27710, USA. Electronic address: scott.antonia@duke.edu.

作者单位

Division of Interventional Radiology, Department of Radiology, Duke University School of Medicine, Durham, NC 27710, USA. Electronic address: meyerhr@mskcc.org.
Division of Medical Oncology, Department of Medicine, Duke University School of Medicine, Durham, NC 27710, USA.
Department of Integrative Immunobiology, Duke University School of Medicine, Durham, NC 27710, USA.
Department of Biomedical Engineering, Duke University, Durham, NC 27710, USA.
Department of Surgery, Duke University School of Medicine, Durham, NC 27710, USA.
Duke Molecular Physiology Institute, Duke University School of Medicine, Durham, NC 27710, USA.
Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC 27710, USA.
Department of Chemistry, Duke University, Durham, NC 27710, USA; Department of Computer Science, Duke University, Durham, NC 27710, USA.
Department of Pathology, Duke University School of Medicine, Durham, NC 27710, USA.
Department of Surgery, Duke University School of Medicine, Durham, NC 27710, USA; Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC 27710, USA.
Department of Integrative Immunobiology, Duke University School of Medicine, Durham, NC 27710, USA; Department of Surgery, Duke University School of Medicine, Durham, NC 27710, USA; Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC 27710, USA. Electronic address: wilton.williams@duke.edu.
Division of Medical Oncology, Department of Medicine, Duke University School of Medicine, Durham, NC 27710, USA. Electronic address: scott.antonia@duke.edu.

摘要

中文

肿瘤浸润B细胞（TIL-Bs）在免疫检查点阻断背景下对塑造抗肿瘤免疫反应的作用尚未完全阐明。本研究在接受了新辅助PD-1阻断治疗的非小细胞肺癌（NSCLC）患者手术切除的肺癌标本中探究了体液免疫反应。我们发现肿瘤组织可构建由CD138+浆细胞构成的第三级淋巴结构，并从这些浆细胞中克隆出具有体细胞高突变和抗体类别转换的B细胞受体（BCRs）来源的重组单克隆抗体（mAbs）。多种mAbs可结合细胞表面的瓜氨酸化蛋白，这是肿瘤细胞的特征。以我们候选抗体（PC-1）的可溶性单链可变区片段（scFv）构建的嵌合抗原受体（CAR）T细胞在体内可特异性靶向肿瘤细胞及促肿瘤髓系细胞，且无脱靶活性。此外，在荷瘤小鼠中敲除瓜氨酸化酶PADI2可消除PC-1的反应性及CAR的细胞毒杀伤作用。我们的研究结果揭示了肿瘤浸润浆细胞的治疗潜力，有望用于癌症治疗。

English

The role of tumor-infiltrating B cells (TIL-Bs) in shaping anti-tumor responses in the context of immune checkpoint blockade remains incompletely understood. Here, we interrogate the humoral response in resected lung tumors from patients with non-small cell lung cancer (NSCLC) treated with neoadjuvant PD-1 blockade. We find that tumors orchestrate tertiary lymphoid structures with CD138+ plasma cells, from which we clone recombinant monoclonal antibodies (mAbs) using B cell receptors (BCRs) exhibiting somatic hypermutation and class switching. Several mAbs bind cell-surface citrullinated proteins, characteristic of cancer cells. Chimeric antigen receptor (CAR) T redirected with the soluble chain fragment variable (scFv) of our lead candidate antibody (PC-1) specifically target tumor cells and tumor-promoting myeloid cells in vivo without off-target activity. Moreover, ablation of the citrullination enzyme PADI2 in tumor-bearing mice eliminates reactivity to PC-1 and cytotoxic killing by the CAR. Our results implicate a therapeutic potential for tumor-infiltrating plasma cells that may be harnessed for cancer treatment.

分类与指标

研究类型: 基础研究
病种: 肺癌
JCR 分区: Q1
影响因子: 56.1
新锐分区: 1区