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<p>Immunologically unresponsive tumours often resist immune checkpoint inhibitors due to the low abundance of tumour-specific T cells and an immunosuppressive microenvironment, despite pronounced infiltration of non-tumour-specific (bystander) T cells. Here we analysed single-cell RNA sequencing data from 300 patients across 17 tumour types, identifying abundant but functionally restrained bystander T cells in multiple malignancies, including ovarian and colorectal cancer. To enhance antitumour immunity in such contexts, we engineered B7H3xCD3xPDL1, a trispecific immunoglobulin-based T cell engager targeting B7H3, CD3 and PDL1, to redirect T cells while mitigating immunosuppression. Functional validation in co-culture systems, patient-derived tumour suspensions and fragments, and humanized mouse models showed T cell activation and tumour killing. Imaging cytometry and single-cell transcriptomics revealed IFNγ-dependent macrophage reprogramming and IL-15 secretion, establishing a feed-forward loop that augments T cell functionality. A machine learning model trained on ex vivo cytotoxicity and transcriptomic data predicted patient responsiveness, supporting data-driven clinical stratification for solid tumour immunotherapy.</p>

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A trispecific antibody engaging T cells with tumour and myeloid cells augments antitumour immunity

  • 期刊论文

  • 发表日期：

    2025年12月10日

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  • Changrui Yang,
  • Shanni Guo,
  • Kaiyan Ye,
  • Yizong Ding,
  • Xingzhong Zhao,
  • Yucheng T. Yang,
  • Bowen Sun,
  • Shuyi Qian,
  • Mei-Chun Cai,
  • Luyan Liu,
  • Libing Xiang,
  • Xia Yin,
  • Xing-Ming Zhao,
  • Jieyi Wang,
  • Jiwei Zhang,
  • Wen Di,
  • Guanglei Zhuang,
  • Fan Yang

摘要

Immunologically unresponsive tumours often resist immune checkpoint inhibitors due to the low abundance of tumour-specific T cells and an immunosuppressive microenvironment, despite pronounced infiltration of non-tumour-specific (bystander) T cells. Here we analysed single-cell RNA sequencing data from 300 patients across 17 tumour types, identifying abundant but functionally restrained bystander T cells in multiple malignancies, including ovarian and colorectal cancer. To enhance antitumour immunity in such contexts, we engineered B7H3xCD3xPDL1, a trispecific immunoglobulin-based T cell engager targeting B7H3, CD3 and PDL1, to redirect T cells while mitigating immunosuppression. Functional validation in co-culture systems, patient-derived tumour suspensions and fragments, and humanized mouse models showed T cell activation and tumour killing. Imaging cytometry and single-cell transcriptomics revealed IFNγ-dependent macrophage reprogramming and IL-15 secretion, establishing a feed-forward loop that augments T cell functionality. A machine learning model trained on ex vivo cytotoxicity and transcriptomic data predicted patient responsiveness, supporting data-driven clinical stratification for solid tumour immunotherapy.