An oncolytic virus delivering tumor-irrelevant bystander T cell epitopes induces anti-tumor immunity and potentiates cancer immunotherapy

IF 23.5 1区 医学 Q1 ONCOLOGY Nature cancer Pub Date : 2024-04-12 DOI:10.1038/s43018-024-00760-x
Xiangyu Chen, Jing Zhao, Shuai Yue, Ziyu Li, Xiang Duan, Yao Lin, Yang Yang, Junjian He, Leiqiong Gao, Zhiwei Pan, Xiaofan Yang, Xingxing Su, Min Huang, Xiao Li, Ye Zhao, Xuehui Zhang, Zhirong Li, Li Hu, Jianfang Tang, Yaxing Hao, Qin Tian, Yifei Wang, Lifan Xu, Qizhao Huang, Yingjiao Cao, Yaokai Chen, Bo Zhu, Yan Li, Fan Bai, Guozhong Zhang, Lilin Ye
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Abstract

Tumor-specific T cells are crucial in anti-tumor immunity and act as targets for cancer immunotherapies. However, these cells are numerically scarce and functionally exhausted in the tumor microenvironment (TME), leading to inefficacious immunotherapies in most patients with cancer. By contrast, emerging evidence suggested that tumor-irrelevant bystander T (TBYS) cells are abundant and preserve functional memory properties in the TME. To leverage TBYS cells in the TME to eliminate tumor cells, we engineered oncolytic virus (OV) encoding TBYS epitopes (OV-BYTE) to redirect the antigen specificity of tumor cells to pre-existing TBYS cells, leading to effective tumor inhibition in multiple preclinical models. Mechanistically, OV-BYTE induced epitope spreading of tumor antigens to elicit more diverse tumor-specific T cell responses. Remarkably, the OV-BYTE strategy targeting human severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific T cell memory efficiently inhibited tumor progression in a human tumor cell-derived xenograft model, providing important insights into the improvement of cancer immunotherapies in a large population with a history of SARS-CoV-2 infection or coronavirus disease 2019 (COVID-19) vaccination. Ye and colleagues show that an oncolytic virus that delivers tumor-irrelevant bystander T cell epitopes to tumor cells can exploit the abundant population of bystander T cells in the tumor for anti-tumor immunity and potentiate cancer immunotherapy.

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提供与肿瘤无关的旁观者 T 细胞表位的溶瘤病毒可诱导抗肿瘤免疫并增强癌症免疫疗法的效果
肿瘤特异性 T 细胞是抗肿瘤免疫的关键,也是癌症免疫疗法的靶点。然而,这些细胞在肿瘤微环境(TME)中数量稀少、功能衰竭,导致大多数癌症患者的免疫疗法效果不佳。相比之下,新出现的证据表明,与肿瘤无关的旁观者 T 细胞(TBYS)数量丰富,并在肿瘤微环境中保留了功能记忆特性。为了利用TME中的TBYS细胞消灭肿瘤细胞,我们设计了编码TBYS表位的溶瘤病毒(OV)(OV-BYTE),将肿瘤细胞的抗原特异性重定向到预先存在的TBYS细胞,从而在多个临床前模型中有效抑制肿瘤。从机理上讲,OV-BYTE 可诱导肿瘤抗原表位扩散,从而激发更多样化的肿瘤特异性 T 细胞反应。值得注意的是,以人类严重急性呼吸系统综合征冠状病毒2(SARS-CoV-2)特异性T细胞记忆为靶点的OV-BYTE策略有效抑制了人类肿瘤细胞衍生异种移植模型中的肿瘤进展,为改善大量有SARS-CoV-2感染史或冠状病毒病2019(COVID-19)疫苗接种史的人群的癌症免疫疗法提供了重要启示。
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来源期刊
Nature cancer
Nature cancer Medicine-Oncology
CiteScore
31.10
自引率
1.80%
发文量
129
期刊介绍: Cancer is a devastating disease responsible for millions of deaths worldwide. However, many of these deaths could be prevented with improved prevention and treatment strategies. To achieve this, it is crucial to focus on accurate diagnosis, effective treatment methods, and understanding the socioeconomic factors that influence cancer rates. Nature Cancer aims to serve as a unique platform for sharing the latest advancements in cancer research across various scientific fields, encompassing life sciences, physical sciences, applied sciences, and social sciences. The journal is particularly interested in fundamental research that enhances our understanding of tumor development and progression, as well as research that translates this knowledge into clinical applications through innovative diagnostic and therapeutic approaches. Additionally, Nature Cancer welcomes clinical studies that inform cancer diagnosis, treatment, and prevention, along with contributions exploring the societal impact of cancer on a global scale. In addition to publishing original research, Nature Cancer will feature Comments, Reviews, News & Views, Features, and Correspondence that hold significant value for the diverse field of cancer research.
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