Pericyte phenotype switching alleviates immunosuppression and sensitizes vascularized tumors to immunotherapy in preclinical models.

IF 13.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Journal of Clinical Investigation Pub Date : 2024-09-17 DOI:10.1172/JCI179860
Zhi-Jie Li, Bo He, Alice Domenichini, Jiulia Satiaputra, Kira H Wood, Devina D Lakhiani, Abate A Bashaw, Lisa M Nilsson, Ji Li, Edward R Bastow, Anna Johansson-Percival, Elena Denisenko, Alistair Rr Forrest, Suraj Sakaram, Rafael Carretero, Günter J Hämmerling, Jonas A Nilsson, Gabriel Yf Lee, Ruth Ganss
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Abstract

T cell-based immunotherapies are a promising therapeutic approach for multiple malignancies, but their efficacy is limited by tumor hypoxia arising from dysfunctional blood vessels. Here, we report that cell-intrinsic properties of a single vascular component, namely the pericyte, contribute to the control of tumor oxygenation, macrophage polarization, vessel inflammation, and T cell infiltration. Switching pericyte phenotype from a synthetic to a differentiated state reverses immune suppression and sensitizes tumors to adoptive T cell therapy, leading to regression of melanoma in mice. In melanoma patients, improved survival is correlated with enhanced pericyte maturity. Importantly, pericyte plasticity is regulated by signaling pathways converging on Rho kinase activity, with pericyte maturity being inducible by selective low-dose therapeutics that suppress pericyte MEK, AKT, or notch signaling. We also show that low-dose targeted anticancer therapy can durably change the tumor microenvironment without inducing adaptive resistance, creating a highly translatable pathway for redosing anticancer targeted therapies in combination with immunotherapy to improve outcome.

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在临床前模型中,周细胞表型转换可减轻免疫抑制,并使血管化肿瘤对免疫疗法敏感。
以 T 细胞为基础的免疫疗法是治疗多种恶性肿瘤的一种很有前景的方法,但其疗效因血管功能失调导致的肿瘤缺氧而受到限制。在这里,我们报告了单个血管成分(即包膜细胞)的细胞内在特性有助于控制肿瘤氧合、巨噬细胞极化、血管炎症和 T 细胞浸润。将包膜表型从合成状态转换为分化状态可逆转免疫抑制,并使肿瘤对采纳性 T 细胞疗法敏感,从而导致小鼠黑色素瘤消退。在黑色素瘤患者中,生存率的提高与周细胞成熟度的提高相关。重要的是,周细胞的可塑性受汇聚于Rho激酶活性的信号通路调控,抑制周细胞MEK、AKT或notch信号传导的选择性低剂量疗法可诱导周细胞成熟。我们还表明,低剂量靶向抗癌疗法可以持久改变肿瘤微环境,而不会诱发适应性抗药性,这为结合免疫疗法重新使用抗癌靶向疗法以改善疗效创造了一个高度可转化的途径。
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来源期刊
Journal of Clinical Investigation
Journal of Clinical Investigation 医学-医学:研究与实验
CiteScore
24.50
自引率
1.30%
发文量
1034
审稿时长
2 months
期刊介绍: The Journal of Clinical Investigation, established in 1924 by the ASCI, is a prestigious publication that focuses on breakthroughs in basic and clinical biomedical science, with the goal of advancing the field of medicine. With an impressive Impact Factor of 15.9 in 2022, it is recognized as one of the leading journals in the "Medicine, Research & Experimental" category of the Web of Science. The journal attracts a diverse readership from various medical disciplines and sectors. It publishes a wide range of research articles encompassing all biomedical specialties, including Autoimmunity, Gastroenterology, Immunology, Metabolism, Nephrology, Neuroscience, Oncology, Pulmonology, Vascular Biology, and many others. The Editorial Board consists of esteemed academic editors who possess extensive expertise in their respective fields. They are actively involved in research, ensuring the journal's high standards of publication and scientific rigor.
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