Targeting heterogeneous tumor microenvironments in pancreatic cancer mouse models of metastasis by TGF-β depletion.

IF 6.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL JCI insight Pub Date : 2024-11-08 DOI:10.1172/jci.insight.182766
Sophia Y Chen, Heng-Chung Kung, Birginia Espinoza, India Washington, Kai Chen, Jianxin Wang, Haley Zlomke, Michael Loycano, Rulin Wang, Michael Pickup, William R Burns, Juan Fu, William L Hwang, Lei Zheng
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Abstract

The dual tumor-suppressive and -promoting functions of TGF-β signaling has made its targeting challenging. We examined the effects of TGF-β depletion by AVID200/BMS-986416 (TGF-β-TRAP), a TGF-β ligand trap, on the tumor microenvironment of pancreatic ductal adenocarcinoma (PDAC) murine models with different organ-specific metastasis. Our study demonstrated that TGF-β-TRAP potentiates the efficacy of anti-programmed cell death 1 (anti-PD-1) in a PDAC orthotopic murine model with liver metastasis tropism, significantly reducing liver metastases. We further demonstrated the heterogeneous response of cytotoxic effector T cells to combination TGF-β-TRAP and anti-PD-1 treatment across several tumor models. Single-nuclear RNA sequencing suggested that TGF-β-TRAP modulates cancer-associated fibroblast (CAF) heterogeneity and suppresses neutrophil degranulation and CD4+ T cell response to neutrophil degranulation. Ligand-receptor analysis indicated that TGF-β-TRAP may modulate the CCL5/CCR5 axis as well as costimulatory and checkpoint signaling from CAFs and myeloid cells. Notably, the most highly expressed ligands of CCR5 shifted from the immunosuppressive CCL5 to CCL7 and CCL8, which may mediate the immune agonist activity of CCR5 following TGF-β-TRAP and anti-PD-1 combination treatment. This study suggested that TGF-β depletion modulates CAF heterogeneity and potentially reprograms CAFs and myeloid cells into antitumor immune agonists in PDAC, supporting the validation of such effects in human specimens.

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通过消耗 TGFβ 靶向胰腺癌小鼠转移模型中的异质性肿瘤微环境
TGFβ 信号具有抑制肿瘤和促进肿瘤生长的双重功能,因此其靶向治疗具有挑战性。我们在此研究了通过TGFβ配体捕获剂AVID200/BMS-986416(TGFβ-TRAP)消耗TGFβ对不同器官特异性转移的胰腺导管腺癌(PDAC)鼠模型肿瘤微环境的影响。我们的研究表明,TGFβ-TRAP 在具有肝转移倾向的 PDAC 正位小鼠模型中增强了抗 PD-1 的疗效,显著减少了肝转移。我们进一步证明了细胞毒性效应 T 细胞在多个肿瘤模型中对 TGFβ-TRAP 和抗 PD-1 联合治疗的异质性反应。单核 RNA 序列分析表明,TGFβ-TRAP 可调节癌症相关成纤维细胞(CAF)的异质性,抑制中性粒细胞脱颗粒和 CD4+ T 细胞对中性粒细胞脱颗粒的反应。配体-受体分析表明,TGFβ-TRAP可调节CCL5-CCR5轴以及CAFs和髓系细胞的共刺激和检查点信号。值得注意的是,在TGFβ-TRAP和抗PD-1联合治疗后,CCR5的高表达配体从免疫抑制性的CCL5转变为CCL7和CCL8,这可能介导了CCR5的免疫激动活性。这项研究表明,TGFβ消耗可调节CAF的异质性,并有可能将PDAC中的CAFs和骨髓细胞重编程为抗肿瘤免疫激动剂,支持在人体标本中验证这种效应。
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来源期刊
JCI insight
JCI insight Medicine-General Medicine
CiteScore
13.70
自引率
1.20%
发文量
543
审稿时长
6 weeks
期刊介绍: JCI Insight is a Gold Open Access journal with a 2022 Impact Factor of 8.0. It publishes high-quality studies in various biomedical specialties, such as autoimmunity, gastroenterology, immunology, metabolism, nephrology, neuroscience, oncology, pulmonology, and vascular biology. The journal focuses on clinically relevant basic and translational research that contributes to the understanding of disease biology and treatment. JCI Insight is self-published by the American Society for Clinical Investigation (ASCI), a nonprofit honor organization of physician-scientists founded in 1908, and it helps fulfill the ASCI's mission to advance medical science through the publication of clinically relevant research reports.
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