TNFR1 signaling promotes pancreatic tumor growth by limiting dendritic cell number and function.

IF 11.7 1区 医学 Q1 CELL BIOLOGY
Cell Reports Medicine Pub Date : 2024-09-17 Epub Date: 2024-08-22 DOI:10.1016/j.xcrm.2024.101696
Muhammad S Alam, Matthias M Gaida, Hagen R Witzel, Shizuka Otsuka, Aamna Abbasi, Theresa Guerin, Abdalla Abdelmaksoud, Nathan Wong, Margaret C Cam, Serguei Kozlov, Jonathan D Ashwell
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引用次数: 0

Abstract

Pancreatic adenocarcinoma (PDAC) is one the most intractable cancers, in part due to its highly inflammatory microenvironment and paucity of infiltrating dendritic cells (DCs). Here, we find that genetic ablation or antibody blockade of tumor necrosis factor receptor 1 (TNFR1) enhanced intratumor T cell activation and slowed PDAC growth. While anti-PD-1 checkpoint inhibition alone had little effect, it further enhanced intratumor T cell activation in combination with anti-TNFR1. The major cellular alteration in the tumor microenvironment in the absence of TNFR1 signaling was a large increase in DC number and immunostimulatory phenotype. This may reflect a direct effect on DCs, because TNF induced TNFR1-dependent apoptosis of bone-marrow-derived DCs. The therapeutic response to anti-TNFR1 alone was superior to the combination of DC-activating agonistic anti-CD40 and Flt3 ligand (Flt3L). These observations suggest that targeting TNFR1, perhaps in concert with other strategies that promote DC generation and mobilization, may have therapeutic benefits.

Abstract Image

TNFR1 信号通过限制树突状细胞的数量和功能促进胰腺肿瘤的生长。
胰腺腺癌(PDAC)是最难治的癌症之一,部分原因是其高度炎症的微环境和浸润性树突状细胞(DC)的缺乏。在这里,我们发现肿瘤坏死因子受体1(TNFR1)的基因消融或抗体阻断增强了肿瘤内T细胞的活化并减缓了PDAC的生长。虽然单独使用抗PD-1检查点抑制剂效果甚微,但与抗TNFR1联合使用可进一步增强肿瘤内T细胞的活化。在没有TNFR1信号传导的情况下,肿瘤微环境的主要细胞变化是DC数量和免疫刺激表型的大幅增加。这可能反映了对直流细胞的直接影响,因为 TNF 会诱导依赖 TNFR1 的骨髓源性直流细胞凋亡。单独使用抗 TNFR1 的治疗效果优于联合使用直流激活激动剂抗 CD40 和 Flt3 配体(Flt3L)。这些观察结果表明,以 TNFR1 为靶点,或许与其他促进 DC 生成和动员的策略配合使用,可能会产生治疗效果。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Cell Reports Medicine
Cell Reports Medicine Biochemistry, Genetics and Molecular Biology-Biochemistry, Genetics and Molecular Biology (all)
CiteScore
15.00
自引率
1.40%
发文量
231
审稿时长
40 days
期刊介绍: Cell Reports Medicine is an esteemed open-access journal by Cell Press that publishes groundbreaking research in translational and clinical biomedical sciences, influencing human health and medicine. Our journal ensures wide visibility and accessibility, reaching scientists and clinicians across various medical disciplines. We publish original research that spans from intriguing human biology concepts to all aspects of clinical work. We encourage submissions that introduce innovative ideas, forging new paths in clinical research and practice. We also welcome studies that provide vital information, enhancing our understanding of current standards of care in diagnosis, treatment, and prognosis. This encompasses translational studies, clinical trials (including long-term follow-ups), genomics, biomarker discovery, and technological advancements that contribute to diagnostics, treatment, and healthcare. Additionally, studies based on vertebrate model organisms are within the scope of the journal, as long as they directly relate to human health and disease.
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