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癌症相关的间充质干细胞驱动肿瘤免疫排斥和对免疫疗法的抗性，而这可以通过抑制刺猬信号通路来克服。

Cancer-associated MSC drive tumor immune exclusion and resistance to immunotherapy, which can be overcome by Hedgehog inhibition.

作者信息

Cascio Sandra, Chandler Chelsea, Zhang Linan, Sinno Sarah, Gao Bingsi, Onkar Sayali, Bruno Tullia C, Vignali Dario A A, Mahdi Haider, Osmanbeyoglu Hatice U, Vlad Anda M, Coffman Lan G, Buckanovich Ronald J

机构信息

Magee-Womens Research Institute, Pittsburgh, PA 15213, USA.

Division of Gynecologic Oncology, Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Pittsburgh, Pittsburgh, PA 15213, USA.

出版信息

Sci Adv. 2021 Nov 12;7(46):eabi5790. doi: 10.1126/sciadv.abi5790.

DOI:10.1126/sciadv.abi5790
PMID:34767446
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8589308/
Abstract

We investigated the impact of cancer-associated mesenchymal stem cells (CA-MSCs) on ovarian tumor immunity. In patient samples, CA-MSC presence inversely correlates with the presence of intratumoral CD8 T cells. Using an immune “hot” mouse ovarian cancer model, we found that CA-MSCs drive CD8 T cell tumor immune exclusion and reduce response to anti–PD-L1 immune checkpoint inhibitor (ICI) via secretion of numerous chemokines (Ccl2, Cx3cl1, and Tgf-β1), which recruit immune-suppressive CD14Ly6CCx3cr1 monocytic cells and polarize macrophages to an immune suppressive Ccr2F4/80Cx3cr1CD206 phenotype. Both monocytes and macrophages express high levels of transforming growth factor β–induced (Tgfbi) protein, which suppresses NK cell activity. Hedgehog inhibitor (HHi) therapy reversed CA-MSC effects, reducing myeloid cell presence and expression of Tgfbi, increasing intratumoral NK cell numbers, and restoring response to ICI therapy. Thus, CA-MSCs regulate antitumor immunity, and CA-MSC hedgehog signaling is an important target for cancer immunotherapy.

摘要

我们研究了癌症相关间充质干细胞（CA-MSCs）对卵巢肿瘤免疫的影响。在患者样本中，CA-MSCs的存在与肿瘤内CD8 T细胞的存在呈负相关。使用免疫“热”小鼠卵巢癌模型，我们发现CA-MSCs通过分泌多种趋化因子（Ccl2、Cx3cl1和Tgf-β1）驱动CD8 T细胞肿瘤免疫排斥并降低对抗PD-L1免疫检查点抑制剂（ICI）的反应，这些趋化因子招募免疫抑制性CD14Ly6CCx3cr1单核细胞并将巨噬细胞极化为免疫抑制性Ccr2F4/80Cx3cr1CD206表型。单核细胞和巨噬细胞均表达高水平的转化生长因子β诱导（Tgfbi）蛋白，该蛋白可抑制NK细胞活性。刺猬因子抑制剂（HHi）疗法逆转了CA-MSCs的作用，减少了髓样细胞的存在和Tgfbi的表达，增加了肿瘤内NK细胞数量，并恢复了对ICI疗法的反应。因此，CA-MSCs调节抗肿瘤免疫，并且CA-MSCs刺猬因子信号传导是癌症免疫治疗的重要靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ee53/8589308/961bdf0a8e23/sciadv.abi5790-f7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ee53/8589308/43de009a6a90/sciadv.abi5790-f1.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ee53/8589308/a05697967400/sciadv.abi5790-f4.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ee53/8589308/961bdf0a8e23/sciadv.abi5790-f7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ee53/8589308/43de009a6a90/sciadv.abi5790-f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ee53/8589308/015f295a4159/sciadv.abi5790-f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ee53/8589308/2047ec0c4063/sciadv.abi5790-f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ee53/8589308/a05697967400/sciadv.abi5790-f4.jpg
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