Targeting a cell surface vitamin D receptor on tumor-associated macrophages in triple-negative breast cancer.
Targeting a cell surface vitamin D receptor on tumor-associated macrophages in triple-negative breast cancer.
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DOI：
10.7554/elife.65145
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发表时间：
2021-06-01
期刊：
影响因子：
7.7
通讯作者：
Pasqualini R
中科院分区：
文献类型：
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作者：
Staquicini FI;Hajitou A;Driessen WH;Proneth B;Cardó-Vila M;Staquicini DI;Markosian C;Hoh M;Cortez M;Hooda-Nehra A;Jaloudi M;Silva IT;Buttura J;Nunes DN;Dias-Neto E;Eckhardt B;Ruiz-Ramírez J;Dogra P;Wang Z;Cristini V;Trepel M;Anderson R;Sidman RL;Gelovani JG;Cristofanilli M;Hortobagyi GN;Bhujwalla ZM;Burley SK;Arap W;Pasqualini R
三阴性乳腺癌（TNBC）是一种侵袭性肿瘤，治疗选择有限，预后差。我们应用体内噬菌体展示技术分离到TNBC免疫抑制细胞微环境的肽，作为发现非恶性靶点的策略。我们发现了一种环肽（CSSTRESAC），它可以特异性结合肿瘤相关巨噬细胞（TAM）细胞表面表达的维生素D受体、蛋白二硫异构酶A3 (PDIA3)，并在同源TNBC、非TNBC异种移植和转基因小鼠模型中靶向乳腺癌。对携带tnbc的小鼠全身给予CSSTRESAC，使细胞因子谱转向抗肿瘤免疫反应，并延缓肿瘤生长。此外，CSSTRESAC使配体定向治疗传递到肿瘤和数学模型证实了我们的实验结果。最后，计算机分析显示TNBC患者中表达pdia3的TAM。这项工作揭示了TAM细胞表面维生素D受体与抗肿瘤免疫反应之间的功能相互作用，可以用于治疗。
Triple-negative breast cancer (TNBC) is an aggressive tumor with limited treatment options and poor prognosis. We applied the in vivo phage display technology to isolate peptides homing to the immunosuppressive cellular microenvironment of TNBC as a strategy for non-malignant target discovery. We identified a cyclic peptide (CSSTRESAC) that specifically binds to a vitamin D receptor, protein disulfide-isomerase A3 (PDIA3) expressed on the cell surface of tumor-associated macrophages (TAM), and targets breast cancer in syngeneic TNBC, non-TNBC xenograft, and transgenic mouse models. Systemic administration of CSSTRESAC to TNBC-bearing mice shifted the cytokine profile toward an antitumor immune response and delayed tumor growth. Moreover, CSSTRESAC enabled ligand-directed theranostic delivery to tumors and a mathematical model confirmed our experimental findings. Finally, in silico analysis showed PDIA3-expressing TAM in TNBC patients. This work uncovers a functional interplay between a cell surface vitamin D receptor in TAM and antitumor immune response that could be therapeutically exploited.