The antitumoral activity of TLR7 ligands is corrupted by the microenvironment of pancreatic tumors

被引:5
作者
Rouanet, Marie [1 ,2 ,3 ]
Hanoun, Naima [1 ]
Lulka, Hubert [1 ]
Ferreira, Cindy [1 ]
Garcin, Pierre [1 ]
Sramek, Martin [1 ]
Jacquemin, Godefroy [5 ]
Coste, Agnes [5 ]
Pagan, Delphine [1 ]
Valle, Carine [4 ]
Sarot, Emeline [4 ]
Pancaldi, Vera [1 ]
Lopez, Frederic [4 ]
Buscail, Louis [1 ,2 ,3 ]
Cordelier, Pierre [1 ]
机构
[1] Univ Toulouse, Univ Paul Sabatier, Ctr Rech Cancerol Toulouse, CNRS,INSERM, Toulouse, France
[2] Dept Gastroenterol, Toulouse, France
[3] Univ Toulouse III, Rangueil Hosp, Toulouse, France
[4] Univ Toulouse, Ctr Rech Cancerol Toulouse, CNRS, INSERM,Technol Duster, Toulouse, France
[5] Univ Paul Sabatier, Univ Toulouse, CNRS, INSERM,Inst RESTORE, Toulouse, France
关键词
TOLL-LIKE RECEPTORS; ACTIVATION; PROLIFERATION; MACROPHAGE; AGONISTS; CELLS;
D O I
10.1016/j.ymthe.2022.01.018
中图分类号
Q81 [生物工程学(生物技术)]; Q93 [微生物学];
学科分类号
071005 ; 0836 ; 090102 ; 100705 ;
摘要
Toll-like receptors (TLRs) are key players in the innate immune system. Recent studies have suggested that they may affect the growth of pancreatic cancer, a disease with no cure. Among them, TLR7 shows promise for therapy but may also promotes tumor growth. Thus, we aimed to clarify the therapeutic potential of TLR7 ligands in experimental pancreatic cancer models, to open the door for clinical applications. In vitro, we found that TLR7 ligands strongly inhibit the proliferation of both human and murine pancreatic cancer cells, compared with TLR2 agonists. Hence, TLR7 treatment alters cancer cells' cell cycle and induces cell death by apoptosis. In vivo, TLR7 agonist therapy significantly delays the growth of murine pancreatic tumors engrafted in immunodeficient mice. Remarkably, TLR7 ligands administration instead increases tumor growth and accelerates animal death when tumors are engrafted in immuno-competent models. Further investigations revealed that TLR7 agonists modulate the intratumoral content and phenotype of macrophages and that depleting such tumor-associated macrophages strongly hampers TLR7 agonist-induced tumor growth. Collectively, our findings shine a light on the duality of action of TLR7 agonists in experimental cancer models and call into question their use for pancreatic cancer therapy.
引用
收藏
页码:1553 / 1563
页数:11
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