Cancer Immunotherapy with Immunomodulatory Anti-CD137 and Anti-PD-1 Monoclonal Antibodies Requires BATF3-Dependent Dendritic Cells.
Cancer Immunotherapy with Immunomodulatory Anti-CD137 and Anti-PD-1 Monoclonal Antibodies Requires BATF3-Dependent Dendritic Cells.
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DOI：
10.1158/2159-8290.cd-15-0510
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发表时间：
2016-01
期刊：
影响因子：
28.2
通讯作者：
Melero I
中科院分区：
文献类型：
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作者：
Sánchez-Paulete AR;Cueto FJ;Martínez-López M;Labiano S;Morales-Kastresana A;Rodríguez-Ruiz ME;Jure-Kunkel M;Azpilikueta A;Aznar MA;Quetglas JI;Sancho D;Melero I
针对PD-1或CD137的免疫调节性单抗可以挽救微弱和无效的抗肿瘤细胞毒性T淋巴细胞(CTL)反应。利用BATF3-/-小鼠，我们发现BATF3依赖的树突状细胞(DC)在抗CD137或抗PD-1单抗治疗的反应中是必不可少的。BATF3-/-小鼠未能启动内源性CTL介导的针对肿瘤相关抗原的免疫反应，包括新抗原。因此，免疫调节型单抗不能在这些小鼠中放大任何治疗功能的免疫反应。此外，全身sFlt3L和局部PolyICLC的应用增强了DC介导的交叉启动，并与抗CD137和抗PD-1介导的免疫刺激协同治疗B16-OVA来源的黑色素瘤，而这一功能在BATF3-/-小鼠中缺失。这些实验表明，依赖Flt3L和BATF3的DC对肿瘤抗原的交叉激发对免疫刺激单抗的疗效至关重要，是提高其临床抗肿瘤效果的一个非常有吸引力的干预点。
Weak and ineffective antitumor cytotoxic T lymphocyte (CTL) responses can be rescued by immunomodulatory monoclonal antibodies (mAbs) targeting PD-1 or CD137. Using Batf3-/- mice, which are defective for cross-presentation of cell-associated antigens, we show that Batf3-dependent dendritic cells (DCs) are essential for the response to therapy with anti-CD137 or anti-PD-1 mAbs. Batf3-/- mice failed to prime an endogenous CTL-mediated immune response toward tumor-associated antigens, including neoantigens. As a result, the immunomodulatory mAbs could not amplify any therapeutically functional immune response in these mice. Moreover, administration of systemic sFlt3L and local poly-ICLC enhanced DC-mediated cross-priming and synergized with anti-CD137- and anti-PD-1-mediated immunostimulation in tumor therapy against B16-OVA-derived melanomas, whereas this function was lost in Batf3-/- mice. These experiments show that cross-priming of tumor antigens by Flt3L- and Batf3-dependent DCs is crucial to the efficacy of immunostimulatory mAbs and represents a very attractive point of intervention to enhance their clinical antitumor effects.