期刊
CANCER DISCOVERY
卷 6, 期 1, 页码 71-79出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/2159-8290.CD-15-0510
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资金
- MICINN [SAF2008-03294, SAF2011-22831]
- Departamento de salud del Gobierno de Navarra, Redes tematicas de investigacion cooperativa RETIC [RD06/0020/0065]
- European commission
- CNIC
- Spanish Ministry of Economy and Competitiveness [SAF-2013-42920R]
- European Research Council (ERC) [ERC-2010-StG 260414]
- Spanish Ministry of Economy and Competitiveness
- Pro-CNIC Foundation
- European Commission [635122-PROCROP H2020]
Weak and ineffective antitumor cytotoxic T lymphocyte (CTL) responses can be rescued by immunomodulatory 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 (DC) 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-ovalbumin-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. SIGNIFICANCE: Immunotherapy with immunostimulatory mAbs is currently achieving durable clinical responses in different types of cancer. We show that cross-priming of tumor antigens by BATF3-dependent DCs is a key limiting factor that can be exploited to enhance the antitumor effi cacy of anti-PD-1 and anti-CD137 immunostimulatory mAbs. (C) 2015 AACR.
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