Heine Annkristin, Flores Chrystel, Gevensleben Heidrun, Diehl Linda, Heikenwalder Mathias, Ringelhan Marc, Janssen Klaus-Peter, Nitsche Ulrich, Garbi Natalio, Brossart Peter, Knolle Percy A, Kurts Christian, Höchst Bastian
Medical Clinic III for Oncology, Hematology and Rheumatology, University Hospital Bonn, Germany.
Institute of Experimental Immunology, University Bonn, Germany.
Oncoimmunology. 2017 Jun 16;6(8):e1338995. doi: 10.1080/2162402X.2017.1338995. eCollection 2017.
Tumor immune escape is a critical problem which frequently accounts for the failure of therapeutic tumor vaccines. Among the most potent suppressors of tumor immunity are myeloid derived suppressor cells (MDSCs). MDSCs can be targeted by all-trans-retinoic-acid (atRA), which reduced their numbers and increased response rates in several vaccination studies. However, not much is known about the optimal administration interval between atRA and the vaccine as well as about its mode of action. Here we demonstrate in 2 different murine tumor models that mice unresponsive to a therapeutic vaccine harbored higher MDSC numbers than did responders. Application of atRA overcame MDSC-mediated immunosuppression and restored tumor control. Importantly, atRA was protective only when administered 3 d after vaccination (delayed treatment), whereas simultaneous administration even decreased the anti-tumor immune response and reduced survival. When analyzing the underlying mechanisms, we found that delayed, but not simultaneous atRA treatment with vaccination abrogated the suppressive capacity in monocytic MDSCs and instead caused them to upregulate MHC-class-II. Consistently, MDSCs from patients with colorectal carcinoma also failed to upregulate HLA-DR after treatment with TLR-ligation. Overall, we demonstrate that atRA can convert non-responders to responders to vaccination by suppressing MDSCs function and not only by reducing their number. Moreover, we identify a novel, strictly time-dependent mode of action of atRA to be considered during immunotherapeutic protocols in the future.
肿瘤免疫逃逸是一个关键问题，常常导致治疗性肿瘤疫苗失效。骨髓来源的抑制性细胞（MDSCs）是肿瘤免疫最强大的抑制因子之一。全反式维甲酸（atRA）可作用于MDSCs，在多项疫苗接种研究中，它能减少MDSCs数量并提高反应率。然而，关于atRA与疫苗之间的最佳给药间隔及其作用方式，人们了解得并不多。在此，我们在两种不同的小鼠肿瘤模型中证明，对治疗性疫苗无反应的小鼠体内的MDSCs数量高于有反应的小鼠。应用atRA可克服MDSC介导的免疫抑制并恢复对肿瘤的控制。重要的是，atRA仅在接种疫苗后3天给药（延迟治疗）时具有保护作用，而同时给药甚至会降低抗肿瘤免疫反应并缩短生存期。在分析潜在机制时，我们发现，接种疫苗后延迟而非同时给予atRA治疗可消除单核细胞MDSCs的抑制能力，反而使其上调MHC-II类分子。同样，来自结直肠癌患者的MDSCs在用TLR连接处理后也未能上调HLA-DR。总体而言，我们证明atRA不仅可以通过减少MDSCs数量，还可通过抑制其功能，将无反应者转变为对疫苗有反应者。此外，我们确定了一种新的、严格依赖时间的atRA作用方式，供未来免疫治疗方案参考。
