Intratumoral IL-12 gene therapy results in the crosspriming of Tc1 cells reactive against tumor-associated stromal antigens.
Intratumoral IL-12 gene therapy results in the crosspriming of Tc1 cells reactive against tumor-associated stromal antigens.
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DOI：
10.1038/mt.2010.295
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发表时间：
2011-04
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通讯作者：
Xi Zhao;A. Bose;H. Komita;Jennifer L. Taylor;M. Kawabe;Nina Chi;Laima Spokas;D. Lowe;C. Goldbach;S. Alber;Simon C Watkins;L. Butterfield;P. Kalinski;J. Kirkwood;W. Storkus
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作者：
Xi Zhao;A. Bose;H. Komita;Jennifer L. Taylor;M. Kawabe;Nina Chi;Laima Spokas;D. Lowe;C. Goldbach;S. Alber;Simon C Watkins;L. Butterfield;P. Kalinski;J. Kirkwood;W. Storkus
通过瘤内（i.t.）注射经转导以表达高水平白细胞介素（IL）-12的同基因树突状细胞（DC），导致CD 8 +T细胞依赖性抗肿瘤保护。在该模型中，HLA-A2限制性CD 8 +T细胞不直接识别肿瘤细胞，并且治疗益处与对基质细胞表达的抗原具有反应性的HLA-A2限制性1型CD 8 +T细胞的交叉免疫相关[即，周细胞和血管内皮细胞（VEC）]。IL-12基因治疗诱导的CD 8 +T细胞直接识别来自B16肿瘤病灶的HLA-A2+周细胞和VEC流式分选，基于干扰素（IFN）-γ分泌和与这些靶细胞共培养后溶解颗粒相关分子CD 107移位至T细胞表面。相比之下，这些CD 8 +T效应细胞未能识别从荷瘤HHD小鼠的肾脏分离的周细胞/VEC。研究的肿瘤相关基质抗原（TASA）衍生肽在进化上是保守的，并且可以被从HLA-A2+正常供体或黑色素瘤患者的血液中收获的CD 8 +T细胞体外刺激后识别。这些TASA和它们的衍生肽可以证明在针对实体癌的疫苗制剂中以及在接受治疗性干预如IL-12基因治疗的HLA-A2+癌症患者的免疫监测中是有用的。
HLA-A2 transgenic mice bearing established HLA-A2negB16 melanomas were effectively treated by intratumoral (i.t.) injection of syngeneic dendritic cells (DCs) transduced to express high levels of interleukin (IL)-12, resulting in CD8+T cell-dependent antitumor protection. In this model, HLA-A2-restricted CD8+T cells do not directly recognize tumor cells and therapeutic benefit was associated with the crosspriming of HLA-A2-restricted type-1 CD8+T cells reactive against antigens expressed by stromal cells [i.e., pericytes and vascular endothelial cells (VEC)]. IL-12 gene therapy-induced CD8+T cells directly recognized HLA-A2+pericytes and VEC flow-sorted from B16 tumor lesions based on interferon (IFN)-γ secretion and translocation of the lytic granule-associated molecule CD107 to the T cell surface after coculture with these target cells. In contrast, these CD8+T effector cells failed to recognize pericytes/VEC isolated from the kidneys of tumor-bearing HHD mice. The tumor-associated stromal antigen (TASA)-derived peptides studied are evolutionarily conserved and could be recognized by CD8+T cells harvested from the blood of HLA-A2+normal donors or melanoma patients afterin vitrostimulation. These TASA and their derivative peptides may prove useful in vaccine formulations against solid cancers, as well as, in the immune monitoring of HLA-A2+cancer patients receiving therapeutic interventions, such as IL-12 gene therapy.