Vaccines targeting tumor blood vessel antigens promote CD8(+) T cell-dependent tumor eradication or dormancy in HLA-A2 transgenic mice.
Vaccines targeting tumor blood vessel antigens promote CD8(+) T cell-dependent tumor eradication or dormancy in HLA-A2 transgenic mice.
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DOI：
10.4049/jimmunol.1101644
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发表时间：
2012-02-15
期刊：
影响因子：
--
通讯作者：
Storkus WJ
中科院分区：
文献类型：
--
作者：
Zhao X;Bose A;Komita H;Taylor JL;Chi N;Lowe DB;Okada H;Cao Y;Mukhopadhyay D;Cohen PA;Storkus WJ
我们最近已经表明，在缺乏鼠MHC I类分子表达的HLA-A2 Tg（HHD）小鼠中实体瘤的有效细胞因子基因疗法导致产生HLA-A2限制性CD 8 + T效应细胞，其选择性地识别肿瘤血管相关周细胞和/或血管内皮细胞（VEC）。使用HHD模型，其中HLA-A2阴性肿瘤（MC 38结肠癌或B16黑色素瘤）细胞不被CD 8 + T细胞库识别，我们现在表明，基于肿瘤相关血管抗原（TBVA）的疫苗引起保护性Tc 1依赖性免疫，能够介导肿瘤消退或延长总生存期。如果将（HLA-A2阴性）野生型C57 BL/6小鼠用作受体动物，则未观察到疫苗效力。在HHD模型中，有效的疫苗接种导致CD 8+（而不是CD 4+）T细胞对肿瘤病变的深度浸润，导致肿瘤微环境（TME）中CD 31+血管的协调减少，并导致CD 8 + T细胞对替代TBVA的反应“扩散”，而这些反应不是疫苗固有的。保护性Tc 1介导的免疫是持久的，直接识别周细胞和/或VEC流分选肿瘤组织，但不是从肿瘤无关的正常肾脏收获这些相同的动物。引人注目的是，在有效治疗后的晚期时间点，CD 8 + T细胞而不是CD 4 + T细胞的耗竭经常导致消退的原发性病变部位的疾病复发。这表明疫苗诱导的抗TBVA T细胞库可以介导临床上优选的结果，即有效地根除肿瘤或维持（隐匿的）肿瘤休眠状态。
We have recently shown that effective cytokine gene therapy of solid tumors in HLA-A2 Tg (HHD) mice lacking murine MHC class I molecule expression results in the generation of HLA-A2-restricted CD8+ T effector cells selectively recognizing tumor blood vessel-associated pericytes and/or vascular endothelial cells (VEC). Using an HHD model in which HLA-A2neg tumor (MC38 colon carcinoma or B16 melanoma) cells are not recognized by the CD8+ T cell repertoire, we now show that vaccines based on tumor-associated blood vessel antigens (TBVA) elicit protective Tc1-dependent immunity capable of mediating tumor regression or extending overall survival. Vaccine efficacy was not observed if (HLA-A2neg) wild-type C57BL/6 mice were instead used as recipient animals. In the HHD model, effective vaccination resulted in profound infiltration of tumor lesions by CD8+ (but not CD4+) T cells, in a coordinate reduction of CD31+ blood vessels in the tumor microenvironment (TME) and in the “spreading” of CD8+ T cell responses to alternate TBVA that were not intrinsic to the vaccine. Protective Tc1-mediated immunity was durable and directly recognized pericytes and/or VEC flow-sorted from tumor tissue, but not from tumor-uninvolved normal kidneys harvested from these same animals. Strikingly, the depletion of CD8+, but not CD4+, T cells at late time points after effective therapy frequently resulted in the recurrence of disease at the site of the regressed primary lesion. This suggests that the vaccine-induced anti-TBVA T cell repertoire can mediate the clinically-preferred outcomes of either effectively eradicating tumors or policing a state of (occult) tumor dormancy.
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DOI：
10.1084/jem.20091846
发表时间：
2010-03-15
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Helfrich I;Scheffrahn I;Bartling S;Weis J;von Felbert V;Middleton M;Kato M;Ergün S;Augustin HG;Schadendorf D
通讯作者：
Schadendorf D
影响因子：
11.2
作者：
Brown CE;Starr R;Martinez C;Aguilar B;D'Apuzzo M;Todorov I;Shih CC;Badie B;Hudecek M;Riddell SR;Jensen MC
通讯作者：
Jensen MC
影响因子：
11.2
作者：
Maciag, Paulo Cesar;Seavey, Matthew M.;Paterson, Yvonne
通讯作者：
Paterson, Yvonne
影响因子：
3.9
作者：
Dong, YJ;Qian, JH;Khleif, SN
通讯作者：
Khleif, SN
影响因子：
4.4
作者：
Firat, H;Cochet, M;Langlade-Demoyen, P
通讯作者：
Langlade-Demoyen, P