Combination therapy with HSP90 inhibitor 17-DMAG reconditions the tumor microenvironment to improve recruitment of therapeutic T cells.
Combination therapy with HSP90 inhibitor 17-DMAG reconditions the tumor microenvironment to improve recruitment of therapeutic T cells.
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DOI：
10.1158/0008-5472.can-12-0538
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发表时间：
2012-07-01
期刊：
影响因子：
11.2
通讯作者：
Storkus WJ
中科院分区：
文献类型：
--
作者：
Rao A;Taylor JL;Chi-Sabins N;Kawabe M;Gooding WE;Storkus WJ
CD 8 + T细胞对肿瘤细胞的无效识别是癌症免疫治疗的限制。因此，协调促进增强的抗肿瘤CD 8 + T细胞活化、递送和靶细胞识别的治疗方案应产生更大的临床益处。使用MCA 205肉瘤模型，我们表明，在体外治疗肿瘤细胞与HSP 90抑制剂17-DMAG的结果在瞬时（蛋白酶体依赖性）的HSP 90客户蛋白EphA 2的降解和随后的增加识别肿瘤细胞的1型抗EphA 2的CD 8 + T细胞。向荷瘤小鼠体内施用17-DMAG导致肿瘤生长减缓，抗EphA 2 CD 8 + T细胞对肿瘤细胞的识别增强/延长，肿瘤微环境（TME）中骨髓源性抑制细胞（MDSC）和调节性T细胞（Treg）的水平降低，以及与1型肿瘤浸润淋巴细胞（TIL）水平升高相关的肿瘤相关血管内皮细胞的活化。当与EphA 2特异性主动疫苗接种或EphA 2特异性CD 8 + T细胞的过继转移组合时，17-DMAG共治疗产生能够使动物免于疾病的上级肿瘤治疗方案。综上所述，我们的发现表明，17-DMAG在靶向EphA 2的疫苗的背景下作为免疫佐剂起作用。
Ineffective recognition of tumor cells by CD8+ T cells is a limitation of cancer immunotherapy. Therefore, treatment regimens that coordinately promote enhanced anti-tumor CD8+ T cell activation, delivery, and target cell recognition should yield greater clinical benefit. Using an MCA205 sarcoma model, we show that in vitro treatment of tumor cells with the HSP90 inhibitor 17-DMAG results in the transient (proteasome-dependent) degradation of the HSP90 client protein EphA2 and the subsequent increased recognition of tumor cells by Type-1 anti-EphA2 CD8+ T cells. In vivo administration of 17-DMAG to tumor-bearing mice led to slowed tumor growth, enhanced/prolonged recognition of tumor cells by anti-EphA2 CD8+ T cells, reduced levels of myeloid-derived suppressor cells (MDSC) and regulatory T cells (Treg) in the tumor microenvironment (TME), and activation of tumor-associated vascular endothelial cells in association with elevated levels of Type-1 tumor infiltrating lymphocytes (TIL). When combined with EphA2-specific active vaccination or the adoptive transfer of EphA2-specific CD8+ T cells, 17-DMAG co-treatment yielded a superior tumor therapeutic regimen that was capable of rendering animals free of disease. Taken together, our findings indicate that 17-DMAG functions as an immune adjuvant in the context of vaccines targeting EphA2.