MHC class II-transduced tumor cells originating in the immune-privileged eye prime and boost CD4+ T lymphocytes that cross-react with primary and metastatic weal melanoma cells
MHC class II-transduced tumor cells originating in the immune-privileged eye prime and boost CD4+ T lymphocytes that cross-react with primary and metastatic weal melanoma cells
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DOI：
10.1158/0008-5472.can-06-3770
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发表时间：
2007-05-01
期刊：
影响因子：
11.2
通讯作者：
Ostrand-Rosenberg, Suzanne
中科院分区：
文献类型：
--
作者：
Bosch, Jacobus J.;Thompson, James A.;Ostrand-Rosenberg, Suzanne
葡萄膜黑色素瘤是最常见的眼部恶性肿瘤，原发性肿瘤较大的患者中，肝转移率为 50%。多种疗法可延长转移患者的生存期；然而，没有一种方法可以治愈，也没有患者能够存活。因此，我们正在探索免疫疗法作为替代或辅助治疗。葡萄膜黑色素瘤可能特别适合免疫治疗，因为原发性肿瘤出现在免疫豁免部位，并且可能表达宿主不耐受的抗原。我们正在开发 MHC 11 类 (MHC II) 匹配的同种异体细胞葡萄膜黑色素瘤疫苗，该疫苗可激活 CD4(+) T 淋巴细胞，CD4(+) T 淋巴细胞是优化 CD8(+) T 细胞免疫、促进免疫记忆和预防耐受的关键细胞。我们之前的研究表明，经过基因改造以表达与受体同源的共刺激分子和 MHC II 分子的肿瘤细胞是抗肿瘤免疫的有效诱导剂。由于 MHC II 匹配的同种异体疫苗不表达辅助分子（不变链），因此它们呈现源自内源编码肿瘤抗原的 MHC II 限制性肽。我们现在报告说，MHC II 匹配的同种异体疫苗是由免疫豁免眼中出现的原发性葡萄膜黑色素瘤制备而成，可以启动并增强健康供体或葡萄膜黑色素瘤患者外周血中分泌 IFN γ 的 CD4(+) T 细胞，与其他患者的原发性葡萄膜黑色素瘤和转移性肿瘤发生交叉反应。相比之下，由肝脏转移细胞制备的疫苗在激活CD4+T细胞方面效果较差，这表明源自免疫豁免位点的肿瘤细胞可能具有增强的诱导抗肿瘤免疫和作为免疫治疗剂的能力。
Uveal melanoma, the most common malignancy of the eye, has a 50% rate of liver metastases among patients with large primary tumors. Several therapies prolong survival of metastatic patients; however, none are curative and no patients survive. Therefore, we are exploring immunotherapy as an alternative or adjunctive treatment. Uveal melanoma may be particularly appropriate for immunotherapy because primary tumors arise in an immune-privileged site and may express antigens to which the host is not tolerized. We are developing MHC class 11 (MHC II)-matched allogeneic, cell-based uveal melanoma vaccines that activate CD4(+) T lymphocytes, which are key cells for optimizing CD8(+) T-cell immunity, facilitating immune memory, and preventing tolerance. Our previous studies showed that tumor cells genetically modified to express costimulatory and MHC II molecules syngeneic to the recipient are potent inducers of antitumor immunity. Because the MHC II-matched allogeneic vaccines do not express the accessory molecule, Invariant chain, they present MHC II-restricted peptides derived from endogenously encoded tumor antigens. We now report that MHC II-matched allogeneic vaccines, prepared from primary uveal melanomas that arise in the immune-privileged eye, prime and boost IFN gamma-secreting CD4(+) T cells from the peripheral blood of either healthy donors or uveal melanoma patients that cross-react with primary uveal melanomas from other patients and metastatic tumors. In contrast, vaccines prepared from metastatic cells in the liver are less effective at activating CD4(+) T cells, suggesting that tumor cells originating in immune-privileged sites may have enhanced capacity for inducing antitumor immunity and for serving as immunotherapeutic agents.