Agonist anti-GITR antibody enhances vaccine-induced CD8+ T-cell responses and tumor immunity
Agonist anti-GITR antibody enhances vaccine-induced CD8+ T-cell responses and tumor immunity
复制标题
DOI：
10.1158/0008-5472.can-05-2813
复制
发表时间：
2006-05-01
期刊：
影响因子：
11.2
通讯作者：
Houghton, AN
中科院分区：
文献类型：
--
作者：
Cohen, AD;Diab, A;Houghton, AN
用编码异种肿瘤分化抗原同源同源物的质粒免疫小鼠，可以打破免疫忽视和对自身的耐受，诱导保护性肿瘤免疫。我们试图通过将异种DNA疫苗与激动剂抗糖皮质激素诱导的肿瘤坏死因子受体家族相关基因(GITR)相关基因(MAb)单抗DTA-1相结合来改进这一策略，DTA-1先前已被证明能共刺激激活的效应分子CD4(+)和CD8(+)T细胞，并抑制CD4(+)CD25(+)调节性T细胞的抑制活性。我们发现，在每周3次DNA免疫的第二次(而不是第一次)之前，将GITR与DTA-1连接起来，可以增强原代CD8(+)T细胞对黑色素瘤分化抗原gp100和酪氨酸酶相关蛋白2/多巴铬互变异构酶的反应，并增强对B16黑色素瘤致命性攻击的保护。肿瘤免疫力的提高与局灶性自体粘连的轻微增加有关，表现为自身免疫功能减退。按照这一计划给予DTA-1还导致抗原特异性CD8(+)T细胞的持续时间延长，以及在初级免疫系列4周后加强加强接种后对Recall CD8(+)T细胞的反应。在初次免疫和加强免疫时给予抗GITR单抗可进一步提高召回反应。最后，这种对疫苗诱导的CD8(+)T细胞反应的影响部分独立于CD4(+)T细胞(辅助性和调节性)，与对效应CD8(+)细胞本身的直接共刺激作用一致。
Immunization of mice with plasmids encoding xenogeneic orthologues of tumor differentiation antigens can break immune ignorance and tolerance to self and induce protective tumor immunity. We sought to improve on this strategy by combining xenogeneic DNA vaccination with an agonist antiglucocorticoid-induced tumor necrosis factor receptor family-related gene (GITR) monoclonal antibody (mAb), DTA-1, which has been shown previously both to costimulate activated effector CD4(+) and CD8(+) T cells and to inhibit the suppressive activity of CD4(+)CD25(+) regulatory T cells. We found that ligation of GITR with DTA-1 just before the second, but not the first, of 3 weekly DNA immunizations enhanced primary CD8(+) T-cell responses against the melanoma differentiation antigens gp100 and tyrosinase-related protein 2/dopachrome tautomerase and increased protection from a lethal challenge with B16 melanoma. This improved tumor immunity was associated with a modest increase in focal autoinimunity, manifested as autoimmnune hypopigmentation. DTA-1 administration on this schedule also led to prolonged persistence of the antigen-specific CD8(+) T cells as well as to an enhanced recall CD8(+) T-cell response to a booster vaccination given 4 weeks after the primary immunization series. Giving the anti-GITR mAb both during primary immunization and at the time of booster vaccination increased the recall response even further. Finally, this effect on vaccine-induced CD8(+) T-cell responses was partially independent of CD4(+) T cells (both helper and regulatory), consistent with a direct costimulatory effect on the effector CD8(+) cells themselves.