CTLA-4 blockade synergizes with tumor-derived granulocyte-macrophage colony-stimulating factor for treatment of an experimental mammary carcinoma
CTLA-4 blockade synergizes with tumor-derived granulocyte-macrophage colony-stimulating factor for treatment of an experimental mammary carcinoma
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DOI：
10.1073/pnas.95.17.10067
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发表时间：
1998-08-18
影响因子：
11.1
通讯作者：
Allison, JP
中科院分区：
文献类型：
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作者：
Hurwitz, AA;Yu, TFY;Allison, JP
T细胞介导的抗肿瘤反应的产生依赖于主要组织相容性复合体/抗原对T细胞受体的参与以及B7对CD28的连接，CTLA-4是T细胞激活时表达的第二种B7受体，与CD28不同，CTLA-4似乎向T细胞传递抑制信号。最近，我们和其他人证明了给予抗CTLA-4抗体足以促进几种小鼠肿瘤的消退。然而，某些肿瘤，如SM1乳腺癌，仍然对这种类型的免疫治疗无效，在本研究中，我们报告了CTLA-4阻断和由表达粒细胞-巨噬细胞集落刺激因子的SMI细胞组成的疫苗的结合导致亲本SM1肿瘤的消退，尽管单独治疗无效。这种协同治疗导致了对SM1的持久免疫，并依赖于CD4(+)和CD8(+)T细胞。有趣的是，CTLA-4和表达B7的SM1疫苗之间没有观察到协同作用。考虑到粒细胞巨噬细胞集落刺激因子促进树突状细胞的分化和激活，以及增强T细胞对肿瘤来源抗原的交叉激发，以及SM1是主要组织相容性复合体II类阴性，我们的发现表明CTLA-4阻断作用于宿主来源的抗原提呈细胞水平。此外，这些结果还支持这样一种观点，即最有效和最协同的疫苗策略针对的是在宿主来源的抗原呈递细胞水平上增强T细胞启动的治疗。
Generation of a T cell-mediated antitumor response depends on T cell receptor engagement by major histocompatibility complex/antigen as well as CD28 ligation by B7, CTLA-4 is a second B7 receptor expressed by T cells upon activation that, unlike CD28, appears to deliver an inhibitory signal to T cells. Recently, we and others demonstrated that administration of an anti-CTLA-4 antibody was sufficient to promote regression of several murine tumors. However, certain tumors, such as the SM1 mammary carcinoma, remain refractory to this type of immunotherapy, In the present study, we report that the combination of both CTLA-4 blockade and a vaccine consisting of granulocyte-macrophage colony-stimulating factor-expressing SMI cells resulted in regression of parental SM1 tumors, despite the ineffectiveness of either treatment alone. This synergistic therapy resulted in long-lasting immunity to SM1 and depended on both CD4(+) and CD8(+) T cells. Interestingly, synergy was not observed between CTLA-4 and a B7-expressing SM1 vaccine. Given that granulocyte-macrophage colony-stimulating factor promotes differentiation and activation of dendritic cells as well as enhances cross-priming of T cells to tumor-derived antigens and that SM1 is major histocompatibility complex class II-negative, our findings suggest that CTLA-4 blockade acts at the level of a host-derived antigen-presenting cell. In addition, these results also support the idea that the most effective and synergistic vaccine strategy targets treatments that enhance T cell priming at the level of host-derived antigen-presenting cells.