免疫检查点阻断抗体正在为癌症患者设定新的护理标准。因此,在免疫检查点阻断的背景下评估任何新的基于免疫的疗法是重要的。这里,我们评估了将具有改善耐受破坏能力的合成共有TERTDNA疫苗与免疫检查点抑制剂联合使用的影响.我们观察到CTLA-4或,在较小程度上,PD-1与TERT疫苗协同作用,与单独的检查点或单独的疫苗相比,产生更强大的抗肿瘤活性。尽管有这种抗肿瘤协同作用,在荷瘤小鼠中,这些免疫检查点疗法均未显示TERT抗原特异性免疫应答的改善.αCTLA-4治疗提高了肿瘤内T-bet+/CD44+效应CD8+T细胞的频率,降低了肿瘤内调节性T细胞的频率,但不是在外周血中。CTLA-4阻断与TERTDNA疫苗协同作用超过Treg消耗,表明CTLA-4阻断的作用更可能是由于肿瘤中效应T细胞的扩增而不是Tregs频率的降低。这些结果表明,免疫检查点抑制剂的功能是改变免疫调节环境,与DNA疫苗协同作用。而不是在疫苗接种部位增强抗原特异性反应。
Immune checkpoint blockade antibodies are setting a new standard of care for cancer patients. It is therefore important to assess any new immune-based therapies in the context of immune checkpoint blockade. Here, we evaluate the impact of combining a synthetic
consensus TERT DNA vaccine that has improved capacity to break tolerance with immune checkpoint inhibitors. We observed that blockade of CTLA-4 or, to a lesser extent, PD-1 synergized with
TERT vaccine, generating more robust anti-tumor activity compared to checkpoint alone or vaccine alone. Despite this anti-tumor synergy, none of these immune checkpoint therapies showed improvement in
TERT antigen-specific immune responses in tumor-bearing mice. αCTLA-4 therapy enhanced the frequency of T-bet+/CD44+ effector CD8+ T cells within the tumor and decreased the frequency of regulatory T cells within the tumor, but not in peripheral blood. CTLA-4 blockade synergized more than Treg depletion with
TERT DNA vaccine, suggesting that the effect of CTLA-4 blockade is more likely due to the expansion of effector T cells in the tumor rather than a reduction in the frequency of Tregs. These results suggest that immune checkpoint inhibitors function to alter the immune regulatory environment to synergize with DNA vaccines, rather than boosting antigen-specific responses at the site of vaccination.