CD27 Agonism Plus PD-1 Blockade Recapitulates CD4+ T-cell Help in Therapeutic Anticancer Vaccination
CD27 Agonism Plus PD-1 Blockade Recapitulates CD4+ T-cell Help in Therapeutic Anticancer Vaccination
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DOI：
10.1158/0008-5472.can-15-3130
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发表时间：
2016-05-15
期刊：
影响因子：
11.2
通讯作者：
Borst, Jannie
中科院分区：
文献类型：
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作者：
Ahrends, Tomasz;Babala, Nikolina;Borst, Jannie
虽然显示出希望，但治疗癌症的疫苗接种策略需要进一步优化。有效性的可能障碍涉及癌症相关的免疫抑制和外周耐受，这限制了有效疫苗特异性细胞毒性T淋巴细胞（CTL）的产生。由于CD 4（+）T细胞可提高CTL反应性，下一代疫苗包括辅助表位。在这里，我们在小鼠中展示了CD 4（+）T细胞如何帮助优化CTL对临床相关DNA疫苗的反应，该疫苗旨在对抗表达人乳头瘤病毒的肿瘤。包含肿瘤无关的辅助表位大大增加了CTL引发，效应和记忆T细胞编程。CD 4（+）T细胞通过CD 27/CD 70共刺激在所有这些方面帮助优化CTL应答。值得注意的是，施用激动性CD 27抗体可以在很大程度上取代辅助表位以促进初级和记忆性CTL应答，直接作用于CD 8（+）T细胞。CD 27激动改善了没有辅助表位的疫苗的功效，比组合的PD-1和CTLA-4阻断更好。联合CD 27激动与CTLA-4阻断改善了疫苗诱导的CTL引发和肿瘤浸润，但只有联合PD-1阻断才能有效根除肿瘤，从而完全重现了CD 4（+）T细胞对疫苗功效的作用。单独的PD-1阻断并不影响CTL引发或肿瘤浸润，因此这些结果表明它与CD 4（+）T细胞帮助合作，减轻了肿瘤中针对CTL的免疫抑制。辅助表位包含或CD 27激动不刺激调节性T细胞，并且在CD 4（+）T细胞辅助的存在下，CD 27激动也提高了疫苗效力。我们的研究结果提供了单独或与PD-1阻断剂组合应用CD 27激动剂抗体以提高癌症疫苗和免疫疗法的治疗效果的临床前理论基础。(C)2016年AACR。
While showing promise, vaccination strategies to treat cancer require further optimization. Likely barriers to efficacy involve cancer-associated immunosuppression and peripheral tolerance, which limit the generation of effective vaccine-specific cytotoxic T lymphocytes (CTL). Because CD4(+) T cells improve CTL responsiveness, next-generation vaccines include helper epitopes. Here, we demonstrate in mice how CD4(+) T-cell help optimizes the CTL response to a clinically relevant DNA vaccine engineered to combat human papillomavirus-expressing tumors. Inclusion of tumor-unrelated helper epitopes greatly increased CTL priming, effector, and memory T-cell programming. CD4(+) T-cell help optimized the CTL response in all these aspects via CD27/CD70 costimulation. Notably, administration of an agonistic CD27 antibody could largely replace helper epitopes in promoting primary and memory CTL responses, acting directly on CD8(+) T cells. CD27 agonism improved efficacy of the vaccine without helper epitopes, more so than combined PD-1 and CTLA-4 blockade. Combining CD27 agonism with CTLA-4 blockade improved vaccine-induced CTL priming and tumor infiltration, but only combination with PD-1 blockade was effective at eradicating tumors, thereby fully recapitulating the effect of CD4(+) T-cell help on vaccine efficacy. PD-1 blockade alone did not affect CTL priming or tumor infiltration, so these results implied that it cooperated with CD4(+) T-cell help by alleviating immune suppression against CTL in the tumor. Helper epitope inclusion or CD27 agonism did not stimulate regulatory T cells, and vaccine efficacy was also improved by CD27 agonism in the presence of CD4(+) T-cell help. Our findings provide a preclinical rationale to apply CD27 agonist antibodies, either alone or combined with PD-1 blockade, to improve the therapeutic efficacy of cancer vaccines and immunotherapy generally. (C) 2016 AACR.