CD27 stimulation unveils the efficacy of linked class I/II peptide vaccines in poorly immunogenic tumors by orchestrating a coordinated CD4/CD8 T cell response
CD27 stimulation unveils the efficacy of linked class I/II peptide vaccines in poorly immunogenic tumors by orchestrating a coordinated CD4/CD8 T cell response
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DOI：
10.1080/2162402x.2018.1502904
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发表时间：
2018-12-02
期刊：
影响因子：
7.2
通讯作者：
Sampson, John H.
中科院分区：
文献类型：
--
作者：
Riccione, Katherine A.;He, Li-Zhen;Sampson, John H.
尽管前景看好，但肿瘤特异性多肽疫苗的疗效有限。CD27是一种表达在CD4(+)和CD8(+)T细胞上的共刺激分子，在免疫激活中起重要作用。在这里，我们确定了一种新的CD27激动剂抗体(αhCD27)是否可以增强多肽疫苗的抗肿瘤T细胞反应和疗效。我们利用一只表达人CD27的转基因小鼠，评估了αhCD27对全蛋白、I类限制性和II类限制性多肽疫苗免疫原性和抗肿瘤效果的影响。我们发现，与仅由SIINFEKL组成的多肽疫苗相比，在由I类和II类卵蛋白表位组成的疫苗(分别为SIINFEKL和TEWTSSNVMEERKIKV)中，αhCD27优先增强CD8(+)T细胞的反应，导致当与含有I/II类卵白蛋白表位的疫苗联合使用时，αhCD27对颅内B16.OVA肿瘤具有抗肿瘤效果。事实上，我们证明了这种疗效是CD8和CD4依赖的，并且其佐剂作用需要卵蛋白特异性的CD4(+)T细胞上的αhCD27活性。对于临床翻译来说，重要的是，连接的通用CD4(+)辅助表位(破伤风P30)足以灌输SIINFEKL肽与αhCD27相结合的疗效，消除了对肿瘤特异性II类限制性肽的需要。这一方法揭示了一种来自肿瘤相关Trp2抗原的I类限制性多肽疫苗在荷有颅内B16肿瘤的小鼠中的有效性。CD27激动剂抗体与含有连接的肿瘤特异性CD8(+)表位和肿瘤特异性或通用的CD4(+)表位的多肽疫苗相结合，可增强主动癌症免疫治疗的疗效。
Despite their promise, tumor-specific peptide vaccines have limited efficacy. CD27 is a costimulatory molecule expressed on CD4(+) and CD8(+) T cells that is important in immune activation. Here we determine if a novel CD27 agonist antibody (alpha hCD27) can enhance the antitumor T cell response and efficacy of peptide vaccines. We evaluated the effects of alpha hCD27 on the immunogenicity and antitumor efficacy of whole protein, class I-restricted, and class II-restricted peptide vaccines using a transgenic mouse expressing human CD27. We found that alpha hCD27 preferentially enhances the CD8(+) T cell response in the setting of vaccines comprised of linked class I and II ovalbumin epitopes (SIINFEKL and TEWTSSNVMEERKIKV, respectively) compared to a peptide vaccine comprised solely of SIINFEKL, resulting in the antitumor efficacy of adjuvant alpha hCD27 against intracranial B16.OVA tumors when combined with vaccines containing linked class I/II ovalbumin epitopes. Indeed, we demonstrate that this efficacy is both CD8- and CD4-dependent and alpha hCD27 activity on ovalbumin-specific CD4(+) T cells is necessary for its adjuvant effect. Importantly for clinical translation, a linked universal CD4(+) helper epitope (tetanus P30) was sufficient to instill the efficacy of SIINFEKL peptide combined with alpha hCD27, eliminating the need for a tumor-specific class II-restricted peptide. This approach unveiled the efficacy of a class I-restricted peptide vaccine derived from the tumor-associated Trp2 antigen in mice bearing intracranial B16 tumors. CD27 agonist antibodies combined with peptide vaccines containing linked tumor-specific CD8(+) epitopes and tumor-specific or universal CD4(+) epitopes enhance the efficacy of active cancer immunotherapy.