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Epitope diversification driven by non-tumor epitope-specific Th1 and Th17 mediates potent antitumor reactivity

机译：由非肿瘤表位特异性Th1和Th17驱动的表位多样化介导了有效的抗肿瘤反应性

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摘要

MHC class I-restricted peptide-based vaccination therapies have been conducted to treat cancer patients, because CD8+ CTL can efficiently induce apoptosis of tumor cells in an MHC class I-restricted epitope-specific manner. Interestingly, clinical responders are known to demonstrate reactivity to epitopes other than those used for vaccination; however, the mechanism underlying how antitumor T cells with diverse specificity are induced is unclear. In this study, we demonstrated that dendritic cells (DCs) that engulfed apoptotic tumor cells in the presence of non-tumor MHC class II-restricted epitope peptides, OVA323–339, efficiently presented tumor-associated antigens upon effector-dominant CD4+ T cell balance against regulatory T cells (Treg) for the OVA323–339 epitope. Th1 and Th17 induced tumor-associated antigens presentation of DC, while Th2 ameliorated tumor-antigen presentation for CD8+ T cells. Blocking experiments with anti-IL-23p19 antibody and anti-IL-23 receptor indicated that an autocrine mechanism of IL-23 likely mediated the diverted tumor-associated antigens presentation of DC. Tumor-associated antigens presentation of DC induced by OVA323–339 epitope-specific CD4+ T cells resulted in facilitated antitumor immunity in both priming and effector phase in vivo. Notably, this immunotherapy did not require pretreatment to reduce Treg induced by tumor. This strategy may have clinical implications for designing effective antitumor immunotherapies.
机译：已经进行了MHC I类限制的基于肽的疫苗接种疗法来治疗癌症患者，因为CD8 + CTL可以以MHC I类限制的表位特异性方式有效诱导肿瘤细胞的凋亡。有趣的是，已知临床反应者对疫苗接种以外的抗原决定簇具有反应性。然而，如何诱导具有不同特异性的抗肿瘤T细胞的机制尚不清楚。在这项研究中，我们证明了在非肿瘤MHC II类限制性表位肽OVA323–339的存在下吞噬凋亡肿瘤细胞的树突状细胞（DC）在效应子为主导的CD4 + T细胞平衡后有效地呈递了肿瘤相关抗原。针对OVA323–339表位的调节性T细胞（Treg）。 Th1和Th17诱导DC的肿瘤相关抗原呈递，而Th2改善CD8 + T细胞的肿瘤抗原呈递。用抗IL-23p19抗体和抗IL-23受体进行的阻断实验表明，IL-23的自分泌机制可能介导了DC转移的肿瘤相关抗原的呈递。 OVA323–339表位特异性CD4 + T细胞诱导的DC的肿瘤相关抗原呈递导致体内启动和效应期的抗肿瘤免疫增强。值得注意的是，该免疫疗法不需要预处理以减少肿瘤诱导的Treg。该策略可能对设计有效的抗肿瘤免疫疗法具有临床意义。

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