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神经白细胞素-2 增强了针对 MHC Ⅱ类 VHH 靶向肽疫苗的抗肿瘤免疫。

Neoleukin-2 enhances anti-tumour immunity downstream of peptide vaccination targeted by an anti-MHC class II VHH.

机构信息

Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA.

Department of Medicine, Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.

出版信息

Open Biol. 2020 Feb;10(2):190235. doi: 10.1098/rsob.190235. Epub 2020 Feb 5.

Abstract

Cancer-specific mutations can lead to peptides of unique sequence presented on MHC class I to CD8 T cells. These neoantigens can be potent tumour-rejection antigens, appear to be the driving force behind responsiveness to anti-CTLA-4 and anti-PD1/L1-based therapies and have been used to develop personalized vaccines. The platform for delivering neoantigen-based vaccines has varied, and further optimization of both platform and adjuvant will be necessary to achieve scalable vaccine products that are therapeutically effective at a reasonable cost. Here, we developed a platform for testing potential CD8 T cell tumour vaccine candidates. We used a high-affinity alpaca-derived VHH against MHC class II to deliver peptides to professional antigen-presenting cells. We show and that peptides derived from the model antigen ovalbumin are better able to activate naive ovalbumin-specific CD8 T cells when conjugated to an MHC class II-specific VHH when compared with an irrelevant control VHH. We then used the VHH-peptide platform to evaluate a panel of candidate neoantigens in a mouse model of pancreatic cancer. None of the candidate neoantigens tested led to protection from tumour challenge; however, we were able to show vaccine-induced CD8 T cell responses to a melanoma self-antigen that was augmented by combination therapy with the synthetic cytokine mimetic Neo2/15.

摘要

癌症特异性突变可导致 MHC I 类呈递的独特序列肽段被 CD8 T 细胞识别。这些新抗原可以作为有效的肿瘤排斥抗原,似乎是对 CTLA-4 和 PD1/L1 抑制剂治疗产生应答的驱动力,并且已被用于开发个体化疫苗。新抗原疫苗的递送平台多种多样,需要进一步优化平台和佐剂,以开发具有治疗效果且价格合理的可扩展疫苗产品。在这里,我们开发了一种用于测试潜在 CD8 T 细胞肿瘤疫苗候选物的平台。我们使用针对 MHC II 类的高亲和力羊驼衍生 VHH 将肽递送至专业抗原呈递细胞。我们发现,与无关对照 VHH 相比,当与 MHC II 类特异性 VHH 偶联时,源自模型抗原卵清蛋白的肽能够更好地激活幼稚的卵清蛋白特异性 CD8 T 细胞。然后,我们使用 VHH-肽平台在胰腺癌小鼠模型中评估了一组候选新抗原。在测试的候选新抗原中,没有一个能防止肿瘤挑战;然而,我们能够证明疫苗诱导的 CD8 T 细胞应答黑色素瘤自身抗原,这种应答通过与合成细胞因子模拟物 Neo2/15 的联合治疗得到增强。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/09d9/7058936/c68e50363da3/rsob-10-190235-g1.jpg

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