Regulatory T cells define affinity thresholds for CD8+ T cell tumor infiltration.

IF 6.9 1区 医学 Q1 IMMUNOLOGY
Mona O Mohsen, Romano Josi, Sanjana V Marar, Anish Ghimire, Lan Yang, Pascal S Krenger, Arnau Solé Casaramona, Daniel E Speiser, Simone De Brot, Martin F Bachmann
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引用次数: 0

Abstract

TCR repertoires against tumors lack high-affinity TCRs and are further suppressed by Tregs. We hypothesized that Treg depletion enhances the antitumor efficacy of low-affinity T cells. Using the weak agonistic peptide A4Y derived from LCMV glycoprotein peptide p33 as a model antigen and VLPs as a vaccine platform, we tested this approach. In a separate low-affinity model, we targeted B16F10 melanoma with our multi-target vaccine. Results revealed limited in vivo lytic cross-reactivity between A4Y and p33 peptides, and the A4Y-vaccine alone failed to inhibit B16F10p33 tumor progression. However, combining A4Y-vaccine with Treg depletion triggered a robust immune response, characterized by increased CD8+ T cell infiltration, enhanced T cell functionality, and tumor-free survival. Infiltrating T cells also exhibited closer spatial proximity and heightened migration from blood vessels. Similarly, combining low-affinity vaccine with Treg depletion enhanced antitumor responses. These findings highlight the potential of Treg depletion to advance vaccination strategies targeting TAAs with low-affinity T cells.

调节性T细胞定义了CD8+ T细胞肿瘤浸润的亲和力阈值。
抗肿瘤的TCR库缺乏高亲和力的TCR,并进一步受到Tregs的抑制。我们假设Treg缺失增强了低亲和力T细胞的抗肿瘤功效。我们以LCMV糖蛋白肽p33衍生的弱激动肽A4Y为模型抗原,以VLPs为疫苗平台,对该方法进行了测试。在一个单独的低亲和力模型中,我们用我们的多靶点疫苗靶向B16F10黑色素瘤。结果显示,A4Y和p33肽之间的体内裂解交叉反应性有限,单独使用A4Y疫苗无法抑制B16F10p33肿瘤的进展。然而,将a4y疫苗与Treg缺失相结合引发了强大的免疫反应,其特征是CD8+ T细胞浸润增加,T细胞功能增强,无肿瘤生存。浸润的T细胞也表现出更紧密的空间接近性和从血管迁移的增强。同样,将低亲和力疫苗与Treg缺失结合可以增强抗肿瘤反应。这些发现突出了Treg耗竭在推进靶向低亲和力T细胞TAAs的疫苗接种策略方面的潜力。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
NPJ Vaccines
NPJ Vaccines Immunology and Microbiology-Immunology
CiteScore
11.90
自引率
4.30%
发文量
146
审稿时长
11 weeks
期刊介绍: Online-only and open access, npj Vaccines is dedicated to highlighting the most important scientific advances in vaccine research and development.
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