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.

© 2025. The Author(s).

肿瘤特异性TCR库缺乏高亲和力的TCR，并且还会被Tregs抑制。我们假设，通过消除Treg可以增强低亲和力T细胞的抗肿瘤效果。使用从LCMV糖蛋白肽p33衍生的弱激动剂肽A4Y作为模型抗原以及VLPs作为疫苗平台，我们测试了这一方法的有效性。在另一个低亲和力模型中，我们用我们的多靶点疫苗针对B16F10黑色素瘤。结果显示，A4Y和p33肽之间体内裂解交叉反应性有限，并且单独使用A4Y疫苗无法抑制B16F10p33肿瘤进展。然而，将A4Y疫苗与Treg清除相结合触发了强大的免疫反应，表现为CD8+ T细胞浸润增加、T细胞功能增强以及无瘤生存期延长。浸润的T细胞还表现出更近的空间接近度和从血管中迁移能力的提高。类似地，将低亲和力疫苗与Treg清除结合可以增强抗肿瘤反应。这些发现强调了通过消除Treg来推进针对具有低亲和力T细胞的TAAs（肿瘤相关抗原）的疫苗策略的潜力。

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