Abstract

Tumor neoantigens derived from genetic alterations are potential T-cell targets for antitumor immunity. However, tumors develop immune escape mechanisms including loss of preexisting neoantigens and/or impairment of T-cell responses during tumor development and progression. Here, we addressed whether newly emerged immunogenic neoantigens in established tumors enabled hosts to inhibit tumor growth via controlling immune escape mechanisms. Using a doxycycline-driven gene expression system, we generated murine MC38, CT26 (colorectal cancer) and B16 (melanoma) cell lines with inducible expression of model immunogenic neoantigens such as chicken ovalbumin and human NY-ESO-1. A model neoantigen was induced by doxycycline administration in the tumors once tumors became palpable. Tumor growth was significantly inhibited upon induction of the neoantigen and this inhibition was abrogated in nude mice lacking T cells and in mice deprived of CD8⁺ T cells, indicating the critical role of CD8⁺ T cells in tumor regression. In addition, PD-1/PD-L1 blockade further augmented the antitumor immune response, resulting in a far stronger inhibition of tumor growth. Accordingly, newly emerged tumor neoantigen-specific CD8⁺ T cells with enhanced effector functions were significantly increased in mice treated with PD-1/PD-L1 blockade. We propose that a newly emerged neoantigen is sufficient to inhibit tumor growth via preventing immune escape in a T-cell-dependent manner. Our results imply that induction of immunogenic tumor neoantigens is a novel strategy to overcome the resistance to immune checkpoint blockade therapy.

中文翻译：

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在已建立的肿瘤中新出现的免疫原性新抗原使宿主能够以 T 细胞依赖性方式重新获得免疫监视。

摘要

源自基因改变的肿瘤新抗原是抗肿瘤免疫的潜在 T 细胞靶标。然而，肿瘤会发展出免疫逃逸机制，包括在肿瘤发展和进展过程中失去预先存在的新抗原和/或 T 细胞反应受损。在这里，我们讨论了已建立肿瘤中新出现的免疫原性新抗原是否使宿主能够通过控制免疫逃逸机制来抑制肿瘤生长。使用强力霉素驱动的基因表达系统，我们产生了小鼠 MC38、CT26（结肠直肠癌）和 B16（黑色素瘤）细胞系，它们可诱导表达模型免疫原性新抗原，如鸡卵清蛋白和人 NY-ESO-1。一旦肿瘤变得可触知，通过在肿瘤中施用多西环素诱导模型新抗原。⁺ T 细胞，表明 CD8 ⁺ T 细胞在肿瘤消退中的关键作用。此外，PD-1/PD-L1 阻断进一步增强了抗肿瘤免疫反应，从而对肿瘤生长产生更强的抑制作用。因此，在用 PD-1/PD-L1 阻断剂治疗的小鼠中，具有增强效应功能的新出现的肿瘤新抗原特异性 CD8 ^{+ T 细胞显着增加。}我们提出一种新出现的新抗原足以通过以 T 细胞依赖性方式阻止免疫逃逸来抑制肿瘤生长。我们的结果表明，诱导免疫原性肿瘤新抗原是一种克服免疫检查点阻断疗法耐药性的新策略。