Background: Checkpoint inhibitors act on exhausted CD8+ T cells and restore their effector function in chronic infections and cancer. The underlying mechanisms of action appear to differ between different types of cancer and are not yet fully understood. Methods: Here, we established a new orthotopic HCC model to study the effects of checkpoint blockade on exhausted CD8+ tumor-infiltrating lymphocytes (TILs). The tumors expressed endogenous levels of HA, which allowed the study of tumor-specific T cells Results: The induced tumors developed an immune-resistant TME in which few T cells were found. The few recovered CD8+ TILs were mostly terminally exhausted and expressed high levels of PD-1. PD-1/CTLA-4 blockade resulted in a strong increase in the number of CD8+ TILs expressing intermediate amounts of PD-1, also called progenitor-exhausted CD8+ TILs, while terminally exhausted CD8+ TILs were almost absent in the tumors of treated mice. Although transferred naïve tumor-specific T cells did not expand in the tumors of untreated mice, they expanded strongly after treatment and generated progenitor-exhausted but not terminally exhausted CD8+ TILs. Unexpectedly, although progenitor-exhausted CD8+ TILs mediated the anti-tumor response after treatment with minimal changes in their transcriptional profile. Conclusion: In our model, few doses of checkpoint inhibitors during the priming of transferred CD8+ tumor-specific T cells were sufficient to induce tumor remission. PD-1/CTLA-4 blockade neither reinvigorated the effector function of CD8+PD-1high TILs nor changed the functionality of CD8+PD-1int TILs. Therefore, PD-1/CTLA-4 blockade has an ameliorative effect the expansion of recently primed CD8+ T cells while preventing their development into CD8+PD-1high TILs in the TME. This finding could have important implications for future T cell therapies.


中文翻译：

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PD-1/CTLA-4 阻断导致 CD8+PD-1int TIL 扩增，导致实验性肝癌肿瘤缓解

背景：检查点抑制剂作用于耗尽的 CD8+ T 细胞，恢复其在慢性感染和癌症中的效应功能。不同类型的癌症之间的潜在作用机制似乎有所不同，并且尚未完全了解。方法：在这里，我们建立了一个新的原位 HCC 模型来研究检查点阻断对耗尽的 CD8+ 肿瘤浸润淋巴细胞 (TIL) 的影响。肿瘤表达内源性水平的 HA，这使得研究肿瘤特异性 T 细胞成为可能。 结果：诱导的肿瘤形成了免疫抵抗性 TME，其中几乎没有发现 T 细胞。少数恢复的 CD8+ TIL 大多最终耗尽并表达高水平的 PD-1。PD-1/CTLA-4 阻断导致表达中等量 PD-1 的 CD8+ TIL 数量大幅增加，也称为祖细胞耗尽的 CD8+ TIL，而最终耗尽的 CD8+ TIL 在治疗小鼠的肿瘤中几乎不存在。尽管转移的初始肿瘤特异性 T 细胞在未经治疗的小鼠肿瘤中并未扩增，但它们在治疗后强烈扩增，并产生祖细胞耗尽但未最终耗尽的 CD8+ TIL。出乎意料的是，尽管祖细胞耗尽的 CD8+ TIL 在治疗后介导了抗肿瘤反应，但其转录谱变化极小。结论：在我们的模型中，在启动转移的 CD8+ 肿瘤特异性 T 细胞期间，少量剂量的检查点抑制剂足以诱导肿瘤缓解。PD-1/CTLA-4 阻断既不会重振 CD8+PD-1high TIL 的效应器功能，也不会改变 CD8+PD-1int TIL 的功能。所以，PD-1/CTLA-4 阻断对最近引发的 CD8+ T 细胞的扩增具有改善作用，同时防止它们在 TME 中发育为 CD8+PD-1high TIL。这一发现可能对未来的 T 细胞疗法产生重要影响。