Protective T cell responses against tumors require the production of Interferon gamma (IFN-γ). However, tumor-infiltrating T cells (TILs) gradually lose their capacity to produce IFN-γ and therefore fail to clear malignant cells. Dissecting the underlying mechanisms that block cytokine production is thus key for improving T cell products. Here we show that although TILs express substantial levels of Ifng mRNA, post-transcriptional mechanisms impede the production of IFN-γ protein due to loss of mRNA stability. CD28 triggering, but not PD1 blocking antibodies, effectively restores the stability of Ifng mRNA. Intriguingly, TILs devoid of AU-rich elements within the 3'untranslated region maintain stabilized Ifng mRNA and produce more IFN-γ protein than wild-type TILs. This sustained IFN-γ production translates into effective suppression of tumor outgrowth, which is almost exclusively mediated by direct effects on the tumor cells. We therefore conclude that post-transcriptional mechanisms could be modulated to potentiate effective T cell therapies in cancer.

中文翻译：

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IFN-γ转录后调控在肿瘤浸润T细胞中的关键作用。

针对肿瘤的保护性T细胞反应需要产生干扰素γ（IFN-γ）。然而，肿瘤浸润性T细胞（TIL）逐渐失去其产生IFN-γ的能力，因此不能清除恶性细胞。因此，剖析阻碍细胞因子产生的潜在机制是改善T细胞产物的关键。在这里，我们显示，尽管TILs表达大量的Ifng mRNA，但转录后的机制由于mRNA稳定性的下降而阻碍IFN-γ蛋白的产生。触发CD28而非触发PD1的抗体可以有效地恢复Ifng mRNA的稳定性。有趣的是，与野生型TIL相比，在3'非翻译区内缺乏富含AU元素的TIL维持稳定的Ifng mRNA并产生更多的IFN-γ蛋白。这种持续的IFN-γ产生转化为对肿瘤生长的有效抑制，这几乎完全由对肿瘤细胞的直接作用介导。因此，我们得出结论，可以调节转录后机制以增强癌症中有效的T细胞疗法。