The advent of immune checkpoint inhibitors has represented a major boost in cancer therapy, but safety concerns are increasingly being recognized. Indeed, although beneficial at the tumor site, unlocking a safeguard mechanism of the immune response may trigger autoimmune-like effects at the periphery, thus making the safety of immune checkpoint inhibitors a research priority. Herein, we demonstrate that thymosin α1 (Tα1), an endogenous peptide with immunomodulatory activities, can protect mice from intestinal toxicity in a murine model of immune checkpoint inhibitor-induced colitis. Specifically, Tα1 efficiently prevented immune adverse pathology in the gut by promoting the indoleamine 2,3-dioxygenase (IDO) 1-dependent tolerogenic immune pathway. Notably, Tα1 did not induce IDO1 in the tumor microenvironment, but rather modulated the infiltration of T-cell subsets by inverting the ratio between CD8⁺ and Treg cells, an effect that may depend on Tα1 ability to regulate the differentiation and chemokine expression profile of DCs. Thus, through distinct mechanisms that are contingent upon the context, Tα1 represents a plausible candidate to improve the safety/efficacy profile of immune checkpoint inhibitors.

中文翻译：

---

胸腺素α1保护免受CTLA-4肠道免疫病理学的影响。

免疫检查点抑制剂的出现代表了癌症治疗的一大推动力，但人们日益认识到安全性问题。实际上，尽管对肿瘤部位有益，但解锁免疫反应的保护机制可能会在周围触发自身免疫样效应，因此使免疫检查点抑制剂的安全性成为研究重点。在这里，我们证明胸腺素α1（Tα1），一种具有免疫调节活性的内源性肽，可以保护小鼠免受免疫检查点抑制剂引起的结肠炎的小鼠肠道毒性。具体来说，Tα1通过促进吲哚胺2，3-二加氧酶（IDO）1依赖性耐受性免疫途径有效地预防了肠道的免疫不良病理。值得注意的是，Tα1在肿瘤微环境中没有诱导IDO1，⁺和Treg细胞，这种作用可能取决于Tα1调节DC分化和趋化因子表达谱的能力。因此，通过取决于上下文的不同机制，Tα1代表了一个合理的候选者，可以改善免疫检查点抑制剂的安全性/功效。