Department of Medicine and Surgery, University of Perugia, Perugia, Italy
Department of Medicine and Surgery, University of Perugia, Perugia, Italy.
J Immunother Cancer. 2022 Mar;10(3). doi: 10.1136/jitc-2021-003725.
Despite the great success, the therapeutic benefits of immune checkpoint inhibitors (ICIs) in cancer immunotherapy are limited by either various resistance mechanisms or ICI-associated toxic effects including gastrointestinal toxicity. Thus, novel therapeutic strategies that provide manageable side effects to existing ICIs would enhance and expand their therapeutic efficacy and application. Due to its proven role in cancer development and immune regulation, gut microbiome has gained increasing expectation as a potential armamentarium to optimize immunotherapy with ICI. However, much has to be learned to fully harness gut microbiome for clinical applicability. Here we have assessed whether microbial metabolites working at the interface between microbes and the host immune system may optimize ICI therapy.
To this purpose, we have tested indole-3-carboxaldehyde (3-IAld), a microbial tryptophan catabolite known to contribute to epithelial barrier function and immune homeostasis in the gut via the aryl hydrocarbon receptor (AhR), in different murine models of ICI-induced colitis. Epithelial barrier integrity, inflammation and changes in gut microbiome composition and function were analyzed. AhR, indoleamine 2,3-dioxygenase 1, interleukin (IL)-10 and IL-22 knockout mice were used to investigate the mechanism of 3-IAld activity. The function of the microbiome changes induced by 3-IAld was evaluated on fecal microbiome transplantation (FMT). Finally, murine tumor models were used to assess the effect of 3-IAld treatment on the antitumor activity of ICI.
On administration to mice with ICI-induced colitis, 3-IAld protected mice from intestinal damage via a dual action on both the host and the microbes. Indeed, paralleling the activation of the host AhR/IL-22-dependent pathway, 3-IAld also affected the composition and function of the microbiota such that FMT from 3-IAld-treated mice protected against ICI-induced colitis with the contribution of butyrate-producing bacteria. Importantly, while preventing intestinal damage, 3-IAld did not impair the antitumor activity of ICI.
This study provides a proof-of-concept demonstration that moving past bacterial phylogeny and focusing on bacterial metabolome may lead to a new class of discrete molecules, and that working at the interface between microbes and the host immune system may optimize ICI therapy.
尽管免疫检查点抑制剂 (ICIs) 在癌症免疫治疗中取得了巨大成功，但它们的治疗益处受到各种耐药机制或 ICI 相关毒性作用的限制，包括胃肠道毒性。因此，提供现有 ICI 可控副作用的新型治疗策略将增强和扩大其治疗效果和应用范围。由于其在癌症发展和免疫调节中的作用已得到证实，肠道微生物组作为一种优化免疫治疗的潜在手段，越来越受到关注。然而，要充分利用肠道微生物组，还有很多需要学习的地方。在这里，我们评估了微生物代谢产物在微生物和宿主免疫系统之间的界面上是否可以优化 ICI 治疗。
为此，我们测试了吲哚-3-甲醛 (3-IAld)，这是一种微生物色氨酸代谢物，已知通过芳香烃受体 (AhR) 促进肠道上皮屏障功能和免疫稳态，在不同的 ICI 诱导的结肠炎小鼠模型中。分析了上皮屏障完整性、炎症以及肠道微生物组组成和功能的变化。使用 AhR、吲哚胺 2,3-双加氧酶 1 (IDO1)、白细胞介素 (IL)-10 和 IL-22 基因敲除小鼠来研究 3-IAld 活性的机制。通过粪便微生物群移植 (FMT) 评估 3-IAld 诱导的微生物群变化的功能。最后，使用小鼠肿瘤模型评估 3-IAld 治疗对 ICI 抗肿瘤活性的影响。
在给予 ICI 诱导的结肠炎小鼠时，3-IAld 通过对宿主和微生物的双重作用来保护小鼠免受肠道损伤。实际上，与宿主 AhR/IL-22 依赖性途径的激活平行，3-IAld 还影响了微生物组的组成和功能，来自 3-IAld 处理小鼠的 FMT 可通过产生丁酸的细菌来预防 ICI 诱导的结肠炎。重要的是，虽然预防了肠道损伤，但 3-IAld 并没有损害 ICI 的抗肿瘤活性。
这项研究提供了一个概念验证，表明超越细菌系统发育并专注于细菌代谢组可能会产生一类新的离散分子，而在微生物和宿主免疫系统之间的界面上工作可能会优化 ICI 治疗。
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