文章：

在结直肠癌模型中，饮食性甲硫氨酸限制增强对免疫检查点抑制剂的反应

Increased Response to Immune Checkpoint Inhibitors with Dietary Methionine Restriction in a Colorectal Cancer Model

原文发布日期：7 September 2023

DOI: 10.3390/cancers15184467

类型: Article

开放获取: 是

英文摘要：

Dietary methionine restriction (MR), defined as a reduction of methionine intake by around 80%, has been shown to reproducibly decrease tumor growth and synergize with cancer therapies. In this study, we combined DMR with immune checkpoint inhibitors (ICIs) in a model of colon adenocarcinoma. In vitro, we observed that MR increased the expression of MHC-I and PD-L1 in both mouse and human colorectal cancer cells. We also saw an increase in the gene expression of STING, a known inducer of type I interferon signaling. Inhibition of the cGAS–STING pathway, pharmacologically or with siRNA, blunted the increase in MHC-I and PD-L1 surface and gene expression following MR. This indicated that the cGAS–STING pathway, and interferon in general, played a role in the immune response to MR. We then combined dietary MR with ICIs targeting CTLA-4 and PD-1 in an MC38 colorectal cancer tumor model developed in immunocompetent C57BL/6 mice. The combination treatment was five times more effective at reducing the tumor size than ICIs alone in male mice. We noted sex differences in the response to dietary MR, with males showing a greater response than females. Finally, we observed an increase in membrane staining for the PD-L1 protein in MC38 tumors from animals who were fed an MR diet. MHC-I was highly expressed in all tumors and showed no expression difference when comparing tumors from control and MR-treated mice. These results indicated that MR increased PD-L1 expression both in vitro and in vivo and improved the response to ICIs in mice.

摘要翻译： 

饮食性甲硫氨酸限制（MR），即甲硫氨酸摄入量减少约80%，已被证实可重复性地抑制肿瘤生长，并与癌症疗法产生协同作用。本研究在结肠腺癌模型中，将饮食性甲硫氨酸限制与免疫检查点抑制剂（ICIs）联合应用。体外实验发现，MR能上调小鼠和人结直肠癌细胞中MHC-I和PD-L1的表达水平。同时，我们观察到I型干扰素信号通路的已知诱导因子STING的基因表达也有所增加。通过药物或siRNA抑制cGAS-STING通路，可减弱MR引起的MHC-I和PD-L1表面及基因表达的上调。这表明cGAS-STING通路及干扰素信号在MR诱导的免疫应答中发挥重要作用。随后，我们在免疫正常的C57BL/6小鼠建立的MC38结直肠癌模型中，将饮食性MR与靶向CTLA-4和PD-1的ICIs联合使用。联合治疗在雄性小鼠中缩小肿瘤体积的效果是单用ICIs的5倍。我们注意到饮食性MR的疗效存在性别差异，雄性小鼠的反应优于雌性。最后，在MR饮食喂养的小鼠MC38肿瘤中，观察到PD-L1蛋白膜染色增强。所有肿瘤中MHC-I均呈高表达，且对照组与MR处理组小鼠的肿瘤间未见表达差异。这些结果表明，MR在体外和体内均能上调PD-L1表达，并增强小鼠对ICIs的治疗反应。

原文链接：

Increased Response to Immune Checkpoint Inhibitors with Dietary Methionine Restriction in a Colorectal Cancer Model