小柯机器人

美国哈佛医学院Arlene H. Sharpe等研究人员合作发现，靶向PD-L2-RGMb克服与微生物相关的免疫疗法抗性。相关论文于2023年5月3日在线发表在《自然》杂志上。

研究人员表明，肠道微生物组下调PD-L2的表达及其结合伙伴排斥性引导分子b（RGMb），从而促进抗肿瘤免疫，并确定了介导这一效果的细菌种类。PD-L1和PD-L2共享PD-1作为结合伙伴，但PD-L2也可以结合RGMb。研究人员证明，阻断PD-L2-RGMb的相互作用可以克服微生物对PD-1通路抑制剂的依赖性抵抗。抗体介导的对PD-L2-RGMb通路的阻断或T细胞中RGMb的条件性缺失与抗PD-1或抗PD-L1抗体相结合，可促进多种小鼠肿瘤模型的抗肿瘤反应，而这些模型对单独的抗PD-1或抗PD-L1没有反应（无菌小鼠、抗生素处理的小鼠，甚至用对治疗无反应病人的粪便样本定居的小鼠）。

这些研究确定了PD-L2-RGMb途径的下调是肠道微生物群可以促进对PD-1检查点阻断的反应的一种特定机制。这些结果还确定了一种潜在的有效免疫学策略，可用于治疗对PD-1癌症免疫疗法没有反应的患者。

据悉，在免疫检查点抑制剂治疗期间，肠道微生物群是抗肿瘤免疫的一个重要调节因素。人们已经在小鼠身上发现了几种促进对免疫检查点抑制剂的抗肿瘤反应的细菌。此外，移植应答者的粪便标本可以提高黑色素瘤患者的抗PD-1疗法的疗效。然而，粪便移植所增加的疗效是可变的，肠道细菌如何促进抗肿瘤免疫力仍不清楚。

附：英文原文

Title: Targeting PD-L2–RGMb overcomes microbiome-related immunotherapy resistance

Author: Park, Joon Seok, Gazzaniga, Francesca S., Wu, Meng, Luthens, Amalia K., Gillis, Jacob, Zheng, Wen, LaFleur, Martin W., Johnson, Sarah B., Morad, Golnaz, Park, Elizabeth M., Zhou, Yifan, Watowich, Stephanie S., Wargo, Jennifer A., Freeman, Gordon J., Kasper, Dennis L., Sharpe, Arlene H.

Issue&Volume: 2023-05-03

Abstract: The gut microbiota is a crucial regulator of anti-tumour immunity during immune checkpoint inhibitor therapy. Several bacteria that promote an anti-tumour response to immune checkpoint inhibitors have been identified in mice1,2,3,4,5,6. Moreover, transplantation of faecal specimens from responders can improve the efficacy of anti-PD-1 therapy in patients with melanoma7,8. However, the increased efficacy from faecal transplants is variable and how gut bacteria promote anti-tumour immunity remains unclear. Here we show that the gut microbiome downregulates PD-L2 expression and its binding partner repulsive guidance moleculeb (RGMb) to promote anti-tumour immunity and identify bacterial species that mediate this effect. PD-L1 and PD-L2 share PD-1 as a binding partner, but PD-L2 can also bind RGMb. We demonstrate that blockade of PD-L2–RGMb interactions can overcome microbiome-dependent resistance to PD-1 pathway inhibitors. Antibody-mediated blockade of the PD-L2–RGMb pathway or conditional deletion of RGMb in Tcells combined with an anti-PD-1 or anti-PD-L1 antibody promotes anti-tumour responses in multiple mouse tumour models that do not respond to anti-PD-1 or anti-PD-L1 alone (germ-free mice, antibiotic-treated mice and even mice colonized with stool samples from a patient who did not respond to treatment). These studies identify downregulation of the PD-L2–RGMb pathway as a specific mechanism by which the gut microbiota can promote responses to PD-1 checkpoint blockade. The results also define a potentially effective immunological strategy for treating patients who do not respond to PD-1 cancer immunotherapy.

DOI: 10.1038/s41586-023-06026-3

Source: https://www.nature.com/articles/s41586-023-06026-3

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
官方网址：http://www.nature.com/
投稿链接：http://www.nature.com/authors/submit_manuscript.html