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

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

Research output: Contribution to journalArticlepeer-review

57 Scopus citations

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 mice1–6. 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 molecule b (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 T cells 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.

Original languageEnglish
Pages (from-to)377-385
Number of pages9
JournalNature
Volume617
Issue number7960
DOIs
StatePublished - May 11 2023

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