Targeting Pd-L2-RGMb Overcomes Microbiome-Related Immunotherapy Resistance

Authors

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

Publication Date

5-1-2023

Journal

Nature

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.

Keywords

Animals, Humans, Mice, Cell Adhesion Molecules, Neuronal, Disease Models, Animal, Down-Regulation, Drug Resistance, Neoplasm, Fecal Microbiota Transplantation, Germ-Free Life, Immune Checkpoint Inhibitors, Immunotherapy, Melanoma, Microbiota, Protein Binding, T-Lymphocytes

Comments

This article has been corrected. See Nature. 2023 Jun 1.

PMID: 37138075