1. Targeting PD-L2-RGMb overcomes microbiome-related immunotherapy resistance.
- Author
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Park JS, Gazzaniga FS, Wu M, Luthens AK, Gillis J, Zheng W, LaFleur MW, Johnson SB, Morad G, Park EM, Zhou Y, Watowich SS, Wargo JA, Freeman GJ, Kasper DL, and Sharpe AH
- Subjects
- Animals, Humans, Mice, Cell Adhesion Molecules, Neuronal, Disease Models, Animal, Down-Regulation, Fecal Microbiota Transplantation, Germ-Free Life, Immune Checkpoint Inhibitors pharmacology, Immune Checkpoint Inhibitors therapeutic use, Protein Binding drug effects, T-Lymphocytes drug effects, T-Lymphocytes immunology, Drug Resistance, Neoplasm drug effects, Immunotherapy, Melanoma immunology, Melanoma microbiology, Melanoma therapy, Microbiota
- 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 mice
1-6 . 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., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)- Published
- 2023
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