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

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 i...

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Published in:	Nature (London) Vol. 617; no. 7960; pp. 377 - 385
Main Authors:	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.
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 11.05.2023 Nature Publishing Group
Subjects:	38 38/1 38/35 38/77 631/250/251 631/250/580 64 64/60 82 Animal models Animals Antibiotics Antibodies Bacteria Binding Cancer Cancer immunotherapy Cell Adhesion Molecules, Neuronal Clonal deletion Disease Models, Animal Down-Regulation Drug resistance Drug Resistance, Neoplasm - drug effects Effectiveness Fecal Microbiota Transplantation Feces Germ-Free Life Germfree Humanities and Social Sciences Humans Immune checkpoint inhibitors Immune Checkpoint Inhibitors - pharmacology Immune Checkpoint Inhibitors - therapeutic use Immunity Immunology Immunotherapy Inhibitors Intestinal microflora Investigations Lymphatic system Lymphocytes Lymphocytes T Melanoma - immunology Melanoma - microbiology Melanoma - therapy Mice Microbiomes Microbiota Microorganisms multidisciplinary PD-1 protein PD-L1 protein Protein Binding - drug effects Science Science (multidisciplinary) T-Lymphocytes - drug effects T-Lymphocytes - immunology Transplantation Transplants Transplants & implants Tumors
ISSN:	0028-0836, 1476-4687, 1476-4687
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Summary:	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 melanoma 7 , 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. Interactions between programmed death ligand 2 (PD-L2) and its binding partner RGMb are downregulated by the gut microbiota, a mechanism that may be exploited to enhance the efficacy of PD-1-based cancer immunotherapies.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 Author contributions: JSP, FSG, GJF, DLK, and AHS designed the experiments. JSP and FSG, performed the experiments. MW analyzed the 16S data. AKL, JG, MWL, and WZ assisted with the experiments. SBJ, GM, EMP, YZ, SSW, JAW provided patient stool samples. JSP and FSG analyzed the data. GJF generated PD-L1, PD-L2 and RGMb antibodies. JSP, FSG, GJF, DLK, and AHS wrote the manuscript. These authors contributed equally to this work.
ISSN:	0028-0836 1476-4687 1476-4687
DOI:	10.1038/s41586-023-06026-3