Journal Article

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

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

2023

Overview

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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 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