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 () and Arlene H. Sharpe ()
Additional contact information
Joon Seok Park: Blavatnik Institute, Harvard Medical School
Francesca S. Gazzaniga: Blavatnik Institute, Harvard Medical School
Meng Wu: Blavatnik Institute, Harvard Medical School
Amalia K. Luthens: Blavatnik Institute, Harvard Medical School
Jacob Gillis: Blavatnik Institute, Harvard Medical School
Wen Zheng: Blavatnik Institute, Harvard Medical School
Martin W. LaFleur: Blavatnik Institute, Harvard Medical School
Sarah B. Johnson: The University of Texas MD Anderson Cancer Center
Golnaz Morad: The University of Texas MD Anderson Cancer Center
Elizabeth M. Park: The University of Texas MD Anderson Cancer Center
Yifan Zhou: The University of Texas MD Anderson Cancer Center
Stephanie S. Watowich: The University of Texas MD Anderson Cancer Center
Jennifer A. Wargo: The University of Texas MD Anderson Cancer Center
Gordon J. Freeman: Dana-Farber Cancer Institute, Harvard Medical School
Dennis L. Kasper: Blavatnik Institute, Harvard Medical School
Arlene H. Sharpe: Blavatnik Institute, Harvard Medical School

Nature, 2023, vol. 617, issue 7960, 377-385

Abstract: 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.

Date: 2023
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41586-023-06026-3 Abstract (text/html)
Access to the full text of the articles in this series is restricted.

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:nature:v:617:y:2023:i:7960:d:10.1038_s41586-023-06026-3

Ordering information: This journal article can be ordered from
https://www.nature.com/

DOI: 10.1038/s41586-023-06026-3

Access Statistics for this article

Nature is currently edited by Magdalena Skipper

More articles in Nature from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().