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

  • Nature. 2023 May;617(7960):377-385. doi: 10.1038/s41586-023-06026-3.
Joon Seok Park  #  1 ,  Francesca S Gazzaniga  #  1  2  3 ,  Meng Wu  1 ,  Amalia K Luthens  1 ,  Jacob Gillis  1 ,  Wen Zheng  1 ,  Martin W LaFleur  1 ,  Sarah B Johnson  4 ,  Golnaz Morad  4 ,  Elizabeth M Park  4  5  6 ,  Yifan Zhou  4  5 ,  Stephanie S Watowich  4  5 ,  Jennifer A Wargo  4  6  7 ,  Gordon J Freeman  8 ,  Dennis L Kasper  9 ,  Arlene H Sharpe  10  11
Affiliations
  • 1. Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.
  • 2. Molecular Pathology Unit, Massachusetts General Hospital, Charlestown, MA, USA.
  • 3. Department of Pathology, Harvard Medical School, Boston, MA, USA.
  • 4. Program for Innovative Microbiome and Translational Research, Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 5. Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 6. Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 7. Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 8. Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA. [email protected].
  • 9. Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA. [email protected].
  • 10. Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA. [email protected].
  • 11. Department of Pathology, Harvard Medical School, Boston, MA, USA. [email protected].
  • # Contributed equally.
PMID: 37138075 DOI: 10.1038/s41586-023-06026-3
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.

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