2. Academic Validation
  3. Targeting PD-L2-RGMb overcomes microbiome-related immunotherapy resistance

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

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. gordon_freeman@dfci.harvard.edu.
  • 9 Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA. dennis_kasper@hms.harvard.edu.
  • 10 Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA. arlene_sharpe@hms.harvard.edu.
  • 11 Department of Pathology, Harvard Medical School, Boston, MA, USA. arlene_sharpe@hms.harvard.edu.
  • # 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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