Focusing on mechanisms by which gut microbiota improve antitumor immunity during checkpoint inhibitor therapy, Park and Gazzaniga et al. found several gram-positive anaerobes (e.g., C.cateniformis) that downregulated PD-L2 and its binding partner RGMb (which does not bind PD-L1). Blockade of PD-L2:RGMb interactions with antibodies or conditional deletion of RGMb in T cells, combined with PD-1 pathway inhibitors, promoted antitumor responses in multiple mouse tumor models known to be resistant to anti-PD-1 or anti-PD-L1 alone. Their results suggest that blockade of the PD-L2:RGMb pathway could be beneficial in patients who are non-responsive to PD-1.
Contributed by Katherine Turner
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 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.
Author Info: (1) Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA. (2) Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA, U
Author Info: (1) Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA. (2) Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA. Molecular Pathology Unit, Massachusetts General Hospital, Charlestown, MA, USA. Department of Pathology, Harvard Medical School, Boston, MA, USA. (3) Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA. (4) Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA. (5) Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA. (6) Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA. (7) Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA. (8) Program for Innovative Microbiome and Translational Research, Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (9) Program for Innovative Microbiome and Translational Research, Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (10) Program for Innovative Microbiome and Translational Research, Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (11) Program for Innovative Microbiome and Translational Research, Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (12) Program for Innovative Microbiome and Translational Research, Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (13) Program for Innovative Microbiome and Translational Research, Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (14) Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA. gordon_freeman@dfci.harvard.edu. (15) Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA. dennis_kasper@hms.harvard.edu. (16) Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA. arlene_sharpe@hms.harvard.edu. Department of Pathology, Harvard Medical School, Boston, MA, USA. arlene_sharpe@hms.harvard.edu.
