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.
