Gut Microbiota Regulate PD-L2 Expression and Immunotherapy Response

Inhibition of the PD-1/PD-L1 immune checkpoint has revolutionized the treatment of cancer, but patient response rates are highly variable. Although gut bacteria have been shown to regulate antitumor immunity, how exactly the microbiota mediates this phenomenon remains unclear. In this study, Park, Gazzaniga, and colleagues sought to identify factors that influence responsiveness to anti–PD-1–based immunotherapy using mouse models with different microbiota constitutions. While germ-free (GF) or antibiotic-treated tumor-bearing mice did not respond to anti–PD-1/PD-L1 treatment, reconstitution with healthy human microbiota (HMB) promoted effective antitumor immune responses by immune checkpoint inhibition. Increased levels of CD4⁺ and CD8⁺ T cells and MHCII⁺CD11b⁺ dendritic cells (DC) were observed in the tumor-draining lymph nodes of HMB-reconstituted mice, and DCs exhibited decreased expression of immune checkpoint molecule PD-L2, suggesting that HMB colonization mediates the antitumor immune response through PD-L2 downregulation. Treatment with combination anti–PD-L1 and anti–PD-L2 reduced tumor growth in GF and antibiotic-treated mice, while neither showed efficacy as a single agent. As expected, GF mice colonized with microbiota from a patient with complete response to anti–PD-1 treatment similarly responded to anti–PD-L1, while those colonized with microbiota from nonresponders responded only to the combination therapy, indicating that responders have specific gut bacteria that suppress PD-L2 expression and thereby increase the efficacy of anti–PD-L1 or anti–PD-1 monotherapy. Indeed, Coprobacillus cateniformis colonization was demonstrated to reduce PD-L2 expression on DCs, leading to increased CD8⁺ T-cell activity and stronger tumor control with anti–PD-L1 therapy. Investigation into whether the PD-L2 effect is mediated through its alternate binding partner, RGMb, demonstrated that blockade of the PD-L2–RGMb interaction was sufficient to enhance the response to anti–PD-1/PD-L1 therapy in GF and antibiotic-treated mice. RGMb expression was elevated on tumor-infiltrating CD8⁺ T cells in nonresponders such as GF or antibiotic-treated mice, and both anti-RGMb treatment and T cell–specific deletion of Rgmb improved the response to anti–PD-L1 therapy in antibiotic-treated mice. In summary, this work reveals that downregulation of PD-L2 expression on DCs is a mechanism by which the “good” gut microbiota impacts immunotherapy response.

Park JS, Gazzaniga FS, Wu M, Luthens AK, Gillis J, Zheng W, et al. Targeting PD-L2–RGMb overcomes microbiome-related immunotherapy resistance. Nature 2023;617:377–85.

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