Fusobacterium nucleatum enhances the efficacy of PD-L1 blockade in colorectal cancer

Yaohui Gao,Tingting Ding,Xianling Guo,Jiayi Zheng,Huanlong Qin,Dexi Bi,Yuan Cao,Huiyuan Zhu,Meichun Xing,Qing Xu,Jing Guo,Hu Liu,Man Li,Qing Wei,Qian Xu,Ruting Xie,Juemin Fang

doi:10.1038/s41392-021-00795-x

Yaohui Gao, Tingting Ding + Show 15 more

Open Access

https://doi.org/10.1038/s41392-021-00795-x

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Abstract

Given that only a subset of patients with colorectal cancer (CRC) benefit from immune checkpoint therapy, efforts are ongoing to identify markers that predict immunotherapeutic response. Increasing evidence suggests that microbes influence the efficacy of cancer therapies. Fusobacterium nucleatum induces different immune responses in CRC with different microsatellite-instability (MSI) statuses. Here, we investigated the effect of F. nucleatum on anti-PD-L1 therapy in CRC. We found that high F. nucleatum levels correlate with improved therapeutic responses to PD-1 blockade in patients with CRC. Additionally, F. nucleatum enhanced the antitumor effects of PD-L1 blockade on CRC in mice and prolonged survival. Combining F. nucleatum supplementation with immunotherapy rescued the therapeutic effects of PD-L1 blockade. Furthermore, F. nucleatum induced PD-L1 expression by activating STING signaling and increased the accumulation of interferon-gamma (IFN-γ)+ CD8+ tumor-infiltrating lymphocytes (TILs) during treatment with PD-L1 blockade, thereby augmenting tumor sensitivity to PD-L1 blockade. Finally, patient-derived organoid models demonstrated that increased F. nucleatum levels correlated with an improved therapeutic response to PD-L1 blockade. These findings suggest that F. nucleatum may modulate immune checkpoint therapy for CRC.

Highlights

Immunotherapy has been successfully used to treat a variety of hematological and solid metastatic malignancies in the clinic.[1]
Since some patients with microsatellite-instabilityhigh (MSI-H) or mismatch repair-deficient colorectal cancer (CRC) appear to be susceptible to PD-1/PD-L1 blockade,[21] we detected the this effect is independent of the routes for F. nucleatum administration
The DH-5α that was used as a control, did not affect the proportions of CD4+, CD8+ and FOXP3+ tumor-infiltrating lymphocytes (TILs) during anti-PD-L1 mAb treatment (Supplemen-To further examine the role of F. nucleatum in the treatment of tary Fig. S6a, b). These results suggest that F. nucleatum CRC with PD-L1 blockade, the tumor growth experiment was supplementation increases the proportion of CD8+ TILs in mice validated with the bacterium administered via gavage

Summary

Introduction

Immunotherapy has been successfully used to treat a variety of hematological and solid metastatic malignancies in the clinic.[1]. It remains challenging to identify CRC patients who will respond to anti-PD-1/PD-L1 treatment, which is necessary to improve the efficacy of this treatment

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