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

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

doi:10.1038/s41392-021-00795-x

Cited by 132 publications

(107 citation statements)

References 39 publications

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“…After establishing tumor models in mice by orthotopic transplantation, these cancer organoids can predict the efficacy of PD-1/PD-L1 blockade as well as other treatment regimens [ 258 – 261 ]. These studies used organoids to investigate PD-1/PD-L1 interaction in various aspects, including testing the anticancer efficacy of PD-1/PD-L1 inhibitors [ 261 – 263 ], analyzing the regulation mechanism of PD-L1 expression [ 258 , 259 ], finding strategies to enhance the therapeutic effect of PD-1/PD-L1 blockade [ 260 , 264 – 268 ], finding new immune checkpoints [ 269 ]. Through these studies, we can see that cancer organoids can be used to simulate the immune microenvironment in cancer patients, providing an effective tool for improving the efficacy of PD-1/PD-L1 blockade.…”

Section: Preclinical Models Used In Research About Pd-1/pd-l1 Blockadementioning

confidence: 99%

Improvement of the anticancer efficacy of PD-1/PD-L1 blockade via combination therapy and PD-L1 regulation

et al. 2022

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Immune checkpoint molecules are promising anticancer targets, among which therapeutic antibodies targeting the PD-1/PD-L1 pathway have been widely applied to cancer treatment in clinical practice and have great potential. However, this treatment is greatly limited by its low response rates in certain cancers, lack of known biomarkers, immune-related toxicity, innate and acquired drug resistance, etc. Overcoming these limitations would significantly expand the anticancer applications of PD-1/PD-L1 blockade and improve the response rate and survival time of cancer patients. In the present review, we first illustrate the biological mechanisms of the PD-1/PD-L1 immune checkpoints and their role in the healthy immune system as well as in the tumor microenvironment (TME). The PD-1/PD-L1 pathway inhibits the anticancer effect of T cells in the TME, which in turn regulates the expression levels of PD-1 and PD-L1 through multiple mechanisms. Several strategies have been proposed to solve the limitations of anti-PD-1/PD-L1 treatment, including combination therapy with other standard treatments, such as chemotherapy, radiotherapy, targeted therapy, anti-angiogenic therapy, other immunotherapies and even diet control. Downregulation of PD-L1 expression in the TME via pharmacological or gene regulation methods improves the efficacy of anti-PD-1/PD-L1 treatment. Surprisingly, recent preclinical studies have shown that upregulation of PD-L1 in the TME also improves the response and efficacy of immune checkpoint blockade. Immunotherapy is a promising anticancer strategy that provides novel insight into clinical applications. This review aims to guide the development of more effective and less toxic anti-PD-1/PD-L1 immunotherapies.

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Section: Preclinical Models Used In Research About Pd-1/pd-l1 Blockadementioning

confidence: 99%

Improvement of the anticancer efficacy of PD-1/PD-L1 blockade via combination therapy and PD-L1 regulation

et al. 2022

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“…Fusobacterium nucleatum was enriched in dMMR/MSI-H CRC and associated with lower number of tumour-infiltrating lymphocytes while the opposite has been suggested for MSS colorectal cancer ( 34 ). However, somewhat counterintuitively, F. nucleatum has been found to be positively associated with response to checkpoint inhibitors, enhancing the expression of PD-1 and PD-L1 and activating the stimulator of interferon genes (STING) signalling ( 35 ). The activity of interferon-γ pathway was also associated with response in dMMR/MSI-H CRC in a recent transcriptomics study while VEGF-A expression characterised poor responders ( 36 ).…”

Section: Biomarkers Of Immunotherapy Efficacy In Dmmr/msi-h Mcrcmentioning

confidence: 99%

Microsatellite Instability and Metastatic Colorectal Cancer – A Clinical Perspective

Büchler

2022

Front. Oncol.

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Approximately 4-5% of patients with metastatic colorectal cancer (mCRC) have mismatch repair deficient (dMMR)/microsatellite instability-high (MSI-H) tumours. These tumours present challenges in the clinical practice due to variant response to fluoropyrimidine-based chemotherapy and, perhaps, also non-immunologic targeted therapies. Recently, a breakthrough in the treatment of dMMR/MSI-H mCRC has been achieved with several clinical trials showing dramatic long-term benefit of immunotherapy using checkpoint inhibitors. Nevertheless, several questions remain regarding the optimisation of immunotherapy regimens and the use of biomarkers to identify populations set to derive the greatest benefit from immunotherapy. Combination regimens and/or the use of immunotherapy as a maintenance after induction non-immunologic systemic therapy may be the way forward to improve outcomes.

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“…Since 2015, multiple studies have elucidated that the composition of gut microbiota was associated with the efficacy of anti-PD-1 therapy (8,9). Notably, three groups (10)(11)(12) reported their work in 2018 observing highly diversified bacterial features (i.e.…”

Section: Introductionmentioning

confidence: 99%

“…Human intestine harbors more than 10 13 microorganisms, which play a key role in mediating human health and disease via shaping systematic and local immune functions (7). Since 2015, multiple studies have elucidated that the composition of gut microbiota was associated with the efficacy of anti-PD-1 therapy (8, 9). Notably, three groups (10-12) reported their work in 2018 observing highly diversified bacterial features (i.e.…”

Section: Introductionmentioning

confidence: 99%

Metagenomic and Metabolomic Analyses Reveal Synergistic Effects of Fecal Microbiota Transplantation and Anti-PD-1 Therapy on Treating Colorectal Cancer

Huang

Zheng

Kang

et al. 2022

Preprint

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Anti-PD-1 immunotherapy has saved numerous lives of cancer patients; however, it only exerts efficacy in 10-15% of patients with colorectal cancer. Fecal microbiota transplantation (FMT) is a potential approach to improving the efficacy of anti-PD-1 therapy, whereas the detailed mechanisms and the applicability of this combination therapy remain unclear. In this study, we evaluated the synergistic effect of FMT with anti-PD-1 in curing colorectal tumor-bearing mice using a multi-omics approach. Mice treated with the combination therapy showed superior survival rate and tumor control, compared to the mice received anti-PD-1 therapy or FMT alone. Metagenomic analysis showed that composition of gut microbiota in tumor-bearing mice treated with anti-PD-1 therapy was remarkably altered through receiving FMT. Particularly, Bacteroides genus, including FMT-increased B. thetaiotaomicron, B. fragilis, and FMT-decreased B. ovatus might contribute to the enhanced efficacy of anti-PD-1 therapy. Furthermore, metabolomic analysis upon mouse plasma revealed several potential metabolites that upregulated after FMT, including punicic acid and aspirin, might promote the response to anti-PD-1 therapy via their immunomodulatory functions. This work broadens our understanding of the mechanism by which FMT improves the efficacy of anti-PD-1 therapy, which may contribute to the development of novel microbiota-based anti-cancer therapies.

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

Cited by 132 publications

References 39 publications

Improvement of the anticancer efficacy of PD-1/PD-L1 blockade via combination therapy and PD-L1 regulation

Improvement of the anticancer efficacy of PD-1/PD-L1 blockade via combination therapy and PD-L1 regulation

Microsatellite Instability and Metastatic Colorectal Cancer – A Clinical Perspective

Metagenomic and Metabolomic Analyses Reveal Synergistic Effects of Fecal Microbiota Transplantation and Anti-PD-1 Therapy on Treating Colorectal Cancer

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