The microbial metabolite trimethylamine N-oxide promotes antitumor immunity in triple-negative breast cancer

Wang, Hai; Rong, Xingyu; Zhao, Genming; Zhou, Yifan; Xiao, Yi; Ma, Ding; Jin, Xi; Wu, Yihe; Yao, Yan; Yang, Hao; Zhou, Yuan; Qian, Manning; Niu, Chen; Hu, Xin; Li, Da‐Qiang; Liu, Qingyun; Wen, Yumei; Jiang, Yi‐Zhou; Zhao, Chao; Shao, Zhi-Ming

doi:10.1016/j.cmet.2022.02.010

Cited by 179 publications

(106 citation statements)

References 60 publications

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“…Thus, remodeling the tumor microenvironment to increase CD8+ T cell numbers and ignite the antitumor immune response may be a viable approach to sensitize tumors to immunotherapy ( 77 , 78 ). For example, Wang et al found that the microbial metabolite trimethylamine N-oxide could induce pyroptosis in breast cancer cells through protein kinase r-like ER kinase and ultimately enhance CD8+ T cell-mediated antitumor immunity ( 79 ). Moreover, combined treatment with BRAF and MEK inhibitors induces GSDME-dependent pyroptosis in melanoma cells and subsequently increases the number of intratumoral CD8+ T cells ( 66 ).…”

Section: Discussionmentioning

confidence: 99%

Optimization of cancer immunotherapy through pyroptosis: A pyroptosis-related signature predicts survival benefit and potential synergy for immunotherapy in glioma

et al. 2022

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BackgroundPyroptosis is a critical type of programmed cell death that is strongly associated with the regulation of tumor and immune cell functions. However, the role of pyroptosis in tumor progression and remodeling of the tumor microenvironment in gliomas has not been extensively studied. Thus, in this study, we aimed to establish a comprehensive pyroptosis-related signature and uncover its potential clinical application in gliomas.MethodsThe TCGA glioma cohort was obtained and divided into training and internal validation cohorts, while the CGGA glioma cohort was used as an external validation cohort. Unsupervised consensus clustering was performed to identify pyroptosis-related expression patterns. A Cox regression analysis was performed to establish a pyroptosis-related risk signature. Real-time quantitative PCR was performed to analyze the expression of signature genes in glioma tissues. Immune infiltration was analyzed and validated by immunohistochemical staining. The expression patterns of signature genes in different cell types were analyzed using single-cell RNA sequencing data. Finally, therapeutic responses to chemotherapy, immunotherapy, and potential small-molecule inhibitors were investigated.ResultsPatients with glioma were stratified into clusters 1 and 2 based on the expression patterns of pyroptosis-related genes. Cluster 2 showed a longer overall (P<0.001) and progression-free survival time (P<0.001) than Cluster 1. CD8+ T cell enrichment was observed in Cluster 1. A pyroptosis-related risk signature (PRRS) was then established. The high PRRS group showed a significantly poorer prognosis than the low PRRS group in the training cohort (P<0.001), with validation in the internal and external validation cohorts. Immunohistochemical staining demonstrated that CD8+ T cells were enriched in high PRRS glioma tissues. PRRS genes also showed cell-specific expression in tumor and immune cells. Moreover, the high PRRS risk group showed higher temozolomide sensitivity and increased response to anti-PD1 treatment in a glioblastoma immunotherapy cohort. Finally, Bcl-2 inhibitors were screened as candidates for adjunct immunotherapy of gliomas.ConclusionThe pyroptosis-related signature established in this study can be used to reliably predict clinical outcomes and immunotherapy responses in glioma patients. The correlation between the pyroptosis signature and the tumor immune microenvironment may be used to further guide the sensitization of glioma patients to immunotherapy.

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Section: Discussionmentioning

confidence: 99%

Optimization of cancer immunotherapy through pyroptosis: A pyroptosis-related signature predicts survival benefit and potential synergy for immunotherapy in glioma

et al. 2022

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“…The main cadaverine-producing bacteria include Aeromonas veronii, Clostridium perfringens, E. coli, Edwardsiella tarda, Hafnia alvei, Raoultella ornithinolytica, Staphylococcus , and Streptomyces species ( Kovacs et al, 2019b ). Recently, Wang et al (2022) found that Clostridiales and the related metabolite trimethylamine N-oxide (TMAO) were more abundant in tumors with an activated immune microenvironment, which could activate the endoplasmic reticulum stress kinase PERK and enhance CD8 + T cell-mediated antitumor immunity in TNBC in vivo . In other tumor models, it was also found that inosine produced by Bifidobacterium pseudolongum can promote Th1 cell differentiation and enhance the effect of immunotherapy mediated by T cell-specific adenosine 2A receptor (A2AR) signaling ( Mager et al, 2020 ).…”

Section: The Role Of Distinct Microbiota In Breast Cancer Tumorigenes...mentioning

confidence: 99%

“…Moreover, these microbiota produced trimethylamine oxide to induce GSDME-mediated pyroptosis of BC cells and recruit CD8 + T cells in the microenvironment. This activated immune environment significantly promotes the response to immunotherapy ( Wang et al, 2022 ). Pretreatment optimization of the gut or tumor microbiota may be a viable strategy for immunotherapy sensitization.…”

Section: Role Of the Microbiota In The Therapy Response Of Breast Cancermentioning

confidence: 99%

New Developments and Opportunities of Microbiota in Treating Breast Cancers

Meng

Zhu

et al. 2022

Front. Microbiol.

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Despite the prevalence of breast cancer (BC), over half of BC cases are unrelated to known risk factors, which highlights the importance of uncovering more cancer-related factors. Currently, the microbiota has been proven to be a potent modulator of the tumor environment in BC, which regulates the immune balance in tumor-related networks. Through a large amount of data accumulation, the microbiota has shown many possibilities to reveal more insights into the development or control of BC. To expand the potential benefits of patients with BC, this study discusses the distribution profile and the effect mechanism of BC-related microbiota on tumors and further discusses its impact on different tumor therapies. Finally, we summarize the possibility of targeting microbiological therapies to improve BC treatment or in combination with other therapies.

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“…Of interest, this large study showed, in contrast with guidelines, that low intake of red and processed meat after colon cancer is associated with an increased risk of death (HR Q1 vs. Q4, 1.72; 95% CI: 1.15–2.58). The microbial metabolite trimethylamine N-oxide (TMAO) has been shown to boost CD8+ T cell-mediated antitumor immunity by inducing pyroptosis in tumour cells, enhancing the efficacy of immunotherapy in triple-negative breast cancer [25]. It therefore appears that patients with cancer but not receiving anticancer therapies should receive a diet providing >1.0 g/kg BW/day, mostly based on animal proteins yet with a substantial proportion of plant protein (i.e., approximately 1/3 of the total intake).…”

Section: The Quality Of Protein Intake As a Key Determinants Of Outcomesmentioning

confidence: 99%

High protein diet in digestive cancers

Laviano¹

2022

Current Opinion in Clinical Nutrition &Amp; Metabolic Care

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Purpose of reviewRecent advances in the nutritional management of patients with digestive cancers suggest that modulation of protein intake may significantly contribute to achieve nutritional and clinical benefits. By reviewing the available evidence, a quantitatively and qualitatively optimal protein intake could be derived.Recent findingsHigh protein diets (i.e., 1–1.5 g/kg body weight/day) appear key to maintain the adequate nutritional status, and may also contribute to achieve clinical benefits. This target appears particularly relevant in patients with digestive cancers at risk or already malnourished, or in older patients. During active cancer treatments, protein intake should be closer to the upper limit of the recommended intake. Also, high protein intake should be maintained beyond the periods of catabolic crisis associated with active treatments. In contrast with general reasoning, animal proteins should represent the majority of the recommended intake. Based on the available evidence, the intake of no specific amino acid can be strongly recommended to enhance anabolic potentials or the immune modulating effects of high protein diets.SummaryHigh protein intake, mostly based on animal proteins, should be recommended to patients with digestive cancers. However, this target should be translated into clinical prescription after considering the clinical and metabolic needs of the patients. The quest for the optimal protein intake of patients with cancer at different time points of their clinical journey is still open.

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The microbial metabolite trimethylamine N-oxide promotes antitumor immunity in triple-negative breast cancer

Cited by 179 publications

References 60 publications

Optimization of cancer immunotherapy through pyroptosis: A pyroptosis-related signature predicts survival benefit and potential synergy for immunotherapy in glioma

Optimization of cancer immunotherapy through pyroptosis: A pyroptosis-related signature predicts survival benefit and potential synergy for immunotherapy in glioma

New Developments and Opportunities of Microbiota in Treating Breast Cancers

High protein diet in digestive cancers

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