Pre-operative exercise therapy triggers anti-inflammatory trained immunity of Kupffer cells through metabolic reprogramming

Zhang, Hongji; Chen, Tianmeng; Ren, Jinghua; Xia, Yuxuan; Onuma, Amblessed E.; Yü, Wang; He, Jianzhong; Wu, Junru; Wang, Han; Hamad, Ahmad; Shen, Chengli; Zhang, Jinxiang; Asara, John M.; Behbehani, Gregory K.; Wen, Haitao; Deng, Meihong; Tsung, Allan; Huang, Hai

doi:10.1038/s42255-021-00402-x

Cited by 43 publications

(26 citation statements)

References 68 publications

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“…Flow cytometry data were acquired using a LSRFortessa Flow Cytometer (Becton Dickinson, Franklin Lakes, NJ, USA) with FASCDiva Software (Version 8.0.1, BD Pharmingen) and analyzed with Flowjo software (version 10). Gates and regions were placed around populations of cells with common characteristics, usually forward scatter, side scatter, and marker expression characteristics, to investigate and quantify these populations of interest [ 27 ].…”

Section: Methodsmentioning

confidence: 99%

Neutrophils Extracellular Traps Inhibition Improves PD-1 Blockade Immunotherapy in Colorectal Cancer

Zhang

Wang

Onuma

et al. 2021

Cancers

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Immune checkpoint inhibitors can improve the prognosis of patients with advanced malignancy; however, only a small subset of advanced colorectal cancer patients in microsatellite-instability-high or mismatch-repair-deficient colorectal cancer can benefit from immunotherapy. Unfortunately, the mechanism behind this ineffectiveness is unclear. The tumor microenvironment plays a critical role in cancer immunity, and may contribute to the inhibition of immune checkpoint inhibitors and other novel immunotherapies in patients with advanced cancer. Herein, we demonstrate that the DNase I enzyme plays a pivotal role in the degradation of NETs, significantly dampening the resistance to anti-PD-1 blockade in a mouse colorectal cancer model by attenuating tumor growth. Remarkably, DNase I decreases tumor-associated neutrophils and the formation of MC38 tumor cell-induced neutrophil extracellular trap formation in vivo. Mechanistically, the inhibition of neutrophil extracellular traps with DNase I results in the reversal of anti-PD-1 blockade resistance through increasing CD8+ T cell infiltration and cytotoxicity. These findings signify a novel approach to targeting the tumor microenvironment using DNase I alone or in combination with immune checkpoint inhibitors.

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Section: Methodsmentioning

confidence: 99%

Neutrophils Extracellular Traps Inhibition Improves PD-1 Blockade Immunotherapy in Colorectal Cancer

Zhang

Wang

Onuma

et al. 2021

Cancers

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“…IRG1 catalyzes the production of itaconate from aconatate. Itaconate hampers OXPHOS by inhibiting SDH, while it supports the activation of Nrf2 and contributes to innate immune tolerance, which is a mechanism that seems to be preserved also in Kupffer cells [96][97][98].…”

Section: Tca Cycle Glutaminolysis and Fatty Acid Oxidationmentioning

confidence: 99%

Metabolism-Associated Epigenetic and Immunoepigenetic Reprogramming in Liver Cancer

Fan

Kam

Ramadori

2021

Cancers

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Metabolic reprogramming and epigenetic changes have been characterized as hallmarks of liver cancer. Independently of etiology, oncogenic pathways as well as the availability of different energetic substrates critically influence cellular metabolism, and the resulting perturbations often cause aberrant epigenetic alterations, not only in cancer cells but also in the hepatic tumor microenvironment. Metabolic intermediates serve as crucial substrates for various epigenetic modulations, from post-translational modification of histones to DNA methylation. In turn, epigenetic changes can alter the expression of metabolic genes supporting on the one hand, the increased energetic demand of cancer cells and, on the other hand, influence the activity of tumor-associated immune cell populations. In this review, we will illustrate the most recent findings about metabolic reprogramming in liver cancer. We will focus on the metabolic changes characterizing the tumor microenvironment and on how these alterations impact on epigenetic mechanisms involved in the malignant progression. Furthermore, we will report our current knowledge about the influence of cancer-specific metabolites on epigenetic reprogramming of immune cells and we will highlight how this favors a tumor-permissive immune environment. Finally, we will review the current strategies to target metabolic and epigenetic pathways and their therapeutic potential in liver cancer, alone or in combinatorial approaches.

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“… 81 Preoperative exercise therapy triggered an anti‐inflammatory trained immunity phenotype via metabolic reprogramming and led to attenuation of liver injury and inflammation from ischemia in mouse models. 82 Sterile tissue injury trained the innate immune system, providing protection against subsequent infection in adult drosophila. 75 The excretory‐secretory products of Fasciola hepatica imprinted a long‐term anti‐inflammatory phenotype in myeloid cells.…”

Section: Mechanisms Of Trained Immunitymentioning

confidence: 99%

Trained immunity: A Yin‐Yang balance

Lowrie

et al. 2022

MedComm

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Traditionally, immune memory is regarded as an exclusive hallmark of adaptive immunity. However, a growing body of evidence suggesting that innate immune cells show adaptive characteristics has challenged this dogma. In the past decade, trained immunity, a de facto innate immune memory, has been defined as a long‐term functional reprogramming of cells of the innate immune system: the reprogramming is evoked by endogenous or exogenous insults, the cells return to a nonactivated state and subsequently show altered inflammatory responses against a second challenge. Trained immunity became regarded as a mechanism selected in evolution to protect against infection; however, a maladaptive effect might result in hyperinflammation. This dual effect is consistent with the Yin‐Yang theory in traditional Chinese philosophy, in which Yang represents active, positive, and aggressive factors, whereas Yin represents passive, negative, and inhibitory factors. In this review, we give a brief overview of history and latest progress about trained immunity, including experimental models, inductors, molecular mechanisms, clinical application and so on. Moreover, this is the first time to put forward the theory of Yin‐Yang balance to understand trained immunity. We envision that more efforts will be focused on developing novel immunotherapies targeting trained immunity in the coming years.

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Pre-operative exercise therapy triggers anti-inflammatory trained immunity of Kupffer cells through metabolic reprogramming

Cited by 43 publications

References 68 publications

Neutrophils Extracellular Traps Inhibition Improves PD-1 Blockade Immunotherapy in Colorectal Cancer

Neutrophils Extracellular Traps Inhibition Improves PD-1 Blockade Immunotherapy in Colorectal Cancer

Metabolism-Associated Epigenetic and Immunoepigenetic Reprogramming in Liver Cancer

Trained immunity: A Yin‐Yang balance

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