Myeloid-derived itaconate suppresses cytotoxic CD8+ T cells and promotes tumour growth

Zhao, Hongyun; Teng, Da; Yang, Lifeng; Xu, Xincheng; Chen, Jiajia; Jiang, Teng-Jia; Feng, Austin Y.; Zhang, Yaqing; Frederick, Dennie T.; Gu, Lei; Li, Cai; Asara, John M.; Magliano, Marina Pasca di; Boland, Genevieve M.; Flaherty, Keith T.; Swanson, Kenneth D.; Liu, David; Rabinowitz, Joshua D.; Zheng, Bin

doi:10.1038/s42255-022-00676-9

Cited by 64 publications

(50 citation statements)

References 42 publications

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“…Despite different cell types and mechanisms of ITA action, non–cell-autonomous T cell proliferation versus cell-autonomous macrophage polarization, the study by Zhao et al. ( 37 ) and our current study show that deletion of Irg1 in mice enhances antitumor immunity.…”

Section: Discussioncontrasting

confidence: 44%

“…Zhao et al. ( 37 ) recently reported that intracellular ITA was higher in polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) than that in naïve bone marrow cells, and they proposed non–cell-autonomous mechanism in which ITA produced by myeloid cells is secreted out, up-taken by T cells, and then attenuates CD8 + T cell proliferation and function Differently, the data presented here support a cell-autonomous mechanism in which ITA produced by myeloid cells regulates gene expression within TAMs, in part, via inhibiting Tet2, thereby changing TAM inflammatory features and their role in recruiting CD8 + T cells into tumor sites. In our mouse tumor models, we cannot detect the intracellular accumulation of ITA in tumor-infiltrating lymphocytes (CD45 + CD11b − ) (fig.…”

Section: Discussionmentioning

confidence: 99%

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Targeting IRG1 reverses the immunosuppressive function of tumor-associated macrophages and enhances cancer immunotherapy

Chen

et al. 2023

Sci. Adv.

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Immune-responsive gene 1 (IRG1) encodes aconitate decarboxylase (ACOD1) that catalyzes the production of itaconic acids (ITAs). The anti-inflammatory function of IRG1/ITA has been established in multiple pathogen models, but very little is known in cancer. Here, we show that IRG1 is expressed in tumor-associated macrophages (TAMs) in both human and mouse tumors. Mechanistically, tumor cells induce Irg1 expression in macrophages by activating NF-κB pathway, and ITA produced by ACOD1 inhibits TET DNA dioxygenases to dampen the expression of inflammatory genes and the infiltration of CD8 + T cells into tumor sites. Deletion of Irg1 in mice suppresses the growth of multiple tumor types and enhances the efficacy of anti–PD-(L)1 immunotherapy. Our study provides a proof of concept that ACOD1 is a potential target for immune-oncology drugs and IRG1 -deficient macrophages represent a potent cell therapy strategy for cancer treatment even in pancreatic tumors that are resistant to T cell–based immunotherapy.

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Section: Discussioncontrasting

confidence: 44%

Section: Discussionmentioning

confidence: 99%

Targeting IRG1 reverses the immunosuppressive function of tumor-associated macrophages and enhances cancer immunotherapy

Chen

et al. 2023

Sci. Adv.

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“…Knockdown of IRG1, on the other hand, leads to a decrease in migration and invasion (Pan et al, 2014) and reduced tumor growth (Weiss et al, 2018). In agreement, the survival of metastatic melanoma patients treated with anti-PD-1 immune checkpoint blockade is longer if they express low levels of IRG1 compared to those where IRG1 expression is high (Zhao et al, 2022). Additionally, the levels of microRNA-378, which targets IRG1, are decreased in glioma (Shi et al, 2018).…”

Section: Itaconatementioning

confidence: 88%

“…In addition to its function in inflammation and immunity, a role for IRG1 in cancer and anti-tumor immunity has also been described. Thus, exposure of RAW264.7 cells to tumor-conditioned medium increases the levels of IRG1 and itaconate secretion ( Zhao et al, 2022 ), and xenografted human cancer cells activate the Irg1-EGFP reporter in zebrafish ( Sanderson et al, 2015 ). Furthermore, itaconate is secreted from tumor-associated MDSCs and suppresses the proliferation, cytotoxic activity and immune effector functions of CD8 + T-cells, whereas loss of IRG1 (and the corresponding decrease in itaconate levels) enhances their anti-tumor activity and increases the sensitivity to anti-PD-1 immune checkpoint blockade in mice ( Zhao et al, 2022 ).…”

Section: Endogenous Nrf2 Activators In the Tumor Immune Microenvironmentmentioning

confidence: 99%

“…Thus, exposure of RAW264.7 cells to tumor-conditioned medium increases the levels of IRG1 and itaconate secretion ( Zhao et al, 2022 ), and xenografted human cancer cells activate the Irg1-EGFP reporter in zebrafish ( Sanderson et al, 2015 ). Furthermore, itaconate is secreted from tumor-associated MDSCs and suppresses the proliferation, cytotoxic activity and immune effector functions of CD8 + T-cells, whereas loss of IRG1 (and the corresponding decrease in itaconate levels) enhances their anti-tumor activity and increases the sensitivity to anti-PD-1 immune checkpoint blockade in mice ( Zhao et al, 2022 ). The levels of IRG1 are increased in monocytes isolated from ascites fluid of ovarian carcinoma patients ( Weiss et al, 2018 ) and in glioma tumors, where this increase is associated with disease progression and poor prognosis ( Pan et al, 2014 ).…”

Section: Endogenous Nrf2 Activators In the Tumor Immune Microenvironmentmentioning

confidence: 99%

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Nrf2 in TIME: The Emerging Role of Nuclear Factor Erythroid 2-Related Factor 2 in the Tumor Immune Microenvironment

Feng

Read

Dinkova‐Kostova

2023

Molecules and Cells

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Nuclear factor erythroid 2-related factor 2 (Nrf2) mediates the cellular antioxidant response, allowing adaptation and survival under conditions of oxidative, electrophilic and inflammatory stress, and has a role in metabolism, inflammation and immunity. Activation of Nrf2 provides broad and long-lasting cytoprotection, and is often hijacked by cancer cells, allowing their survival under unfavorable conditions. Moreover, Nrf2 activation in established human tumors is associated with resistance to chemo-, radio-, and immunotherapies. In addition to cancer cells, Nrf2 activation can also occur in tumor-associated macrophages (TAMs) and facilitate an anti-inflammatory, immunosuppressive tumor immune microenvironment (TIME). Several cancer cell-derived metabolites, such as itaconate, L-kynurenine, lactic acid and hyaluronic acid, play an important role in modulating the TIME and tumor-TAMs crosstalk, and have been shown to activate Nrf2. The effects of Nrf2 in TIME are context-depended, and involve multiple mechanisms, including suppression of pro-inflammatory cytokines, increased expression of programmed cell death ligand 1 (PD-L1), macrophage colony-stimulating factor (M-CSF) and kynureninase, accelerated catabolism of cytotoxic labile heme, and facilitating the metabolic adaptation of TAMs. This understanding presents both challenges and opportunities for strategic targeting of Nrf2 in cancer.

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Deciphering metabolic crosstalk in context: lessons from inflammatory diseases

Verheijen,

Tran,

Chang

et al. 2024

Molecular Oncology

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Metabolism plays a crucial role in regulating the function of immune cells in both health and disease, with altered metabolism contributing to the pathogenesis of cancer and many inflammatory diseases. The local microenvironment has a profound impact on the metabolism of immune cells. Therefore, immunological and metabolic heterogeneity as well as the spatial organization of cells in tissues should be taken into account when studying immunometabolism. Here, we highlight challenges of investigating metabolic communication. Additionally, we review the capabilities and limitations of current technologies for studying metabolism in inflamed microenvironments, including single‐cell omics techniques, flow cytometry‐based methods (Met‐Flow, single‐cell energetic metabolism by profiling translation inhibition (SCENITH)), cytometry by time of flight (CyTOF), cellular indexing of transcriptomes and epitopes by sequencing (CITE‐Seq), and mass spectrometry imaging. Considering the importance of metabolism in regulating immune cells in diseased states, we also discuss the applications of metabolomics in clinical research, as well as some hurdles to overcome to implement these techniques in standard clinical practice. Finally, we provide a flowchart to assist scientists in designing effective strategies to unravel immunometabolism in disease‐relevant contexts.

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Myeloid-derived itaconate suppresses cytotoxic CD8+ T cells and promotes tumour growth

Cited by 64 publications

References 42 publications

Targeting IRG1 reverses the immunosuppressive function of tumor-associated macrophages and enhances cancer immunotherapy

Targeting IRG1 reverses the immunosuppressive function of tumor-associated macrophages and enhances cancer immunotherapy

Nrf2 in TIME: The Emerging Role of Nuclear Factor Erythroid 2-Related Factor 2 in the Tumor Immune Microenvironment

Deciphering metabolic crosstalk in context: lessons from inflammatory diseases

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