The role of glycolysis and lactate in the induction of tumor-associated macrophages immunosuppressive phenotype

Zhang, Yijia; Zhang, Xue; Meng, Yuting; Xü, Xinsheng; Zuo, Daiying

doi:10.1016/j.intimp.2022.108994

Cited by 13 publications

(4 citation statements)

References 126 publications

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“…Differences in metabolic activity may also play a role in the diversity of the TIME across various molecular subtypes. Specifically, the metabolic reprogramming observed in LAR tumors, with the upregulation in glycolysis and lipid metabolism [22,23], aligns with recent research showing that the accumulation of lactic acid and other lipid-derived metabolites inhibits the function of various pro-inflammatory immune cells, such as cytotoxic T-cells, while also promoting the expansion of immunosuppressive cell populations like MDSCs and M2 TAMs [39,40]. Nonetheless, the contrasting findings in the study by Thompson et al, which reported a downregulation of glycolysis in LAR tumors, emphasize the complexity of metabolic reprogramming in TNBC and suggest that further investigation is necessary to fully understand these dynamics [26].…”

Section: Discussionsupporting

confidence: 74%

Triple Negative Breast Cancer: Molecular Subtype-Specific Immune Landscapes with Therapeutic Implications

Syrnioti,

Petousis,

Newman

et al. 2024

Cancers

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Triple Negative Breast Cancer (TNBC) is characterized by distinct molecular subtypes with unique biological and clinical features. This systematic review aimed to identify articles examining the differences in the tumor immune microenvironment (TIME) across different TNBC molecular subtypes. Six studies meeting inclusion criteria were analyzed, utilizing gene expression profiling and bioinformatic analyses to classify TNBC samples into molecular subtypes, as well as immunohistochemistry and cell deconvolution methods to characterize the TIME. Results revealed significant heterogeneity in immune cell composition among TNBC subtypes, with the immunomodulatory (IM) subtype demonstrating robust immune infiltration, composed mainly of adaptive immune cells along with an increased density of CTLA-4+ and PD-1+ TILs, high PD-L1 tumor cell expression, and upregulation of FOXP3+ Tregs. A more immunosuppressive TIME with a predominance of innate immune cells and lower levels of tumor-infiltrating lymphocytes (TILs) was observed in luminal androgen receptor (LAR) tumors. In mesenchymal stem-like (MSL) tumors, the TIME was mainly composed of innate immune cells, with a high number of M2 tumor-associated macrophages (TAMs), while the BL and M tumors displayed poor adaptive and innate immune responses, indicating an “immune-cold” phenotype. Differential activation of signaling pathways, genomic diversity, and metabolic reprogramming were identified as contributors to TIME heterogeneity. Understanding this interplay is crucial for tailoring therapeutic strategies, especially regarding immunotherapy.

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Section: Discussionsupporting

confidence: 74%

Triple Negative Breast Cancer: Molecular Subtype-Specific Immune Landscapes with Therapeutic Implications

Syrnioti,

Petousis,

Newman

et al. 2024

Cancers

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“…We were interested in the potential mediators of MΦ polarization to a TAM phenotype. Several tumor-derived metabolites (e.g., lactate), cytokines, and chemokines [45][46][47][48] have previously been suggested to induce TAM polarization. Here, we used a membrane-based human proteome profiler assay to determine changes in the expression levels of more than hundred human cytokines, chemokines, growth factors, and other soluble proteins in MΦ-tumor cell co-cultures compared to pure MΦ cultures.…”

Section: Discussionmentioning

confidence: 99%

PARP14 Contributes to the Development of the Tumor-Associated Macrophage Phenotype

Sturniolo,

Váróczy,

Regdon

et al. 2024

IJMS

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Cancers reprogram macrophages (MΦs) to a tumor-growth-promoting TAM (tumor-associated MΦ) phenotype that is similar to the anti-inflammatory M2 phenotype. Poly(ADP-ribose) polymerase (PARP) enzymes regulate various aspects of MΦ biology, but their role in the development of TAM phenotype has not yet been investigated. Here, we show that the multispectral PARP inhibitor (PARPi) PJ34 and the PARP14 specific inhibitor MCD113 suppress the expression of M2 marker genes in IL-4-polarized primary murine MΦs, in THP-1 monocytic human MΦs, and in primary human monocyte-derived MΦs. MΦs isolated from PARP14 knockout mice showed a limited ability to differentiate to M2 cells. In a murine model of TAM polarization (4T1 breast carcinoma cell supernatant transfer to primary MΦs) and in a human TAM model (spheroids formed from JIMT-1 breast carcinoma cells and THP-1-MΦs), both PARPis and the PARP14 KO phenotype caused weaker TAM polarization. Increased JIMT-1 cell apoptosis in co-culture spheroids treated with PARPis suggested reduced functional TAM reprogramming. Protein profiling arrays identified lipocalin-2, macrophage migration inhibitory factor, and plasminogen activator inhibitor-1 as potential (ADP-ribosyl)ation-dependent mediators of TAM differentiation. Our data suggest that PARP14 inhibition might be a viable anticancer strategy with a potential to boost anticancer immune responses by reprogramming TAMs.

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“…Tumor-associated macrophages (TAMs) are known to play an important role in HCC progression [33], and active secretion of GAPDH by miR-4669 overexpression in Hep3B cells may generate an immunosuppressive tumor microenvironment through M2 macrophage polarization [26]. Indeed, tumor cells prefer to use aerobic glycolysis for adenosine triphosphate (ATP) production [34], and molecular mechanisms of glycolysis and lactate (the end product of aerobic glycolysis) for M2 macrophage polarization have recently been proposed [35]. Despite no direct evidence to support the impact of miR-4669 on M2 macrophage polarization, downregulation of circulating exosomal miR-4669 is reported as a novel biomarker for early prediction of effective treatment response to subcutaneous immunotherapy (SCIT) in pediatric patients with allergic rhinitis [36], which is associated with type 2 immune responses, and M2 macrophages correlate with disease severity [37,38].…”

Section: Discussionmentioning

confidence: 99%

Overexpression of miR-4669 Enhances Tumor Aggressiveness and Generates an Immunosuppressive Tumor Microenvironment in Hepatocellular Carcinoma: Its Clinical Value as a Predictive Biomarker

Nakano

Chen

et al. 2023

IJMS

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Accumulating evidence suggests the involvement of tumor-derived exosomes in the development and recurrence of hepatocellular carcinoma (HCC). We previously identified miR-4669 as a highly expressed microRNA in circulating exosomes obtained from patients with post-transplant HCC recurrence. This study aimed to explore how overexpression of miR-4669 affects HCC development and recurrence. The impact of miR-4669 overexpression in Hep3B cells on tumor cell behavior and the tumor microenvironment was evaluated in vitro. In addition, the clinical value of exosomal miR-4669 for the prediction of treatment response to HCC downstaging therapies and following post-transplant HCC recurrence was explored. Overexpression of miR-4669 enhanced migration ability and led to acquired sorafenib resistance with an elevation of sirtuin 1 and long noncoding RNA associated with microvascular invasion. Active release of tumor-derived exosomes and glyceraldehyde 3-phosphate dehydrogenase (GAPDH) contributed to generating an immunosuppressive tumor microenvironment through the induction of M2 macrophage polarization. The retrospective analysis demonstrated the clinical value of exosomal miR-4669 for predicting treatment response to HCC downstaging therapies and for risk assessment of post-transplant HCC recurrence. In summary, the present data demonstrate the impact of exosomal miR-4669 on HCC recurrence through the enhancement of tumor aggressiveness and generation of an immunosuppressive tumor microenvironment.

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The role of glycolysis and lactate in the induction of tumor-associated macrophages immunosuppressive phenotype

Cited by 13 publications

References 126 publications

Triple Negative Breast Cancer: Molecular Subtype-Specific Immune Landscapes with Therapeutic Implications

Triple Negative Breast Cancer: Molecular Subtype-Specific Immune Landscapes with Therapeutic Implications

PARP14 Contributes to the Development of the Tumor-Associated Macrophage Phenotype

Overexpression of miR-4669 Enhances Tumor Aggressiveness and Generates an Immunosuppressive Tumor Microenvironment in Hepatocellular Carcinoma: Its Clinical Value as a Predictive Biomarker

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