Metabolites in the Tumor Microenvironment Reprogram Functions of Immune Effector Cells Through Epigenetic Modifications

Li, Yijia; Wu, Yangzhe; Hu, Yi

doi:10.3389/fimmu.2021.641883

Cited by 19 publications

(19 citation statements)

References 150 publications

(165 reference statements)

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“…It is commonly recognized that the TME is immunosuppressive, which results from many regulatory factors, including low pH value, hypoxia, nutritional deficiency, metabolic pathways remodeling, inflammation, and others ( 24 , 25 ). Our focus in this work is to decipher the immune landscape of the HCC TME, facilitating clinical efficacy predictions of immunotherapies.…”

Section: Discussionmentioning

confidence: 99%

Apoptosis, Pyroptosis, and Ferroptosis Conspiringly Induce Immunosuppressive Hepatocellular Carcinoma Microenvironment and γδ T-Cell Imbalance

Chen

Hong

et al. 2022

Front. Immunol.

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Hepatocellular carcinoma (HCC) is highly malignant and prone to metastasize due to the heterogeneous and immunosuppressive tumor microenvironment (TME). Programmed cell deaths (PCDs) including apoptosis, ferroptosis, and pyroptosis routinely occur in the HCC TME and participate in tumorigenesis. However, how apoptosis, ferroptosis, and pyroptosis are involved in constructions of the immunosuppressive TME and their underlying cross-talk remains to be further unveiled. In this work, we deciphered the immunosuppressive landscape of HCC TME, which demonstrated high expressions of inhibitory checkpoint molecules and infiltration of protumor immune cells but low infiltration of antitumor effector immune cells. Further investigations unequivocally revealed that marker genes of apoptosis, ferroptosis, and pyroptosis are closely correlated with expressions and infiltrations of inhibitory checkpoint molecules and immune cells and that higher “-optosis” links to poorer patient prognosis. Notably, such three types of “-optosis” interact with each other at both the gene and protein levels, suggesting that they conspiringly induce the establishment of the immunosuppressive HCC TME. Interestingly, examinations of circulating γδ T cells in HCC patients revealed a noticeable dysfunction phenotype. The strikingly elevated ratio of the Vδ1+ versus the Vδ2+ subset suggested that the Vδ1+/Vδ2+ ratio would be a potential biomarker for the diagnosis and prognosis in HCC patients. Altogether, this work thoroughly decrypted the underlying correlations between apoptosis, ferroptosis, and pyroptosis and the formation of immunosuppressive HCC TME and, meanwhile, indicated that allogeneic Vδ2+ γδ T-cell transfer would be a promising adjuvant strategy for renormalizing circulating γδ T cell and thus achieving sound clinical efficacy against HCC.

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Section: Discussionmentioning

confidence: 99%

Apoptosis, Pyroptosis, and Ferroptosis Conspiringly Induce Immunosuppressive Hepatocellular Carcinoma Microenvironment and γδ T-Cell Imbalance

Chen

Hong

et al. 2022

Front. Immunol.

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“…Increasing evidence suggests that epigenetic modifications and metabolism are highly interconnected (Saggese et al, 2020;Zheng et al, 2020;Li et al, 2021). Some metabolites (e.g., acetyl-coenzyme A (CoA), α-ketoglutarate, and nicotinamide adenine dinucleotide (NAD + )) are used as donors or cofactors for epigenetic modifications that regulate gene expression (Hosios and Vander Heiden, 2017;Palzer et al, 2018;Wang ZJ et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

Integrated metabolism and epigenetic modifications in the macrophages of mice in responses to cold stress

Dai

et al. 2022

J. Zhejiang Univ. Sci. B

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The negative effects of low temperature can readily induce a variety of diseases. We sought to understand the reasons why cold stress induces disease by studying the mechanisms of fine-tuning in macrophages following cold exposure. We found that cold stress triggers increased macrophage activation accompanied by metabolic reprogramming of aerobic glycolysis. The discovery, by genome-wide RNA sequencing, of defective mitochondria in mice macrophages following cold exposure indicated that mitochondrial defects may contribute to this process. In addition, changes in metabolism drive the differentiation of macrophages by affecting histone modifications. Finally, we showed that histone acetylation and lactylation are modulators of macrophage differentiation following cold exposure. Collectively, metabolism-related epigenetic modifications are essential for the differentiation of macrophages in cold-stressed mice, and the regulation of metabolism may be crucial for alleviating the harm induced by cold stress.

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“…Secondy, tumor cells can shape and train the TME and ultimately help their survival and migration in an organism (44). Moreover, immune effector cells in TME are comprehensively reprogrammed as accomplices of tumor cells, which could protect cancer from immune destruction, subsequently evade immune surveillance and ultimately promote tumor progression and metastasis (17,(46)(47)(48)(49)(50)(51). Accumulating evidences showed that TME might be a main obstacle for effective cancer immunotherapy (52,53) and confers resistance to the immunotherapies (54).…”

Section: Introductionmentioning

confidence: 99%

CMTM6 and CMTM4 as two novel regulators of PD-L1 modulate the tumor microenvironment

Zhang

Dai

2022

Front. Immunol.

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The tumor microenvironment (TME) plays crucial roles in regulating tumor occurrence, progress, metastasis and drug resistance. However, it remains largely elusive how the components of TME are regulated to govern its functions in tumor biology. Here, we discussed how the two novel functional proteins, chemokine-like factor (CKLF)-like MARVEL transmembrane domain-containing 6 (CMTM6) and CMTM4, which involved in the post-translational regulation of PD-L1, modulate the TME functions. The roles of CMTM6 and CMTM4 in regulating TME components, including immune cells and tumor cells themselves were discussed in this review. The potential clinical applications of CMTM6 and CMTM4 as biomarkers to predict therapy efficacy and as new or combined immunotherapy targets are also highlighted. Finally, the current hot topics for the biological function of CMTM6/4 and several significant research directions for CMTM6/4 are also briefly summarized in the review.

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Metabolites in the Tumor Microenvironment Reprogram Functions of Immune Effector Cells Through Epigenetic Modifications

Cited by 19 publications

References 150 publications

Apoptosis, Pyroptosis, and Ferroptosis Conspiringly Induce Immunosuppressive Hepatocellular Carcinoma Microenvironment and γδ T-Cell Imbalance

Apoptosis, Pyroptosis, and Ferroptosis Conspiringly Induce Immunosuppressive Hepatocellular Carcinoma Microenvironment and γδ T-Cell Imbalance

Integrated metabolism and epigenetic modifications in the macrophages of mice in responses to cold stress

CMTM6 and CMTM4 as two novel regulators of PD-L1 modulate the tumor microenvironment

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