Tumor metabolite lactate promotes tumorigenesis by modulating MOESIN lactylation and enhancing TGF-β signaling in regulatory T cells

Gu, Jian; Zhou, Jiang; Chen, Qiuyang; Xu, Xiaozhang; Gao, Junfang; Li, Xiangyu; Shao, Qing; Zhou, Bo; Sun, Yu; Song, Wei; Wang, Qi; Liang, Yuan; Lü, Ling

doi:10.1016/j.celrep.2022.110986

Cited by 166 publications

(117 citation statements)

References 42 publications

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“…Therefore, some researchers have speculated that lactate could ultimately promote the differentiation of Th1 and Th2 effector cells through signal transduction and metabolic regulation while inhibiting Treg induction and T-cell inactivation 264 , 265 . It is worth mentioning that a recent study found that in tumors, the metabolite lactate affected the TME by regulating the lactylation of MOESIN in Tregs and enhancing TGF-β signal transduction, thus promoting a new mechanism of tumorigenesis 266 . Regarding innate immunity, lactate can increase the expression of VEGF and ARG1 in TAMs, polarizing them toward the immunosuppressive and protumorigenic M2 phenotype 156 .…”

Section: Roles Of Lactic Acid In Pathophysiological Processesmentioning

confidence: 99%

Lactate metabolism in human health and disease

Yang

Zhang

et al. 2022

Sig Transduct Target Ther

441

234

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The current understanding of lactate extends from its origins as a byproduct of glycolysis to its role in tumor metabolism, as identified by studies on the Warburg effect. The lactate shuttle hypothesis suggests that lactate plays an important role as a bridging signaling molecule that coordinates signaling among different cells, organs and tissues. Lactylation is a posttranslational modification initially reported by Professor Yingming Zhao’s research group in 2019. Subsequent studies confirmed that lactylation is a vital component of lactate function and is involved in tumor proliferation, neural excitation, inflammation and other biological processes. An indispensable substance for various physiological cellular functions, lactate plays a regulatory role in different aspects of energy metabolism and signal transduction. Therefore, a comprehensive review and summary of lactate is presented to clarify the role of lactate in disease and to provide a reference and direction for future research. This review offers a systematic overview of lactate homeostasis and its roles in physiological and pathological processes, as well as a comprehensive overview of the effects of lactylation in various diseases, particularly inflammation and cancer.

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Section: Roles Of Lactic Acid In Pathophysiological Processesmentioning

confidence: 99%

Lactate metabolism in human health and disease

Yang

Zhang

et al. 2022

Sig Transduct Target Ther

441

234

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“…To date, glycolysis inhibitors are still in the preclinical stage, so their effects in humans are unclear. Another study demonstrated that inhibition of patient-derived and B16 melanoma LDHA with the inhibitor GSK2837808A could enhance T cell function in vitro and in vivo and enhance adoptive cell therapy [ 100 ].…”

Section: Advances In Targeting Lactate-lactylation Combined With Immu...mentioning

confidence: 99%

“…Preclinical trials have shown that combined therapy with the MCT1 inhibitor AZD3965 and anti-PD-1 treatment reduces the lactic acid secretion into the TME and the infiltration of exhaustive PD-1+ Tim-3+ T cells in solid tumors and improves antitumor immunity [ 105 ]. In light of this, it helped inhibit tumor growth and combined with anti–PD-1 therapy by knocking out MCT1 specifically on Tregs; it suggests that pharmacologic inhibition of MCT1 may play a dual role in inhibiting lactate secretion [ 100 ]. In hepatocellular carcinoma (HCC) patients, overexpression of MCT4 is positively associated with poor patient prognosis.…”

Section: Advances In Targeting Lactate-lactylation Combined With Immu...mentioning

confidence: 99%

Lactate-Lactylation Hands between Metabolic Reprogramming and Immunosuppression

Chen

Huang

et al. 2022

IJMS

109

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Immune evasion and metabolic reprogramming are two fundamental hallmarks of cancer. Interestingly, lactate closely links them together. However, lactate has long been recognized as a metabolic waste product. Lactate and the acidification of the tumor microenvironment (TME) promote key carcinogenesis processes, including angiogenesis, invasion, metastasis, and immune escape. Notably, histone lysine lactylation (Kla) was identified as a novel post-modification (PTM), providing a new perspective on the mechanism by which lactate functions and providing a promising and potential therapy for tumors target. Further studies have confirmed that protein lactylation is essential for lactate to function; it involves important life activities such as glycolysis-related cell functions and macrophage polarization. This review systematically elucidates the role of lactate as an immunosuppressive molecule from the aspects of lactate metabolism and the effects of histone lysine or non-histone lactylation on immune cells; it provides new ideas for further understanding protein lactylation in elucidating lactate regulation of cell metabolism and immune function. We explored the possibility of targeting potential targets in lactate metabolism for cancer treatment. Finally, it is promising to propose a combined strategy inhibiting the glycolytic pathway and immunotherapy.

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“…Lactate improves the function of iTregs in tumors and is one of the most important mechanisms mediating immunosuppression and tumor immune escape ( 16 , 17 ). We treated the sensitive and resistant groups with lactate (10 mM) to investigate its effects on iTreg induction.…”

Section: Resultsmentioning

confidence: 99%

“…A recent study showed that lactate, a metabolite produced by tumors, is critical for regulating the tumor environment, especially the expression of Tregs and macrophages ( 29 ). Lactate can regulate the number, induction, inhibitory function, and metabolic mechanisms of Tregs in the TME ( 17 ). Tregs acquire higher PD-1 expression than effector T cells in the TME, which is mediated by MCT1.…”

Section: Discussionmentioning

confidence: 99%

Monocarboxylate transporter upregulation in induced regulatory T cells promotes resistance to anti-PD-1 therapy in hepatocellular carcinoma patients

Zhou

Shao

et al. 2022

Front. Oncol.

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BackgroundProgrammed cell death-1 (PD-1) immune checkpoint inhibitors are not effective in treating all patients with hepatocellular carcinoma (HCC), and regulatory T cells (Tregs) may determine the resistance to anti-PD-1 therapy.MethodsPatients were divided into two groups based on the clinical efficacy of anti-PD-1 therapy. Flow cytometry was used to determine the phenotype of CD4+, CD8+, and Tregs in peripheral blood mononuclear cells (PBMCs). CD4+CD45RA+T cells were sorted to analyze Treg differentiation and function.ResultsNo significant differences were found between resistant and sensitive patients in the percentage of CD4+ T cells and Tregs in PBMCs or the differentiation and function of induced Tregs (iTregs). However, iTregs from resistant patients presented higher monocarboxylate transporter (MCT) expression. Lactate induced more iTregs and improved OXPHOS levels in the resistant group. MCT1 and MCT2 were highly expressed in tumor-infiltrating Tregs, and patients with higher MCT1 expression had worse clinical outcomes. Combinatorial therapy with MCT antibody and anti-PD-1 therapy effectively inhibited tumor growth.ConclusionMCT and its downstream lactate signal in Tregs can confer anti-PD-1 resistance and may be a marker of poor prognosis in HCC.

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Tumor metabolite lactate promotes tumorigenesis by modulating MOESIN lactylation and enhancing TGF-β signaling in regulatory T cells

Cited by 166 publications

References 42 publications

Lactate metabolism in human health and disease

Lactate metabolism in human health and disease

Lactate-Lactylation Hands between Metabolic Reprogramming and Immunosuppression

Monocarboxylate transporter upregulation in induced regulatory T cells promotes resistance to anti-PD-1 therapy in hepatocellular carcinoma patients

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