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Glycolysis induced by METTL14-related m6A methylation is essential for macrophage phagocytosis and phenotype in cervical cancer

ABSTRACT: N6-methyladenosine (m6A) is the most abundant mRNA modification in mammals and it plays a vital role in various biological processes. However, the roles of m6A on cervical cancer tumorigenesis, especially macrophages infiltrated in the tumor microenvironment (TME) of cervical cancer, are still unclear. We analyzed the abnormal m6A methylation in cervical cancer, using CaSki and THP-1 cell lines, that might influence macrophages' polarization and/or function. In addition, C57bl-6j and Balb/c-nude mice were used for validation in vivo In this study, MeRIP-Seq analysis revealed the m6A profiles in cervical cancer. Then, we discovered the high expression of METTL14 (methyltransferase 14, N6-adenosine-methyltransferase subunit) in cervical cancer tissues can promote the proportion of PD-1 positive tumor-associated macrophages (TAMs), which have an obstacle to devour tumor cells. Functional, changes of METTL14 in cervical cancer inhibits the recognition and phagocytosis of macrophages to tumor cells. Mechanistically, the abnormality of METTL14 could target the glycolysis of tumor in vivo and vitro. Moreover, lactate acid produced by tumor glycolysis has an important role in the PD-1 expression of TAMs as a proinflammatory and immunosuppressive mediator. The study revealed the effect of glycolysis regulated by METTL14-related methylation on the expression of PD-1 and phagocytosis of macrophages, which showed that METTL14 was a potential therapeutic target for treating advanced human cancers.

ORGANISM(S): Homo sapiens

PROVIDER: GSE242071 | GEO | 2023/10/05

REPOSITORIES: GEO

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Project description:Obesity is a leading risk factor for progression and metastasis of many cancers1,2, yet can also promote improved survival for some cancers3-5 and enhance responses to some immune checkpoint blockade therapies6-8. The role of the immune system in the obesity-cancer connection and how obesity influences immunotherapy, however, remain unclear. While PD-1 expression by macrophages has been described9-12, we found that obesity selectively induced PD-1 on macrophages and that PD-1 directly impaired macrophage function. Single cell RNA sequencing of murine colorectal carcinoma tumors showed obesity remodeled myeloid and T cell populations, with fewer clonally expanded effector T cells and increased abundance of PD-1+ tumor-associated macrophages (TAM). Cytokines and molecules associated with obesity, including IL-6, leptin, and insulin, and the unsaturated fatty acid palmitate, induced PD-1 expression on macrophages in a glycolysis-dependent manner and that MTORC1 pathway signaling is essential for PD1 expression. PD-1+ TAMs had increased mitochondrial respiration, fatty acid metabolism and cell cylewhile PD-1- TAMs had increased inflammatory signature , phagocytosis and antigen presentation to T cells. These patterns were directly regulated by PD-1, as recombinant PD-L1 reduced macrophage glycolysis, phagocytic capacity and antigen presentation, and this was reversed with blocking PD-1 antibody. Further, inhibition of glycolysis with 2-deoxyglucose prevented the increase in CD86, MHC-I and MHC-II that would otherwise occur with anti-PD-1 treatment. Conversely, PD-1-deficient Pdcd1-/- TAMs had high rates of glycolysis, phagocytosis, and expression of MHC-II. Myeloid-specific PD-1 deficiency correlated with slower tumor growth, enhanced TAM antigen presentation capability, and increased CD8 T cell activation together with reduced markers of exhaustion. These findings show metabolic signaling and type 1 inflammatory cues in obesity induces PD-1-mediated suppression of TAM function and reveal a unique macrophage-specific and glycolysis-dependent mechanism to modulate immune tumor surveillance and checkpoint blockade. This may contribute to increased cancer risk yet improved response to PD-1 blockade in TAM-enriched tumors and obesity.

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Glycolysis induced by METTL14-related m6A methylation is essential for macrophage phagocytosis and phenotype in cervical cancer

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