ALKBH5/MAP3K8 axis regulates PD-L1+ macrophage infiltration and promotes hepatocellular carcinoma progression

Abstract

Hepatocellular carcinoma is one of the most common malignant tumors.M6A is a novel epigenetic modification that have been emerged as vital regulators for the progression of HCC. However, the regulatory role, clinical significance and the details of the modification, such as the impact on the local tumor environment, remain largely unclear. Our study showed that ALKBH5 was highly expressed in HCC and high ALKBH5 expression predicted a worse prognosis of HCC patients. Prediction of ALKBH5 function by tissue samples and single cell sequencing Gene Set Variation Analysis. Primary CD3 + T lymphocytes and bone marrow-derived macrophages were used to evaluate the effect of ALKBH5 on immune microenvironment. The results indicated that ALKBH5 promote HCC cell proliferation, metastasis and PD-L1+macrophage recruitment. Mechanistically the results showed that ALKBH5 regulates MAP3K8 expression in a m6A dependent manner which mediates the proliferation and metastasis of HCC cells. ALKBH5 also promotes the activation of JNK and ERK pathways through upregulating MAP3K8, thus regulating the expression of IL-8 and promoting macrophage recruitment. Taken together, these data show that ALKBH5 promotes HCC growth, metastasis and macrophage recruitment through ALKBH5/MAP3K8 axis and it may serve as a potential diagnostic marker and target for treatment of HCC patients.

LRPPRC facilitates tumor progression and immune evasion through upregulation of m6A modification of PD-L1 mRNA in hepatocellular carcinoma

“…Tumor-intrinsic ALKBH5 attenuates the expansion and cytotoxicity of T cells through maintaining PD-L1 expression with YTHDF2-independnet m 6 A modification in intrahepatic cholangiocarcinoma ( 32 ). ALKBH5 is capable of facilitating the recruitment of PD-L1+ macrophages as well as accelerating HCC growth and metastases ( 33 ). In murine models, YTHDF1 deficiency can enhance antigen-specific CD8+ T-cell anti-tumor response as well as improve the therapeutic efficacy of anti–PD-L1 antibody ( 34 ).…”

Prognostic and clinicopathological value of m6A regulators in human cancers: a meta-analysis

“…Therefore, targeting the YTHDF1-m 6 A-ARHGEF2 axis may be a promising therapeutic strategy to inhibit tumor growth, invasion, and metastasis. In addition, ALKBH5, as the second m6A demethylated enzyme discovered after FTO, was reported to promote tumor stem formation in gliomas and promote tumor progression in breast cancer, colon cancer and hepatocellular carcinoma [ 85 , 86 ]. Conversely, ALKBH5 could inhibit tumor growth in bladder cancer and pancreatic cancer.…”

The Role of m6A Modification and m6A Regulators in Esophageal Cancer

“…The deletion of METTL3 disturbed T cells differentiation and macrophage activation via regulating different downstream target genes [ 172 , 173 ]. In addition, a change in the expression of m 6 A regulators also might influence the distribution and function of immune cells in TIME [ 174 , 175 , 176 ]. In hepatocellular carcinoma, ALKBH5 promoted macrophage recruitment through upregulating MAP3K8 expression in an m 6 A-dependent manner [ 174 ].…”

“…In addition, a change in the expression of m 6 A regulators also might influence the distribution and function of immune cells in TIME [ 174 , 175 , 176 ]. In hepatocellular carcinoma, ALKBH5 promoted macrophage recruitment through upregulating MAP3K8 expression in an m 6 A-dependent manner [ 174 ]. In ESCA, some studies revealed that the expression of m 6 A regulators was associated with PD-L1 expression and immune cells infiltration, suggesting the role of m 6 A regulators as an immune therapy target individually or in combination with ICIs [ 128 , 155 , 156 , 177 ].…”