NAT10 regulates tumor progression and immune microenvironment in pancreatic ductal adenocarcinoma via the N4-acetylated LAMB3-mediated FAK/ERK pathway

Abstract

Background: N-acetyltransferase 10 (NAT10) was reported to be associated with the immune microenvironment in several cancers. However, it is not known in pancreatic ductal adenocarcinoma (PDAC). This study aimed to elucidate the roles and mechanisms of NAT10 in tumor malignancy and the tumor microenvironment (TME) in PDAC.

Methods: NAT10 expression and its role in tumor progression and clinical prognosis were analyzed using bioinformatics and functional assays. Downstream genes regulated by NAT10 and their underlying mechanisms were explored using acetylated RNA immunoprecipitation, quantitative polymerase chain reaction, RNA immunoprecipitation, and Western blotting. The role and mechanism of NAT10 in the PDAC TME were further explored using bioinformatics, single-cell RNA sequencing, multiplexed immunofluorescence, and flow cytometry. The association between NAT10 and immunotherapeutic response was investigated in a mouse model by inhibiting the programmed cell death 1/programmed cell death ligand 1(PD-1/PD-L1) axis with a PD-1/PD-L1 binding inhibitor, Naamidine J.

Results: NAT10 was upregulated in PDAC tissues and cell lines, and was associated with poor progression-free survival of PDAC patients. NAT10 promoted tumor progression by enhancing the mRNA stability of laminin β3 (LAMB3) via N4-acetylation modification, thereby activating the focal adhesion kinase (FAK)/extracellular regulated protein kinases (ERK) pathway. NAT10 promoted subcutaneous tumor growth, increased the proportion of exhausted CD8⁺ T cells (CD8⁺ Tex), especially the intermediate CD8⁺ Tex subset, and decreased the proportion of cytotoxic CD8⁺ T cell (CD8⁺ Tc) subset in the PDAC TME. Naamidine J treatment significantly enhanced the proportion of CD8⁺ Tc subset and reduced the proportion of intermediate CD8⁺ Tex subset in mice bearing subcutaneous tumors with high NAT10 expression. Regarding the regulatory mechanism, NAT10 increased PD-L1 expression and abundance in tumor cells by activating the LAMB3/FAK/ERK pathway, thereby reducing the cytotoxicity of CD8⁺ T cells. Inhibition of the PD-1/PD-L1 axis with Naamidine J retrieved CD8⁺ T cell cytotoxicity.

Conclusions: This study proposes a regulatory role of NAT10 in tumor progression and immune microenvironment via the LAMB3/FAK/ERK pathway in PDAC. These findings may favor the selection of candidates who may benefit from immunotherapy, optimize current therapeutic strategies, and improve the clinical prognosis of PDAC patients.

Keywords

NAT10 / LAMB3 / CD8⁺ T cell exhaustion / PD-1/PD-L1 / pancreatic ductal adenocarcinoma

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