Galectin-1-Induced Tumor Associated Macrophages Repress Antitumor Immunity in Hepatocellular Carcinoma Through Recruitment of Tregs

Abstract

Tumor-associated macrophages (TAMs) are commonly considered accomplices in tumorigenesis and tumor development. However, the precise mechanism by which tumor cells prompt TAMs to aid in evading immune surveillance remains to be further investigated. Here, it is elucidated that tumor-secreted galectin-1 (Gal1) conferred immunosuppressive properties to TAMs. Specifically, patient specimens and a public database is first used to analyze the clinical relevance of Gal1 in hepatocellular carcinoma (HCC). Then, it is demonstrated that TAMs functioned as a critical mediator in the Gal1-induced progression of HCC and the establishment of an immunosuppressive tumor microenvironment. Furthermore, RNA-sequencing determined that Gal1 promoted the upregulation of chemokine (C-C motif) ligand 20 (CCL20) in TAMs via activating the PI3K/AKT/NF-κB pathway. Employing an anti-CCL20 neutralizing antibody and Foxp3DTR mice, it is demonstrated that CCR6⁺Foxp3⁺ regulatory T cells (Tregs) recruited by Gal1-induced TAMs contributed to reduced infiltration and dysfunctional state of CD8⁺ T cells, subsequently facilitating tumor progression. Targeting Gal1 dampened the secretion of CCL20 and inhibits the recruitment of Tregs, thereby activating anti-tumor immunity and ameliorating anti-PD-1 resistance. Together, this findings revealed that Gal1-induced TAMs recruited Tregs through the CCL20-CCR6 axis. Inhibition of Gal1 improves the effectiveness of anti-PD1 therapy, shedding important new light on the combination immunotherapy of HCC.

Keywords: Galectin‐1; hepatocellular carcinoma; immunotherapy; tregs; tumor‐associated macrophages.