Amuc_1434 From Akkermansia muciniphila Enhances CD8+ T Cell-Mediated Anti-Tumor Immunity by Suppressing PD-L1 in Colorectal Cancer

Abstract

Colorectal cancer (CRC) shows a limited response to programmed death-ligand 1 (PD-L1) immunotherapies. Akkermansia muciniphila (AKK) may enhance tumor immunity. This study examines how its Outer Membrane Vesicles (OMVs) and Amuc_1434 influence PD-L1 expression and CD8+ T cell activity in CRC. OMVs were isolated and their characteristics were examined through transmission electron microscopy and Western blotting. PD-L1 expression was quantified via Western blot, while CD8+ T cell proliferation was measured using flow cytometry. Cytokine production (interferon-gamma (IFN-γ) and interleukin-2 (IL-2)) was evaluated using ELISA. A CRC mouse model was employed to examine its impact on tumor growth and immune cell infiltration. In CRC cells, treatment with AKK-derived OMVs (AKK-OMVs) significantly downregulated PD-L1 expression (p < 0.05) and markedly increased CD8+ T cell proliferation and the levels of IFN-γ and IL-2 (p < 0.01). Amuc_1434 was identified as the key protein mediating these effects. In vivo, AKK-OMVs treatment substantially reduced tumor volume (p < 0.01) and significantly enhanced CD8+ T cell infiltration into the tumor microenvironment (p < 0.01). Additionally, AKK-OMVs-treated mice showed increased expression of immune activation markers within the tumor tissue, further indicating enhanced antitumor immunity. This study reveals that AKK-OMVs, particularly those containing Amuc_1434, can modulate PD-L1 expression and potentiate CD8+ T cell-mediated antitumor immunity in CRC. These findings suggest a novel approach to overcoming resistance to immune checkpoint inhibitors in CRC.