Microwave ablation combined with anti-LAG-3 therapy enhances anti-tumor immunity in hepatocellular carcinoma mice by regulating CXCL10/CXCR3-mediated CD8+ T cell activation

Vollständiger Abstract

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Abstract Background The therapeutic potential of combining microwave ablation (MWA) with lymphocyte-activation gene 3 (LAG-3) blockade has been demonstrated in various cancers, while its specific efficacy and molecular mechanisms in hepatocellular carcinoma (HCC) remain unclear. Methods LAG-3 expression in clinical samples was investigated. LAG-3 expression in tumor-infiltrating lymphocytes (TILs) was further explored using HCC-bearing mice treated with MWA. Moreover, the survival rate, tumor growth, TIL recruitment, and CD8 + T cell function were monitored in mice treated with MWA and LAG-3 blockade. Further CXCL10 blockade or CD8 blockade strategies were employed to elucidate the underlying mechanisms of the anti-tumor immunity. Results LAG-3, CXCL10, CXCR3, and CD8 were highly expressed in human HCC tissues. MWA treatment elevated LAG-3 expression in subsets of TILs. In contrast to MWA or anti-LAG-3 therapy alone, the combination of MWA and anti-LAG-3 therapy exhibited a synergistic effect, resulting in prolonged survival, inhibited tumor growth, increased infiltration of TILs, elevated serum CXCL10 level, an enhanced population of CXCR3 + CD8 + T cells, and increased CD8 + T cell cytotoxic activity in HCC-bearing mice. Furthermore, blockade of CXCL10 weakened the CD8 + T cell function in the combined therapy group. Additionally, CD8 blockade promoted tumor growth and impaired CD8 + T cell function under the combined treatment. Conclusion MWA combined LAG-3 blockade emerged as a distinctive therapeutic approach for HCC, and the underlying mechanism is rooted in the CXCL10/CXCR3-mediated activation of CD8 + T cells.