Association of intratumoral regulatory T-cell accumulation in patients with hepatocellular carcinoma (HCC) with poor survival: Effect of autologous dendritic cell immunotherapy on selective reduction of regulatory T cells and survival.

Abstract

e14023 Background: The immune status of the tumor microenvironment influences tumor progression in HCC. Regulatory T cells (Tregs) inhibit effector cell responses, and play a pivotal role in effective cancer surveillance. This study examines the role on overall survival of intratumoral Tregs in patients with HCC, and evaluates the impact of autologous dendritic cell (DC) immunotherapy on Treg depletion, tumor progression, and overall survival in an orthotopic murine HCC model. Methods: The expression of Foxp3 and CD4 in 63 paired tumor and non-neoplastic liver resection tissue specimens of HCC patients was evaluated using RT-PCR. Orthotopic murine HCC was established by implanting Hepa1-6 cells in the liver. The effect of DC immunotherapy loaded with Hepa1-6 cell lysate on tumor progression, survival, tumor infiltrating lymphocytes and cytokines was examined. Results: High intratumoral Foxp3 expression in HCC patients treated with resection was associated with poor overall survival. DC immunotherapy in HCC bearing mice resulted in reduced Foxp3+CD4+ regulatory T cell accumulation and TGF-b production within the tumor microenvironment. Moreover, DC immunotherapy reversed murine HCC progression, as assessed by plasma a-fetoprotein levels and in vivo bioluminescence imaging, and increased survival to 90% by day 60, as compared to < 5% in untreated tumor-bearing mice. This anti-tumor response was accompanied by inhibition of STAT3 phosphorylation within tumor tissue Conclusions: High levels of intratumoral Tregs in patients undergoing hepatectomy is with associated poor overall survival. Tumor cell lysate-loaded DC immunotherapy results in tumor regression and increased survival in a clinically relevant orthotopic murine HCC model. The inhibitory effect of DC immunotherapy on the accumulation of Foxp3+CD4+ regulatory T cells within the tumor microenvironment and on the production of TGF-b suggests that effective DC immunotherapy can alter the immunosuppressive tumor microenvironment, thus resulting in tumor regression.