Depletion of plasmacytoid dendritic cells and HIF-1 inhibition enhance immunotherapy against hepatocellular carcinoma

Abstract Hepatocellular Carcinoma (HCC) is one of the deadliest forms of cancer. Recent years have seen significant advances for HCC treatment, but up to 70% of patients remain at high risk for recurrence necessitating the urgent need for more effective therapies. Plasmacytoid dendritic cells (pDCs) heavily infiltrate liver tumor tissues, contribute to an immunosuppressive tumor microenvironment (TEM), and promote HCC growth. Furthermore, hypoxia often occurs in HCC tumor tissues and plays the central role of an immunosuppressive TME. A hypoxic TME enhances pDC recruitment into tumor tissues via the upregulation of hypoxia-inducible factor 1α (HIF-1α). Here we show that the distribution of pDCs does not co-localized with hypoxic areas in HCC. In the immunocompetent HCC mouse model, depletion of pDCs using the antibody or HIF-1α inhibitor echinomycin significantly suppressed tumor growth. The combination of pDC depletion and HIF-1α inhibition suppressed HCC growth more effectively. Both treatments reshaped the TME with changes of the cytokine profile and increased tumor-infiltrating CD8 T cells. Reduced basic helix-loop-helix transcription factor E2-2 expression by treatments abrogated protumor functions of pDCs in HCC resulting in reactivating tumor-reactive CD8 T cells. This study demonstrates that targeting both pDCs and HIF-1α may serve as more effective immunotherapy for HCC.