Human CD14⁺CTLA-4⁺regulatory dendritic cells suppress T-cell response by cytotoxic T-lymphocyte antigen-4-dependent IL-10 and indoleamine-2,3-dioxygenase production in hepatocellular carcinoma

Abstract

Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide with limited therapeutic options. HCC‐induced immunosuppression often leads to ineffectiveness of immuno‐promoting therapies. Currently, suppressing the suppressors has become the potential strategy for cancer immunotherapy. So, figuring out the immunosuppressive mechanisms induced and employed by HCC will be helpful to the design and application of HCC immunotherapy. Here, we identified one new subset of human CD14+CTLA‐4+ regulatory dendritic cells (CD14+DCs) in HCC patients, representing ∼13% of peripheral blood mononuclear cells. CD14+DCs significantly suppress T‐cell response in vitro through interleukin (IL)‐10 and indoleamine‐2,3‐dioxygenase (IDO). Unexpectedly, CD14+DCs expressed high levels of cytotoxic T‐lymphocyte antigen‐4 (CTLA‐4) and programmed death‐1, and CTLA‐4 was found to be essential to IL‐10 and IDO production. So, we identified a novel human tumor‐induced regulatory DC subset, which suppresses antitumor immune response through CTLA‐4‐dependent IL‐10 and IDO production, thus indicating the important role of nonregulatory T‐cell‐derived CTLA‐4 in tumor‐immune escape or immunosuppression. Conclusions: These data outline one mechanism for HCC to induce systemic immunosuppression by expanding CD14+DCs, which may contribute to HCC progression. This adds new insight to the mechanism for HCC‐induced immunosuppression and may also provide a previously unrecognized target of immunotherapy for HCC. (Hepatology 2014;59:567–579)

Combination of radiation and interleukin 12 eradicates large orthotopic hepatocellular carcinoma through immunomodulation of tumor microenvironment

“…5 Recently, immune suppressive regulatory DCs have also been identified in HCC patients. 34 DCs differentiate into mature DCs through microenvironmental stimuli that can efficiently launch immune responses. Kerkar and colleagues found that IL-12 could reprogram immunosuppressive DCs to regain immunostimulating functions that promote anti-tumor T cells.…”

Rationally Combining Anti-VEGF Therapy with Checkpoint Inhibitors in Hepatocellular Carcinoma

“…These regulatory DCs express high amounts of IL-10, nitric oxide (NO), VEGF and arginase I, and thus contribute to immune evasion by tumors [14]. In humans, regulatory DCs have been described as CD14 + CD11b high CTLA-4 + PD-1 + and represent less than 13% of peripheral bone marrow-derived cells in [15]. Human regulatory DCs have been reported to suppress T-cell activation not only through IL-10 but also indoleamine 2,3-dioxygenase (IDO) production [15].…”

Immunology of hepatocellular carcinoma

“…Recently, a new regulatory subset of DCs called CD14 + cytotoxic Tlymphocyteassociated protein (CTLA)4 + DCs, which expresses inhibitory molecule like CTLA4 and programmed death receptor (PD)1, were observed in the peripheral blood lymphocytes and tumor masses of HCC patients [16] . High levels of anti-inflammatory cytokine, IL-10, and indoleamine 2, 3dioxygenase secreted by these cells' poststimulation suppressed the CD4 + Tcell immune response, thereby assisting tumor progression and immune escape.…”