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Lee Cell-mediated immunotherapy for HCC

immune responses [36] . with liver tumor cell line lysate (Hep G2) to treat 35
patients with advanced HCC. Twenty-five patients
Regulatory T-cells are not the only immunosuppressive who received at least 3 courses of DC infusion were
cells in hosts with cancer. In a murine cancer model, assessed for tumor response. Disease control rate
a group of cells expressing CD11b and Gr-1 in the was 28%. Qiu et al. [51] conducted a phase II clinical
spleen was noted when the cell population of spleen trial using a-1,3-galactosyl epitopes pulsed DC to treat
was analyzed. These cells are currently called myeloid- stage III HCC patients. They enrolled 9 patients to have
derived suppressor cells (MDSC) [37] . Actually, MDSC DC vaccination and 9 patients as control. The results
are a population of cells of myeloid origin, including showed that all patients had delayed hypersensitivity.
myeloid progenitors, immature macrophages, Three of the 9 patients with DC vaccination had
immature granulocytes, and immature dendritic cells. partial response. Compared to control, mean survival
MDSC are characterized by production of reactive was prolonged from 10.1 to 17.1 months [51] . In our
oxygen, nitrogen species, and arginase I to suppress previous study, DC progenitors from peripheral blood
immunity [38,39] . The CD11b /Gr-1 cells were expanded monocytes (PBMC) were cultured in granulocyte-
+
+
in mice bearing large tumors [40] . Deletion of CD11b / macrophage colony-stimulating factor (GM-CSF)
+
Gr-1 cells in vitro or in vivo reverses the depression of and interleukin (IL)-4, pulsed with autologous tumor
+
CD8 T-cell function. lysates and maturated by cytokine cocktail (tumor
+
necrosis factor-a, IL-1, IL-6 and PGE2). These DCs
Many researchers attempt to decrease or deplete MDSC were positive for CD83 and expressed high levels of
to enhance cancer treatment [41-44] . Kusmartsev et al. CD40, CD80, CD86 and HLA-DR. In in-vitro study,
[45]
implanted slow-releasing all-trans-retinoic acid these DCs could activate T-cells. These ex-vivo
subcutaneously in order to decrease MDSC from 27% prepared DCs were applied intravenously to treat 31
to 11%. De Santo et al. [46] used nitro-aspirin, which patients with advanced HCC. Among 31 patients, 4
released NO to interfere MDSC inhibitory enzymatic (12.9%) patients had partial response and 17 (54.8%)
activity. Gemcitabine, amino-biphosphonase, and patients had stable diseases. Disease control rate was
celecoxib all have been used to reduce the number 67.7%. Compared to the same stage patients without
of MDSC in order to enhance cancer treatment [47] . DC treatment, the 1- and 2-year survival rates were
Moreover, all-trans-retinoic acid has been employed to significantly prolonged [25] . DC can be injected into the
treat renal cancer patients with metastasis, and there tumors directly. Nakamoto et al. [52] enrolled 10 patients
was a clinical response in 1 patient (1/18) [48] . These to receive autologous DC infusion into tumors following
data in animal models and a limited number of clinical TACE. DC could be detected in the tumors for up to
trials implied that depletion or decrease of MDSC might 17 days when the DCs were labelled with 111 Indium.
be helpful in cancer treatment. Tumor antigen-specific lymphocytes could be found
around the tumors. However, no clinical benefit was
CLINICAL CELL-MEDIATED found in this study.
IMMUNOTHERAPY FOR HCC
Checkpoint inhibitor immunotherapy
DC-based immunotherapy Activation of naïve T-cells by DC is through ligation
As mentioned, DCs are the most potent antigen- of MHC class I/II and T-cell receptor (signal 1)
presenting cells. Theoretically, DCs can capture and costimulatory molecular pathways (signal 2).
HCC-associated antigens, process the antigens, and Costimulatory molecular pathways may deliver
activate antigen-specific T-cells to get rid of the tumors. positive or negative signals to T-cells and result in
However, the function of DCs is defective in advanced T-cell activation or T-cell anergy to specific antigens.
HCC, and antigen-specific T-cells cannot be activated In immunotherapy of cancer, checkpoint inhibitors
properly. Therefore, DCs are cultured and matured ex can block negative costimulatory molecular pathways
vivo for immunotherapy. and enhance T-cell-mediated immunity. Clinically,
checkpoint inhibitor immunotherapy already has
In a phase I trial, Iwashita et al. [49] enrolled 10 patients obtained promising results in treating advanced
to receive autologous DC to treat unresectable HCC. melanoma. Tremelimumab, a blockade of cytotoxic
DC was administered by injection into inguinal lymph T-cell antigen 4 (CTLA-4), was used to treat hepatitis
nodes. Seven of 10 patients experienced delayed-type C patients with HCC in a clinical trial [53] . Twenty
hypersensitivity response and one patient had tumor patients were enrolled and 17 patients were available
response. It was concluded that DC administered was to assess therapeutic responses. Partial response
safe and no major toxic effects were found. In another rate was 17.6%, stable disease was 76.4%, and time
study, Palmer et al. [50] used autologous DC pulsed to progression was 6.48 months. Nivolumab, anti-

246 Journal of Cancer Metastasis and Treatment ¦ Volume 3 ¦ October 31, 2017