Dendritic Cell (DC) Vaccine in Mouse Lung Cancer Minimal Residual Model; Comparison of Monocyte-derived DC vs. Hematopoietic Stem Cell Derived-DC

Abstract

The anti-tumor effect of monocyte-derived DC (MoDC) vaccine was studied in lung cancer model with feasible but weak Ag-specific immune response and incomplete blocking of tumor growth. To overcome this limitation, the hematopoietic stem cell-derived DC (SDC) was cultured and the anti-tumor effect of MoDC & SDC was compared in mouse lung cancer minimal residual model (MRD). Therapeutic DCs were cultured from either CD34+ hematopoietic stem cells with GM-CSF, SCF and IL-4 for 14 days (SDC) or monocytes with GM-CSF and IL-4 for 7 days (MoDC). DCs were injected twice by one week interval into the peritoneum of mice that are inoculated with Lewis Lung Carcinoma cells (LLC) one day before the DC injection. Anti-tumor responses and the immune modulation were observed 3 weeks after the final DC injection. CD11c expression, IL-12 and TGF-β secretion were higher in SDC but CCR7 expression, IFN-γ and IL-10 secretion were higher in MoDC. The proportion of CD11c+CD8a+ cells was similar in both DC cultures. Although both DC reduced the tumor burden, histological anti-tumor effect and the frequencies of IFN-γ secreting CD8+ T cells were higher in SDC treated group than in MoDC. Conclusively, although both MoDC and SDC can induce the anti-tumor immunity, SDC may be better module as anti-tumor vaccine than MoDC in mouse lung cancer.

Antitumor Vaccines Based on Dendritic Cells: From Experiments using Animal Tumor Models to Clinical Trials

“…Eight of them were devoted to therapeutic DC-based vaccines, where DCs were administered to tumor-bearing mice, four studies focused on preventive DC-based vaccines with DCs administered to animals before tumor grafting, and three studies were devoted to both types of DC-based vaccines. The antitumor potential of DCs was studied in murine tumor models such as colorectal cancer [ 47 , 48 ], hepatocellular carcinoma [ 49 , 50 ], Dalton’s lymphoma [ 51 ] and EL4 lymphoma [ 52 ], FBL3 leukemia[ 53 ], 4T1 breast carcinoma [ 54 ], B16 melanoma [ 30 , 55 - 57 ], Lewis lung carcinoma [ 58 , 59 ], and SCCVII squamous cell lung cancer models [ 60 ] ( Table 1 ). In almost all the publications under analysis, DCs were prepared by incubation of bone marrow-derived pre-DCs in the presence of the cytokines GM-CSF and IL-4.…”

“…Protein antigens (first of all, lysate and the total protein of tumor cells) were the most typically used as a source of TAAs to load DCs. The vaccines being used can be subdivided into (1) DC-based vaccines without additional stimuli (B16 melanoma [ 30 ] and Lewis lung carcinoma [ 59 ]); (2) DC-based vaccines additionally treated with siRNA against immunosuppressive enzyme indolamine 2,3-dioxygenase (4T1 breast carcinoma [ 54 ]) or with plant-based immunostimulatory polysaccharide (EL4 lymphoma [ 52 ]); and (3) DC-based vaccines combined with injections of cucurbitacin I that selectively inhibits STAT3 in tumor cells (Dalton’s lymphoma [ 51 ]). In addition, AH1 tumor peptide (gp70 fragment) in combination with the non-tumor helper peptide (ovalbumin), whose key function was to increase the stability and efficiency of antigen presentation to T cells by DCs, was used as a source of TAAs for the model of colorectal cancer [ 47 ].…”

“…In addition, injection of preventive DC-based vaccines transfected with mRNA encoding polypeptide β2m-tumor peptide-TLR4 [ 55 ] or prepared using living B16 melanoma cells as a source of TAA [ 56 ] fully protected animals against the development of B16 melanoma. Antitumor DC-based vaccines significantly reduced the number of metastases in mice [ 30 , 53 , 57 , 59 , 60 ], considerably increased the lifespan of tumor-bearing animals [ 47 , 49 , 51 , 53 , 55 , 58 , 60 ], and induced the development of a strong antitumor response from cytotoxic T lymphocytes [ 47 - 50 , 53 - 56 , 58 , 60 ].…”

Immunotherapy of DC-CIK cells enhances the efficacy of chemotherapy for solid cancer: a meta-analysis of randomized controlled trials in Chinese patients

“…Different kinds of DCvaccines have shown anti-tumor effects (Palucka et al, 2010;Baek et al, 2012). The innate quality of DCs in antigen presenting could effectively counteract the specificity deficiency and enhance the cytotoxicity of CIK cells.…”

Tumor Cell Clone Expressing the Membrane-bound Form of IL-12p35 Subunit Stimulates Antitumor Immune Responses Dominated by CD8+T Cells

“…Alternatively, expression of cytokine as a membrane-bound form further confined the functional range of the cytokines and lowered toxicity of various cytokines (24); TNF-α (25,26), GM-CSF (12,27-29), IFN-γ (27), IL-2 (30-34), IL-4 (35,36), and IL-12 (32,33,35,37,38). We hypothesized that a tumor cell vaccine may avoid such side effect if it stimulates selectively the TAA-specific CD8 + T cells, without involving CD4 + T helper cells and antigen presenting cells like dendritic cells (39). …”