Immune Netw.  2012 Dec;12(6):269-276. 10.4110/in.2012.12.6.269.

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

Affiliations
  • 1Office of Biomedical Professors, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 135-710, Korea. andyjosh@skku.edu
  • 2Department of Thoracic & Cardiovascular Surgery, Jeju National University School of Medicine, Jeju 690-767, Korea.

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-beta secretion were higher in SDC but CCR7 expression, IFN-gamma 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-gamma 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.

Keyword

Dendritic cell; Lung cancer; Anti-tumor immunity

MeSH Terms

Animals
Carcinoma, Lewis Lung
Dendritic Cells
Granulocyte-Macrophage Colony-Stimulating Factor
Hematopoietic Stem Cells
Interleukin-10
Interleukin-12
Interleukin-4
Lung
Lung Neoplasms
Mice
Monocytes
Peritoneum
T-Lymphocytes
Transforming Growth Factor beta
Tumor Burden
Granulocyte-Macrophage Colony-Stimulating Factor
Interleukin-10
Interleukin-12
Interleukin-4
Transforming Growth Factor beta

Figure

  • Figure 1 Treatment schedule. D-0: LLC cells were inoculated 1×105/mouse i.v. D-1 and 8: In order to minimal residual model, therapeutic-DCs were injected twice by one week interval into the peritoneum of tumor cell inoculated-mice. D-29: Mouse sacrifice and immune monitoring. Each experimental group was composed of 5~7 mice.

  • Figure 2 Characterization of cultured DCs. DCs cultured from either CD34+ cells with GM-CSF, SCF and IL-4 for 14 days (SDC) or antibody-panned monocytes with GM-CSF and IL-4 for 7 days (MoDC). Each DC type was pulsed with LLC lysate (SDC/lysate and MoDC/lysate). Cytokines IL-12, IL-10, IFN-γ and TGF-β produced into the culture supernatant were measured by ELISA and expressed as pg/ml/1×106 cells. Statistical significance (p<0.05) was compared by asterisks between the SDC and MoDC. Statistical differences (p<0.05) between the lysate pulsed DCs were expressed by + signs.

  • Figure 3 Immunogenic phenotypes of cultured DCs were analyzed by flow cytometry. Dendritic cell marker CD11c as well as MHC II, CD8a and CCR7 with CD54 were measured to characterize and differentiate the cultured SDC and MoDC.

  • Figure 4 Anti-tumor effect of DCs for LLC formed in lung. Tumor bearing mice were sacrificed after three weeks from the last DC injection. (A) Circle represents number of tumor size over 0.2 mm in a mouse lung. Number and red line show mean value±standard error (SE). Same value represents one circle. Each experimental group was composed of 5~7 mice. (B) Pulmonary tissues of tumor-bearing mice were H&E stained.

  • Figure 5 Induction of tumor antigen-specific IFN-secreting cells. Tumor antigen-specific alterations in immunological parameters were analyzed with splenic lymphocytes obtained from the tumor-bearing mice treated with DC vaccine. As an effector molecule of therapeutic response, the proportion of IFN-secreting CD8+ T cells was observed by ELISPOT assay. Asterisk indicate the statistical significance (p<0.05) compared with MoDC.


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Reference

1. Steinman RM. The dendritic cell system and its role in immunogenicity. Annu Rev Immunol. 1991. 9:271–296.
Article
2. Banchereau J, Steinman RM. Dendritic cells and the control of immunity. Nature. 1998. 392:245–252.
Article
3. Paglia P, Chiodoni C, Rodolfo M, Colombo MP. Murine dendritic cells loaded in vitro with soluble protein prime cytotoxic T lymphocytes against tumor antigen in vivo. J Exp Med. 1996. 183:317–322.
Article
4. Palucka K, Banchereau J. Dendritic cells: a link between innate and adaptive immunity. J Clin Immunol. 1999. 19:12–25.
5. Paczesny S, Banchereau J, Wittkowski KM, Saracino G, Fay J, Palucka AK. Expansion of melanoma-specific cytolytic CD8+ T cell precursors in patients with metastatic melanoma vaccinated with CD34+ progenitor-derived dendritic cells. J Exp Med. 2004. 199:1503–1511.
Article
6. Kim JH, Lee Y, Bae YS, Kim WS, Kim K, Im HY, Kang WK, Park K, Choi HY, Lee HM, Baek SY, Lee H, Doh H, Kim BM, Kim CY, Jeon C, Jung CW. Phase I/II study of immunotherapy using autologous tumor lysate-pulsed dendritic cells in patients with metastatic renal cell carcinoma. Clin Immunol. 2007. 125:257–267.
Article
7. Baek S, Kim CS, Kim SB, Kim YM, Kwon SW, Kim Y, Kim H, Lee H. Combination therapy of renal cell carcinoma or breast cancer patients with dendritic cell vaccine and IL-2: results from a phase I/II trial. J Transl Med. 2011. 9:178.
Article
8. Ragde H, Cavanagh WA, Tjoa BA. Dendritic cell based vaccines: progress in immunotherapy studies for prostate cancer. J Urol. 2004. 172:2532–2538.
Article
9. Iwashita Y, Tahara K, Goto S, Sasaki A, Kai S, Seike M, Chen CL, Kawano K, Kitano S. A phase I study of autologous dendritic cell-based immunotherapy for patients with unresectable primary liver cancer. Cancer Immunol Immunother. 2003. 52:155–161.
Article
10. Hirschowitz EA, Foody T, Kryscio R, Dickson L, Sturgill J, Yannelli J. Autologous dendritic cell vaccines for non-small-cell lung cancer. J Clin Oncol. 2004. 22:2808–2815.
Article
11. Hege KM, Carbone DP. Lung cancer vaccines and gene therapy. Lung Cancer. 2003. 41 Suppl 1:S103–S113.
Article
12. Fong L, Hou Y, Rivas A, Benike C, Yuen A, Fisher GA, Davis MM, Engleman EG. Altered peptide ligand vaccination with Flt3 ligand expanded dendritic cells for tumor immunotherapy. Proc Natl Acad Sci U S A. 2001. 98:8809–8814.
Article
13. Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA Cancer J Clin. 2005. 55:74–108.
Article
14. Spira A, Ettinger DS. Multidisciplinary management of lung cancer. N Engl J Med. 2004. 350:379–392.
Article
15. Lee SJ, Kim MJ, In SH, Baek S, Lee H. Immunocell Therapy for Lung Cancer: Dendritic Cell Based Adjuvant Therapy in Mouse Lung Cancer Model. Immune Netw. 2005. 5:36–44.
Article
16. Ward KA, Stewart LA, Schwarer AP. CD34+-derived CD11c+ + + BDCA-1+ + CD123+ + DC: expansion of a phenotypically undescribed myeloid DC1 population for use in adoptive immunotherapy. Cytotherapy. 2006. 8:130–140.
Article
17. Encabo A, Solves P, Mateu E, Sepúlveda P, Carbonell-Uberos F, Miñana MD. Selective generation of different dendritic cell precursors from CD34+ cells by interleukin-6 and interleukin-3. Stem Cells. 2004. 22:725–740.
Article
18. Guo G, Chen S, Zhang J, Luo L, Yu J, Dong H, Xu H, Su Z, Wu L. Antitumor activity of a fusion of esophageal carcinoma cells with dendritic cells derived from cord blood. Vaccine. 2005. 23:5225–5230.
Article
19. Xu RL, Tang Y, Ogburn PL, Malinowski K, Madajewicz S, Santiago-Schwarz F, Fan Q. Implication of delayed TNF-alpha exposure on dendritic cell maturation and expansion from cryopreserved cord blood CD34+ hematopoietic progenitors. J Immunol Methods. 2004. 293:169–182.
Article
20. Baleeiro RB, Anselmo LB, Soares FA, Pinto CA, Ramos O, Gross JL, Haddad F, Younes RN, Tomiyoshi MY, Bergami-Santos PC, Barbuto JA. High frequency of immature dendritic cells and altered in situ production of interleukin-4 and tumor necrosis factor-alpha in lung cancer. Cancer Immunol Immunother. 2008. 57:1335–1345.
Article
21. Hirschowitz EA, Foody T, Hidalgo GE, Yannelli JR. Immunization of NSCLC patients with antigen-pulsed immature autologous dendritic cells. Lung Cancer. 2007. 57:365–372.
Article
22. Moser M, Murphy KM. Dendritic cell regulation of TH1-TH2 development. Nat Immunol. 2000. 1:199–205.
Article
23. Martín P, del Hoyo GM, Anjuère F, Ruiz SR, Arias CF, Marín AR, Ardavín C. Concept of lymphoid versus myeloid dendritic cell lineages revisited: both CD8alpha(-) and CD8alpha(+) dendritic cells are generated from CD4(low) lymphoid-committed precursors. Blood. 2000. 96:2511–2519.
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