Active immunotherapy for mouse breast cancer with irradiated whole-cell vaccine expressing VEGFR2

Yan,Heng-Xiu; Cheng,Ping; Wei,Hai-Yan; Shen,Guo-Bo; Fu,Li-Xin; Ni,Jie; Wu,Yang; Wei,Yu-Quan

doi:10.3892/or.2013.2282

Active immunotherapy for mouse breast cancer with irradiated whole-cell vaccine expressing VEGFR2

Authors:
- Heng-Xiu Yan
- Ping Cheng
- Hai-Yan Wei
- Guo-Bo Shen
- Li-Xin Fu
- Jie Ni
- Yang Wu
- Yu-Quan Wei
View Affiliations

Affiliations: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan, P.R. China, College of Life Science and Technology, Southwest University for Nationalities, Chengdu, Sichuan, P.R. China
Published online on: February 7, 2013 https://doi.org/10.3892/or.2013.2282
Pages: 1510-1516

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

As tumor-associated antigens are not well characterized for the majority of human tumors, polyvalent vaccines prepared with whole-tumor antigens are an attractive approach for tumor vaccination. Vascular endothelial growth factor receptor-2 (VEGFR2), as a model antigen with which to explore the feasibility of immunotherapy, has shown great promise as a tumor vaccine. However, the efficacy of immunotherapy is often not ideal when used alone. In this study, we explored the therapeutic efficacy of an irradiated AdVEGFR2-infected cell vaccine-based immunotherapy in the weakly immunogenic and highly metastatic 4T1 murine mammary cancer model. An adenovirus encoding the VEGFR2 gene (AdVEGFR2) was constructed. Lethally irradiated, virus-infected 4T1 cells were used as vaccines. Vaccination with lethally irradiated AdVEGFR2-infected 4T1 cells inhibited subsequent tumor growth and pulmonary metastasis compared with challenge inoculations. Angiogenesis was inhibited, and the number of CD8+ T lymphocytes was increased within the tumors. Antitumor activity was also caused by the adoptive transfer of isolated spleen lymphocytes. In vitro, the expression of HMGB1 and HSP70 in the AdVEGFR2‑infected 4T1 cells was increased, and was involved in the activation of tumor antigen-speciﬁc T-cell immunity. Our results indicate that the immunotherapy based on irradiated AdVEGFR2-infected whole-cancer cell vaccines may be a potentially effective strategy for 4T1 cancer treatment.

View Figures

View References

1	Perez CA, Fu A, Onishko H, Hallahan DE and Geng L: Radiation induces an antitumour immune response to mouse melanoma. Int J Radiat Biol. 85:1126–1136. 2009. View Article : Google Scholar : PubMed/NCBI
2	Chakravarty PK, Guha C, Alfieri A, et al: Flt3L therapy following localized tumor irradiation generates long-term protective immune response in metastatic lung cancer: its implication in designing a vaccination strategy. Oncology. 70:245–254. 2006. View Article : Google Scholar
3	Nakajima K, Yanagawa T, Watanabe H and Takagishi K: Hyperthermia reduces migration of osteosarcoma by suppression of autocrine motility factor. Oncol Rep. 28:1953–1958. 2012.PubMed/NCBI
4	Weiss EM, Frey B, Rodel F, et al: Ex vivo- and in vivo-induced dead tumor cells as modulators of antitumor responses. Ann NY Acad Sci. 1209:109–117. 2010. View Article : Google Scholar : PubMed/NCBI
5	Das A and Ali N: Vaccine prospects of killed but metabolically active Leishmania against visceral leishmaniasis. Expert Rev Vaccines. 11:783–785. 2012. View Article : Google Scholar : PubMed/NCBI
6	Dols A, Smith JW II, Meijer SL, et al: Vaccination of women with metastatic breast cancer, using a costimulatory gene (CD80)-modified, HLA-A2-matched, allogeneic, breast cancer cell line: clinical and immunological results. Hum Gene Ther. 14:1117–1123. 2003. View Article : Google Scholar : PubMed/NCBI
7	Riedl K, Baratelli F, Batra RK, et al: Overexpression of CCL-21/secondary lymphoid tissue chemokine in human dendritic cells augments chemotactic activities for lymphocytes and antigen presenting cells. Mol Cancer. 2:352003. View Article : Google Scholar
8	Li B, VanRoey M, Wang C, Chen TH, Korman A and Jooss K: Anti-programmed death-1 synergizes with granulocyte macrophage colony-stimulating factor-secreting tumor cell immunotherapy providing therapeutic benefit to mice with established tumors. Clin Cancer Res. 15:1623–1634. 2009. View Article : Google Scholar
9	van Elsas A, Hurwitz AA and Allison JP: Combination immunotherapy of B16 melanoma using anti-cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and granulocyte/macrophage colony-stimulating factor (GM-CSF)-producing vaccines induces rejection of subcutaneous and metastatic tumors accompanied by autoimmune depigmentation. J Exp Med. 190:355–366. 1999.
10	van den Eertwegh AJ, Versluis J, van den Berg HP, et al: Combined immunotherapy with granulocyte-macrophage colony-stimulating factor-transduced allogeneic prostate cancer cells and ipilimumab in patients with metastatic castration-resistant prostate cancer: a phase 1 dose-escalation trial. Lancet Oncol. 13:509–517. 2012.
11	Guckel B, Stumm S, Rentzsch C, Marme A, Mannhardt G and Wallwiener D: A CD80-transfected human breast cancer cell variant induces HER-2/neu-specific T cells in HLA-A*02-matched situations in vitro as well as in vivo. Cancer Immunol Immunother. 54:129–140. 2005.PubMed/NCBI
12	Gille H, Kowalski J, Li B, et al: Analysis of biological effects and signaling properties of Flt-1 (VEGFR-1) and KDR (VEGFR-2). A reassessment using novel receptor-specific vascular endothelial growth factor mutants. J Biol Chem. 276:3222–3230. 2001. View Article : Google Scholar
13	Zeng H, Dvorak HF and Mukhopadhyay D: Vascular permeability factor (VPF)/vascular endothelial growth factor (VEGF) peceptor-1 down-modulates VPF/VEGF receptor-2-mediated endothelial cell proliferation, but not migration, through phosphatidylinositol 3-kinase-dependent pathways. J Biol Chem. 276:26969–26979. 2001. View Article : Google Scholar
14	Takahashi Y, Kitadai Y, Bucana CD, Cleary KR and Ellis LM: Expression of vascular endothelial growth factor and its receptor, KDR, correlates with vascularity, metastasis, and proliferation of human colon cancer. Cancer Res. 55:3964–3968. 1995.PubMed/NCBI
15	Vajkoczy P, Farhadi M, Gaumann A, et al: Microtumor growth initiates angiogenic sprouting with simultaneous expression of VEGF, VEGF receptor-2, and angiopoietin-2. J Clin Invest. 109:777–785. 2002. View Article : Google Scholar : PubMed/NCBI
16	Breier G, Blum S, Peli J, et al: Transforming growth factor-beta and Ras regulate the VEGF/VEGF-receptor system during tumor angiogenesis. Int J Cancer. 97:142–148. 2002. View Article : Google Scholar : PubMed/NCBI
17	Prewett M, Huber J, Li Y, et al: Antivascular endothelial growth factor receptor (fetal liver kinase 1) monoclonal antibody inhibits tumor angiogenesis and growth of several mouse and human tumors. Cancer Res. 59:5209–5218. 1999.
18	Wood JM, Bold G, Buchdunger E, et al: PTK787/ZK 222584, a novel and potent inhibitor of vascular endothelial growth factor receptor tyrosine kinases, impairs vascular endothelial growth factor-induced responses and tumor growth after oral administration. Cancer Res. 60:2178–2189. 2000.
19	Thomas AL, Morgan B, Drevs J, et al: Vascular endothelial growth factor receptor tyrosine kinase inhibitors: PTK787/ZK 222584. Semin Oncol. 30:32–38. 2003. View Article : Google Scholar : PubMed/NCBI
20	Liu JY, Wei YQ, Yang L, et al: Immunotherapy of tumors with vaccine based on quail homologous vascular endothelial growth factor receptor-2. Blood. 102:1815–1823. 2003. View Article : Google Scholar : PubMed/NCBI
21	Li G, Tian L, Hou JM, et al: Improved therapeutic effectiveness by combining recombinant CXC chemokine ligand 10 with cisplatin in solid tumors. Clin Cancer Res. 11:4217–4224. 2005. View Article : Google Scholar : PubMed/NCBI
22	Seong SY and Matzinger P: Hydrophobicity: an ancient damage-associated molecular pattern that initiates innate immune responses. Nat Rev Immunol. 4:469–478. 2004. View Article : Google Scholar : PubMed/NCBI
23	Jiang D, Liang J, Fan J, et al: Regulation of lung injury and repair by Toll-like receptors and hyaluronan. Nat Med. 11:1173–1179. 2005. View Article : Google Scholar : PubMed/NCBI
24	Tsung A, Sahai R, Tanaka H, et al: The nuclear factor HMGB1 mediates hepatic injury after murine liver ischemia-reperfusion. J Exp Med. 201:1135–1143. 2005. View Article : Google Scholar : PubMed/NCBI
25	Apetoh L, Ghiringhelli F, Tesniere A, et al: Toll-like receptor 4-dependent contribution of the immune system to anticancer chemotherapy and radiotherapy. Nat Med. 13:1050–1059. 2007. View Article : Google Scholar
26	Soliman H: Developing an effective breast cancer vaccine. Cancer Control. 17:183–190. 2010.PubMed/NCBI
27	Solbrig CM, Saucier-Sawyer JK, Cody V, Saltzman WM and Hanlon DJ: Polymer nanoparticles for immunotherapy from encapsulated tumor-associated antigens and whole tumor cells. Mol Pharm. 4:47–57. 2007. View Article : Google Scholar : PubMed/NCBI
28	Liu S, Wang H, Yang Z, et al: Enhancement of cancer radiation therapy by use of adenovirus-mediated secretable glucose-regulated protein 94/gp96 expression. Cancer Res. 65:9126–9131. 2005. View Article : Google Scholar : PubMed/NCBI
29	Shalaby F, Rossant J, Yamaguchi TP, et al: Failure of blood-island formation and vasculogenesis in Flk-1-deficient mice. Nature. 376:62–66. 1995. View Article : Google Scholar : PubMed/NCBI
30	Wei YQ, Wang QR, Zhao X, et al: Immunotherapy of tumors with xenogeneic endothelial cells as a vaccine. Nat Med. 6:1160–1166. 2000. View Article : Google Scholar : PubMed/NCBI
31	Pe'er J, Shweiki D, Itin A, Hemo I, Gnessin H and Keshet E: Hypoxia-induced expression of vascular endothelial growth factor by retinal cells is a common factor in neovascularizing ocular diseases. Lab Invest. 72:638–645. 1995.PubMed/NCBI
32	Plate KH, Breier G, Weich HA and Risau W: Vascular endothelial growth factor is a potential tumour angiogenesis factor in human gliomas in vivo. Nature. 359:845–848. 1992. View Article : Google Scholar : PubMed/NCBI
33	Folkman J: What is the evidence that tumors are angiogenesis dependent? J Natl Cancer Inst. 82:4–6. 1990. View Article : Google Scholar : PubMed/NCBI
34	Fine BA, Valente PT, Feinstein GI and Dey T: VEGF, flt-1, and KDR/flk-1 as prognostic indicators in endometrial carcinoma. Gynecol Oncol. 76:33–39. 2000. View Article : Google Scholar : PubMed/NCBI
35	Fidler IJ and Ellis LM: The implications of angiogenesis for the biology and therapy of cancer metastasis. Cell. 79:185–188. 1994. View Article : Google Scholar : PubMed/NCBI
36	Yancopoulos GD, Klagsbrun M and Folkman J: Vasculogenesis, angiogenesis, and growth factors: ephrins enter the fray at the border. Cell. 93:661–664. 1998. View Article : Google Scholar : PubMed/NCBI