A novel potential effective strategy for enhancing the antitumor immune response in breast cancer patients using a viable cancer cell‑dendritic cell‑based vaccine

Abdellateif,Mona  S.; Shaarawy,Sabry  M.; Kandeel,Eman  Z.; El‑Habashy,Ahmed  H.; Salem,Mohamed  L.; El‑Houseini,Motawa  E.

doi:10.3892/ol.2018.8631

A novel potential effective strategy for enhancing the antitumor immune response in breast cancer patients using a viable cancer cell‑dendritic cell‑based vaccine

Authors:
- Mona S. Abdellateif
- Sabry M. Shaarawy
- Eman Z. Kandeel
- Ahmed H. El‑Habashy
- Mohamed L. Salem
- Motawa E. El‑Houseini
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Affiliations: Medical Biochemistry and Molecular Biology Unit, Department of Cancer Biology, National Cancer Institute, Cairo University, Cairo 11976, Egypt, Department of Clinical Pathology, National Cancer Institute, Cairo University, Cairo 11976, Egypt, Department of Pathology, National Cancer Institute, Cairo University, Cairo 11976, Egypt, Department of Zoology, Faculty of Science, Tanta University, Tanta, Gharbia 31511, Egypt
Published online on: May 4, 2018 https://doi.org/10.3892/ol.2018.8631
Pages: 529-535

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Abstract

Dendritic cells (DCs) have been used in a number of clinical trials for cancer immunotherapy; however, they have achieved limited success in solid tumors. Consequently the aim of the present study was to identify a novel potential immunotherapeutic target for breast cancer patients through in vitro optimization of a viable DC‑based vaccine. Immature DCs were primed by viable MCF‑7 breast cancer cells and the activity and maturation of DCs were assessed through measuring CD83, CD86 and major histocompatibility complex (MHC)‑II expression, in addition to different T cell subpopulations, namely CD4+ T cells, CD8+ T cells, and CD4+CD25+ forkhead box protein 3 (Foxp3)+ regulatory T cells (Tregs), by flow cytometric analysis. Foxp3 level was also measured by enzyme‑linked immunosorbent assay (ELISA) in addition to reverse‑transcription quantitative polymerase chain reaction. The levels of interleukin‑12 (IL‑12) and interferon‑γ (IFN‑γ) were determined by ELISA. Finally, the cytotoxicity of cytotoxic T lymphocytes (CTLs) was evaluated through measuring lactate dehydrogenase (LDH) release by ELISA. The results demonstrated that CD83+, CD86+ and MHC‑II+ DCs were significantly elevated (P<0.001) following priming with breast cancer cells. In addition, there was increased activation of CD4+ and CD8+ T‑cells, with a significant decrease of CD4+CD25+Foxp3+ Tregs (P<0.001). Furthermore, a significant downregulation of FOXP3 gene expression (P<0.001) was identified, and a significant decrease in the level of its protein following activation (P<0.001) was demonstrated by ELISA. Additionally, significant increases in the secretion of IL‑12 and IFN‑γ (P=0.001) were observed. LDH release was significantly increased (P<0.001), indicating a marked cytotoxicity of CTLs against cancer cells. Therefore viable breast cancer cell‑DC‑based vaccines could expose an innovative avenue for a novel breast cancer immunotherapy.

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1	Siegel RL, Miller KD and Jemal A: Cancer statistics, 2016. CA Cancer J Clin. 66:7–30. 2016. View Article : Google Scholar : PubMed/NCBI
2	Lee J, Park S, Kim S, Kim J, Ryu J, Park HS, Kim SI and Park BW: Characteristics and survival of breast cancer patients with multiple synchronous or metachronous primary cancers. Yonsei Med J. 56:1213–1220. 2015. View Article : Google Scholar : PubMed/NCBI
3	Ibrahim AS, Khaled HM, Mikhail NN, Baraka H and Kamel H: Cancer incidence in Egypt: Results of the national population-based cancer registry program. J Cancer Epidemiol. 2014:4379712014. View Article : Google Scholar : PubMed/NCBI
4	Caffarel MM, Andradas C, Pérez-Gómez E, Guzmán M and Sánchez C: Cannabinoids: A new hope for breast cancer therapy? Cancer Treat Rev. 38:911–918. 2012. View Article : Google Scholar : PubMed/NCBI
5	Zhang P, Yi S, Li X, Liu R, Jiang H, Huang Z, Liu Y, Wu J and Huang Y: Preparation of triple-negative breast cancer vaccine through electrofusion with day-3 dendritic cells. PLoS One. 9:e1021972014. View Article : Google Scholar : PubMed/NCBI
6	Berneman Z, Van de Velde A, Anguille S, Willemen Y, Huizing M, Germonpré P, Saevels K, Nijs G, Cools N, Van Driessche A, et al: Vaccination with Wilms' Tumor Antigen (WT1) mRNA-electroporated dendritic cells as an adjuvant treatment in 60 cancer patients: Report of clinical effects and increased survival in acute myeloid leukemia, metastatic breast cancer, glioblastoma and mesothelioma. Cytotherapy. 18:S13–S14. 2016. View Article : Google Scholar
7	Bigalke I, Honnashagen K, Lundby M, Solum G, Skoge L, Inderberg EMS, Kasten J, Saboe-Larssen S, Schendel DJ and Kvalheim G: Abstract 2516: A new generation of dendritic cells to improve cancer therapy shows prolonged progression-free survival in patients with solid tumors. Cancer Res. 75 15 Suppl:S25162015. View Article : Google Scholar
8	Song QK, Ren J, Zhou XN, Wang XL, Song GH, Di LJ, Yu J, Hobeika A, Morse MA, Yuan YH, et al: The prognostic value of peripheral CD4⁺CD25⁺ T lymphocytes among early stage and triple negative breast cancer patients receiving dendritic cells-cytokine induced killer cells infusion. Oncotarget. 6:41350–41359. 2015. View Article : Google Scholar : PubMed/NCBI
9	Iranpour S, Nejati V, Delirezh N, Biparva P and Shirian S: Enhanced stimulation of anti-breast cancer T cells responses by dendritic cells loaded with poly lactic-co-glycolic acid (PLGA) nanoparticle encapsulated tumor antigens. J Exp Clin Cancer Res. 35:1682016. View Article : Google Scholar : PubMed/NCBI
10	Ciccocioppo R, Ricci G, Rovati B, Pesce I, Mazzocchi S, Piancatelli D, Cagnoni A, Millimaggi D, Danova M and Corazza GR: Reduced number and function of peripheral dendritic cells in coeliac disease. Clin Exp Immunol. 149:487–496. 2007. View Article : Google Scholar : PubMed/NCBI
11	Bøyum A: Isolation of lymphocytes, granulocytes and macrophages. Scand J Immunol. Suppl 5:S9–S15. 1976. View Article : Google Scholar
12	Kwok S: Procedures to minimize PCR-product carry-over. PCR protocols: A Guide Met Appl. 142–145. 1990.
13	Schmittgen TD and Livak KJ: Analyzing real-time PCR data by the comparative C(T) method. Nat Protoc. 3:1101–1108. 2008. View Article : Google Scholar : PubMed/NCBI
14	Pfaffl MW: A new mathematical model for relative quantification in real-time RT-PCR. Nucleic Acids Res. 29:e452001. View Article : Google Scholar : PubMed/NCBI
15	Wei FQ, Sun W, Wong TS, Gao W, Wen YH, Wei JW, Wei Y and Wen WP: Eliciting cytotoxic T lymphocytes against human laryngeal cancer-derived antigens: Evaluation of dendritic cells pulsed with a heat-treated tumor lysate and other antigen-loading strategies for dendritic-cell-based vaccination. J Exp Clin Cancer Res. 35:182016. View Article : Google Scholar : PubMed/NCBI
16	Fields R, Shimizu K and Mulé JJ: Murine dendritic cells pulsed with whole tumor lysates mediate potent antitumor immune responses in vitro and in vivo. Proc Natl Acad Sci USA. 95:9482–9487. 1998. View Article : Google Scholar : PubMed/NCBI
17	Nesrua FO, Atuaolcl S, Gilliet M, Sun Y, Grabbe S, Dummer R, Burg G and Schadendorf D: Vaccination of melanoma patients with peptide- or tumor lysate-pulsed dendritic cells. Nat Med. 4:328–332. 1998. View Article : Google Scholar : PubMed/NCBI
18	Jouanneau E, Poujol D, Gulia S, Le Mercier I, Blay J, Belin MF and Puisieux I: Dendritic cells are essential for priming but inefficient for boosting antitumour immune response in an orthotopic murine glioma model. Cancer Immunol Immunother. 55:254–267. 2006. View Article : Google Scholar : PubMed/NCBI
19	Zhang Y, Yoneyama H, Wang Y, Ishikawa S, Hashimoto S, Gao JL, Murphy P and Matsushima K: Mobilization of dendritic cell precursors into the circulation by administration of MIP-1alpha in mice. J Natl Cancer Inst. 96:201–209. 2004. View Article : Google Scholar : PubMed/NCBI
20	Hersey P, Menzies SW, Halliday GM, Nguyen T, Farrelly ML, DeSilva C and Lett M: Phase I/II study of treatment with dendritic cell vaccines in patients with disseminated melanoma. Cancer Immunol Immunother. 53:125–134. 2004. View Article : Google Scholar : PubMed/NCBI
21	Höltl L, Zelle-Rieser C, Gander H, Papesh C, Ramoner R, Bartsch G, Rogatsch H, Barsoum AL, Coggin JH Jr and Thurnher M: Immunotherapy of metastatic renal cell carcinoma with tumor lysate-pulsed autologous dendritic cells. Clin Cancer Res. 8:3369–3376. 2002.PubMed/NCBI
22	Ascierto ML, Idowu MO, Zhao Y, Khalak H, Payne KK, Wang XY, Dumur CI, Bedognetti D, Tomei S, Ascierto PA, et al: Molecular signatures mostly associated with NK cells are predictive of relapse free survival in breast cancer patients. J Transl Med. 11:1452013. View Article : Google Scholar : PubMed/NCBI
23	Idoyaga J, Moreno J and Bonifaz L: Tumor cells prevent mouse dendritic cell maturation induced by TLR ligands. Cancer Immunol Immunother. 56:1237–1250. 2007. View Article : Google Scholar : PubMed/NCBI
24	Vieira PL, de Jong EC, Wierenga EA, Kapsenberg ML and Kaliński P: Development of Th1-inducing capacity in myeloid dendritic cells requires environmental instruction. J Immunol. 164:4507–4512. 2000. View Article : Google Scholar : PubMed/NCBI
25	Benchetrit F, Gazagne A, Adotevi O, Haicheur N, Godard B, Badoual C, Fridman WH and Tartour E: Cytotoxic T lymphocytes: Role in immunosurveillance and in immunotherapy. Bull Cancer. 90:677–685. 2003.PubMed/NCBI
26	Bailur Kini J, Gueckel B and Pawelec G: Prognostic impact of high levels of circulating plasmacytoid dendritic cells in breast cancer. J Transl Med. 14:1512016. View Article : Google Scholar : PubMed/NCBI
27	Morse MA, Secord AA, Blackwell K, Hobeika AC, Sinnathamby G, Osada T, Hafner J, Philip M, Clay TM, Lyerly HK and Philip R: MHC class I-presented tumor antigens identified in ovarian cancer by immunoproteomic analysis are targets for T-cell responses against breast and ovarian cancer. Clin Cancer Res. 17:3408–3419. 2011. View Article : Google Scholar : PubMed/NCBI
28	Woo EY, Yeh H, Chu CS, Schlienger K, Carroll RG, Riley JL, Kaiser LR and June CH: Cutting edge: Regulatory T cells from lung cancer patients directly inhibit autologous T cell proliferation. J Immunol. 168:4272–4276. 2002. View Article : Google Scholar : PubMed/NCBI
29	Wang ZK, Yang B, Liu H, Hu Y, Yang JL, Wu LL, Zhou ZH and Jiao SC: Regulatory T cells increase in breast cancer and in stage IV breast cancer. Cancer Immunol Immunother. 61:911–916. 2012. View Article : Google Scholar : PubMed/NCBI
30	Jaberipour M, Habibagahi M, Hosseini A, Habibabad SR, Talei A and Ghaderi A: Increased CTLA-4 and FOXP3 transcripts in peripheral blood mononuclear cells of patients with breast cancer. Pathol Oncol Res. 16:547–551. 2010. View Article : Google Scholar : PubMed/NCBI
31	Suzuki S, Ishida T, Yoshikawa K and Ueda R: Progress in clinical use of CC chemokine receptor 4 antibody for regulatory T cell suppression. Inflam Immun Cancer: Springer. 207–227. 2015.
32	Liu F, Lang R, Zhao J, Zhang X, Pringle GA, Fan Y, Yin D, Gu F, Yao Z and Fu L: CD8⁺ cytotoxic T cell and FOXP3⁺ regulatory T cell infiltration in relation to breast cancer survival and molecular subtypes. Breast Cancer Res Treat. 130:645–655. 2011. View Article : Google Scholar : PubMed/NCBI
33	Hamidinia M, Boroujerdnia Ghafourian M, Talaiezadeh A, Solgi G, Roshani R, Iranprast S and Khodadadi A: Increased P-35, EBI3 transcripts and other treg markers in peripheral blood mononuclear cells of breast cancer patients with different clinical stages. Adv Pharm Bull. 5:261–267. 2015. View Article : Google Scholar : PubMed/NCBI
34	Faloppi L, Bianconi M, Memeo R, Gardini Casadei A, Giampieri R, Bittoni A, Andrikou K, Del Prete M, Cascinu S and Scartozzi M: Lactate dehydrogenase in hepatocellular carcinoma: Something old, something new. Biomed Res Int. 2016:71962802016. View Article : Google Scholar : PubMed/NCBI