Doxorubicin treatment induces tumor cell death followed by immunomodulation in a murine neuroblastoma model

Inoue,Seiichiro; Setoyama,Yumiko; Odaka,Akio

doi:10.3892/etm.2014.1489

2014-March Volume 7 Issue 3

Full Size Image

Journals

International Journal of Molecular Medicine

International Journal of Molecular Medicine is an international journal devoted to molecular mechanisms of human disease.

International Journal of Oncology

International Journal of Oncology is an international journal devoted to oncology research and cancer treatment.

Molecular Medicine Reports

Covers molecular medicine topics such as pharmacology, pathology, genetics, neuroscience, infectious diseases, molecular cardiology, and molecular surgery.

Oncology Reports

Oncology Reports is an international journal devoted to fundamental and applied research in Oncology.

Experimental and Therapeutic Medicine

Experimental and Therapeutic Medicine is an international journal devoted to laboratory and clinical medicine.

Oncology Letters

Oncology Letters is an international journal devoted to Experimental and Clinical Oncology.

Biomedical Reports

Explores a wide range of biological and medical fields, including pharmacology, genetics, microbiology, neuroscience, and molecular cardiology.

Molecular and Clinical Oncology

International journal addressing all aspects of oncology research, from tumorigenesis and oncogenes to chemotherapy and metastasis.

World Academy of Sciences Journal

Multidisciplinary open-access journal spanning biochemistry, genetics, neuroscience, environmental health, and synthetic biology.

International Journal of Functional Nutrition

Open-access journal combining biochemistry, pharmacology, immunology, and genetics to advance health through functional nutrition.

International Journal of Epigenetics

Publishes open-access research on using epigenetics to advance understanding and treatment of human disease.

Medicine International

An International Open Access Journal Devoted to General Medicine.

2014-March Volume 7 Issue 3

Full Size Image

Article

Doxorubicin treatment induces tumor cell death followed by immunomodulation in a murine neuroblastoma model

Authors:
- Seiichiro Inoue
- Yumiko Setoyama
- Akio Odaka
View Affiliations / Copyright

Affiliations: Department of Hepato‑Biliary‑Pancreatic and Pediatric Surgery, Saitama Medical Center, Saitama Medical University, Kawagoe, Saitama 3508550, Japan, Department of Medical Research, Saitama Medical Center, Saitama Medical University, Kawagoe, Saitama 3508550, Japan
Pages: 703-708
|
Published online on: January 17, 2014

https://doi.org/10.3892/etm.2014.1489
Expand metrics +

Abstract

Chemotherapy of malignant tumors induces tumor cell death. Numerous antitumor agents induce apoptosis of tumor cells, which are subsequently engulfed by phagocytes, initiating an immune reaction. The induction of immunogenic cell death by antitumor agents may be advantageous for antitumor immunity. The purpose of this study was to determine whether doxorubicin is capable of inducing an immunogenic reaction in murine neuroblastoma cells. The murine neuroblastoma cell line (neuro‑2a cells) was cultured in a medium containing doxorubicin or cisplatin (CDDP), and induction of cell death was confirmed by cell viability assays. Cluster of differentiation (CD)8α+ lymphocytes were co‑cultured with neuro‑2a cells that had died following treatment with either doxorubicin or CDDP, and CD11b+ spleen cells or bone marrow‑derived dendritic cells (BM‑DCs) were added to the culture. Proliferation of CD8α+ lymphocytes and interferon (IFN)‑γ production were evaluated. When CD8α+ cells were co‑cultured with doxorubicin‑treated neuro‑2a cells and BM‑DCs, CD8α+ cells reacted to anti‑CD3/CD28 antibody stimulation, proliferated and increased IFN‑γ production. IFN‑γ production was more effectively promoted by co‑culture with doxorubicin‑treated neuro‑2a cells than by co‑culture with CDDP‑treated neuro‑2a cells. These findings suggest that doxorubicin is capable of inducing immunogenic cell death in neuroblastoma cells, and thus has an immunological advantage for chemotherapy of neuroblastoma compared with CDDP. BM‑DCs are considered to be the key antigen‑presenting cells in the immune reaction following the induction of immunogenic neuroblastoma cell death and phagocytosis.

View Figures

View References

1	Liu G, Wu C, Wu Y and Zhao Y: Phagocytosis of apoptotic cells and immune regulation. Scand J Immunol. 64:1–9. 2006. View Article : Google Scholar : PubMed/NCBI
2	Jubinsky PT, Dickens DS and Short MK: New roles for mononuclear phagocytes in cancer biology. J Pediatr Hematol Oncol. 30:584–591. 2008. View Article : Google Scholar : PubMed/NCBI
3	Kepp O, Tesniere A, Schlemmer F, et al: Immunogenic cell death modalities and their impact on cancer treatment. Apoptosis. 14:364–375. 2009. View Article : Google Scholar : PubMed/NCBI
4	Chen G and Emens LA: Chemoimmunotherapy: reengineering tumor immunity. Cancer Immunol Immunother. 62:203–216. 2013. View Article : Google Scholar : PubMed/NCBI
5	Obeid M, Tesniere A, Ghiringhelli F, et al: Calreticulin exposure dictates the immunogenicity of cancer cell death. Nat Med. 13:54–61. 2007. View Article : Google Scholar : PubMed/NCBI
6	Martins I, Kepp O, Galluzzi L, et al: Surface-exposed calreticulin in the interaction between dying cells and phagocytes. Ann NY Acad Sci. 1209:77–82. 2010. View Article : Google Scholar : PubMed/NCBI
7	Zitvogel L, Apetoh L, Ghiringhelli F and Kroemer G: Immunological aspects of cancer chemotherapy. Nat Rev Immunol. 8:59–73. 2008. View Article : Google Scholar
8	Tufi R, Panaretakis T, Bianchi K, et al: Reduction of endoplasmic reticulum Ca²⁺ levels favors plasma membrane surface exposure of calreticulin. Cell Death Differ. 15:274–282. 2008.
9	Maris JM, Hogarty MD, Bagatell R and Cohn SL: Neuroblastoma. Lancet. 369:2106–2120. 2007. View Article : Google Scholar : PubMed/NCBI
10	Maris JM: Recent advances in neuroblastoma. N Engl J Med. 362:2202–2211. 2010. View Article : Google Scholar : PubMed/NCBI
11	Hara J: Development of treatment strategies for advanced neuroblastoma. Int J Clin Oncol. 17:196–203. 2012. View Article : Google Scholar
12	Brodeur GM: Neuroblastoma: biological insights into a clinical enigma. Nat Rev Cancer. 3:203–216. 2003. View Article : Google Scholar : PubMed/NCBI
13	Verneris MR and Wagner JE: Recent developments in cell-based immune therapy for neuroblastoma. J Neuroimmune Pharmacol. 2:134–139. 2007. View Article : Google Scholar : PubMed/NCBI
14	Martins I, Kepp O, Schlemmer F, et al: Restoration of the immunogenicity of cisplatin-induced cancer cell death by endoplasmic reticulum stress. Oncogene. 30:1147–1158. 2011. View Article : Google Scholar : PubMed/NCBI
15	Ullrich E, Menard C, Flament C, et al: Dendritic cells and innate defense against tumor cells. Cytokine Growth Factor Rev. 19:79–92. 2008. View Article : Google Scholar : PubMed/NCBI
16	Mantovani A and Sica A: Macrophages, innate immunity and cancer: balance, tolerance, and diversity. Curr Opin Immunol. 22:231–237. 2010. View Article : Google Scholar : PubMed/NCBI
17	Sica A: Role of tumour-associated macrophages in cancer-related inflammation. Exp Oncol. 32:153–158. 2010.PubMed/NCBI
18	Buhtoiarov IN, Sondel PM, Eickhoff JC and Rakhmilevich AL: Macrophages are essential for antitumour effects against weakly immunogenic murine tumours induced by class B CpG-oligodeoxynucleotides. Immunology. 120:412–423. 2007. View Article : Google Scholar
19	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
20	Tesniere A, Apetoh L, Ghiringhelli F, et al: Immunogenic cancer cell death: a key-lock paradigm. Curr Opin Immunol. 20:504–511. 2008. View Article : Google Scholar : PubMed/NCBI
21	Sica A and Bronte V: Altered macrophage differentiation and immune dysfunction in tumor development. J Clin Invest. 117:1155–1166. 2007. View Article : Google Scholar : PubMed/NCBI
22	Kuroda T, Morikawa N, Matsuoka K, et al: Prognostic significance of circulating tumor cells and bone marrow micrometastasis in advanced neuroblastoma. J Pediatr Surg. 43:2182–2185. 2008. View Article : Google Scholar : PubMed/NCBI
23	Kuroda T: Cellular kinetics of neuroblastoma and the role of surgery. Pediatr Surg Int. 27:913–917. 2011. View Article : Google Scholar : PubMed/NCBI
24	Emens LA: Chemoimmunotherapy. Cancer J. 16:295–303. 2010. View Article : Google Scholar

Journals

International Journal of Molecular Medicine

International Journal of Oncology

Molecular Medicine Reports

Oncology Reports

Experimental and Therapeutic Medicine

Oncology Letters

Biomedical Reports

Molecular and Clinical Oncology

World Academy of Sciences Journal

International Journal of Functional Nutrition

International Journal of Epigenetics

Medicine International

Doxorubicin treatment induces tumor cell death followed by immunomodulation in a murine neuroblastoma model

This article is mentioned in:

Abstract

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Related Articles