Research Article
No access
Published Online: 3 April 2012

Preconditioning Chemotherapy with Cisplatin Enhances the Antitumor Activity of Cytokine-Induced Killer Cells in a Murine Melanoma Model

Publication: Cancer Biotherapy and Radiopharmaceuticals
Volume 27, Issue Number 3

Abstract

Accumulating evidence has indicated that preconditioning chemotherapy could eliminate the suppressive factors in antitumor immune response, thereby leading to the full release of the efficacy of the subsequent immunotherapy. In this study, a single subtoxic dose (5 mg/kg, intraperitoneally) of cisplatin was chosen as the preconditioning chemotherapy in combination with cytokine-induced killer (CIK) cells (4×106, intravenously) to treat the murine B16 melanoma xenografts. It was found that cisplatin pretreatment could enhance the antitumor activity of CIK cells. To explore the potential mechanisms underlying the efficacy-enhancing effect of cisplatin, the in vivo trafficking and distribution of the infused CIK cells were traced. It was found that cisplatin could augment the homing ability of CIK cells into the tumor, tumor-draining lymph nodes (TDLNs), and spleen tissues. The endogenous effector cells, CD3+ T lymphocytes also had an increased accumulation in the tumor and TDLNs after cisplatin precondition. Moreover, cisplatin could also modulate the percentages of myeloid cells, thus encouraging immune responses by increasing the percentages of dendritic cells and relieving the immunosuppression by preferentially eliminating the myeloid-derived suppressor cells. In conclusion, our findings suggested that cisplatin preconditioning chemotherapy could enhance the antitumor activity of CIK cells in a murine melanoma model, and this efficacy-enhancing effect was attributed to the augmented homing ability of exogenous and endogenous effector cells and the modulation of the myeloid cells.

Get full access to this article

View all available purchase options and get full access to this article.

References

1.
Garbe CLeiter U. Melanoma epidemiology and trendsClin Dermatol2009273.1. Garbe C, Leiter U. Melanoma epidemiology and trends. Clin Dermatol 2009;27:3.
2.
Kaufmann R. Surgical management of primary melanomaClin Exp Dermatol200025476.2. Kaufmann R. Surgical management of primary melanoma. Clin Exp Dermatol 2000;25:476.
3.
Bedikian AYMillward MPehamberger H et al. Bcl-2 antisense (oblimersen sodium) plus dacarbazine in patients with advanced melanoma: The Oblimersen Melanoma Study GroupJ Clin Oncol2006244738.3. Bedikian AY, Millward M, Pehamberger H, et al. Bcl-2 antisense (oblimersen sodium) plus dacarbazine in patients with advanced melanoma: The Oblimersen Melanoma Study Group. J Clin Oncol 2006;24:4738.
4.
Ledford H. Melanoma drug wins US approvalNature2011471561.4. Ledford H. Melanoma drug wins US approval. Nature 2011;471:561.
5.
Chapman PBHauschild ARobert C et al. Improved survival with vemurafenib in melanoma with BRAF V600EN Engl J Med20113642507.5. Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemurafenib in melanoma with BRAF V600E. N Engl J Med 2011;364:2507.
6.
Klebanoff CAKhong HTAntony PA et al. Sinks, suppressors and antigen presenters: How lymphodepletion enhances T cell-mediated tumor immunotherapyTrends Immunol200526111.6. Klebanoff CA, Khong HT, Antony PA, et al. Sinks, suppressors and antigen presenters: How lymphodepletion enhances T cell-mediated tumor immunotherapy. Trends Immunol 2005;26:111.
7.
Lutsiak MESemnani RTDe Pascalis R et al. Inhibition of CD4(+)25+ T regulatory cell function implicated in enhanced immune response by low-dose cyclophosphamideBlood20051052862.7. Lutsiak ME, Semnani RT, De Pascalis R, et al. Inhibition of CD4(+)25+ T regulatory cell function implicated in enhanced immune response by low-dose cyclophosphamide. Blood 2005;105:2862.
8.
Dudley MEWunderlich JRYang JC et al. Adoptive cell transfer therapy following non-myeloablative but lymphodepleting chemotherapy for the treatment of patients with refractory metastatic melanomaJ Clin Oncol2005232346.8. Dudley ME, Wunderlich JR, Yang JC, et al. Adoptive cell transfer therapy following non-myeloablative but lymphodepleting chemotherapy for the treatment of patients with refractory metastatic melanoma. J Clin Oncol 2005;23:2346.
9.
Morgan RADudley MEWunderlich JR et al. Cancer regression in patients after transfer of genetically engineered lymphocytesScience2006314126.9. Morgan RA, Dudley ME, Wunderlich JR, et al. Cancer regression in patients after transfer of genetically engineered lymphocytes. Science 2006;314:126.
10.
Kim HMLim JKang JS et al. Inhibition of human cervical carcinoma growth by cytokine-induced killer cells in nude mouse xenograft modelInt Immunopharmacol20099375.10. Kim HM, Lim J, Kang JS, et al. Inhibition of human cervical carcinoma growth by cytokine-induced killer cells in nude mouse xenograft model. Int Immunopharmacol 2009;9:375.
11.
Kim HMKang JSLim J et al. Antitumor activity of cytokine-induced killer cells in nude mouse xenograft modelArch Pharm Res200932781.11. Kim HM, Kang JS, Lim J, et al. Antitumor activity of cytokine-induced killer cells in nude mouse xenograft model. Arch Pharm Res 2009;32:781.
12.
Nishimura RBaker JBeilhack A et al. In vivo trafficking and survival of cytokine-induced killer cells resulting in minimal GVHD with retention of antitumor activityBlood20081122563.12. Nishimura R, Baker J, Beilhack A, et al. In vivo trafficking and survival of cytokine-induced killer cells resulting in minimal GVHD with retention of antitumor activity. Blood 2008;112:2563.
13.
Introna MBorleri GConti E et al. Repeated infusions of donor-derived cytokine-induced killer cells in patients relapsing after allogeneic stem cell transplantation: A phase I studyHaematologica200792952.13. Introna M, Borleri G, Conti E, et al. Repeated infusions of donor-derived cytokine-induced killer cells in patients relapsing after allogeneic stem cell transplantation: A phase I study. Haematologica 2007;92:952.
14.
Gasser SRaulet DH. The DNA damage response arouses the immune systemCancer Res2006663959.14. Gasser S, Raulet DH. The DNA damage response arouses the immune system. Cancer Res 2006;66:3959.
15.
Baker JVerneris MRIto M et al. Expansion of cytolytic CD8+ natural killer T cells with limited capacity for graft-versus-host disease induction due to interferon gamma productionBlood2001972923.15. Baker J, Verneris MR, Ito M, et al. Expansion of cytolytic CD8+ natural killer T cells with limited capacity for graft-versus-host disease induction due to interferon gamma production. Blood 2001;97:2923.
16.
Ohtani H. Focus on TILs: prognostic significance of tumor infiltrating lymphocytes in human colorectal cancerCancer Immun200774.16. Ohtani H. Focus on TILs: prognostic significance of tumor infiltrating lymphocytes in human colorectal cancer. Cancer Immun 2007;7:4.
17.
Wang LXShu SPlautz GE. Host lymphodepletion augments T cell adoptive immunotherapy through enhanced intratumoral proliferation of effector cellsCancer Res2005659547.17. Wang LX, Shu S, Plautz GE. Host lymphodepletion augments T cell adoptive immunotherapy through enhanced intratumoral proliferation of effector cells. Cancer Res 2005;65:9547.
18.
Muranski PBoni AWrzesinski C et al. Increased intensity lymphodepletion and adoptive immunotherapy—How far can we go?Nat Clin Pract Oncol20063668.18. Muranski P, Boni A, Wrzesinski C, et al. Increased intensity lymphodepletion and adoptive immunotherapy—How far can we go? Nat Clin Pract Oncol 2006;3:668.
19.
Salem MLEl-Naggar SACole DJ. Cyclophosphamide induces bone marrow to yield higher numbers of precursor dendritic cells in vitro capable of functional antigen presentation to T cells in vivoCell Immunol2010261134.19. Salem ML, El-Naggar SA, Cole DJ. Cyclophosphamide induces bone marrow to yield higher numbers of precursor dendritic cells in vitro capable of functional antigen presentation to T cells in vivo. Cell Immunol 2010;261:134.
20.
Radojcic VBezak KBSkarica M et al. Cyclophosphamide resets dendritic cell homeostasis and enhances antitumor immunity through effects that extend beyond regulatory T cell eliminationCancer Immunol Immunother201059137.20. Radojcic V, Bezak KB, Skarica M, et al. Cyclophosphamide resets dendritic cell homeostasis and enhances antitumor immunity through effects that extend beyond regulatory T cell elimination. Cancer Immunol Immunother 2010;59:137.
21.
Schmidt JEisold SBüchler MW et al. Dendritic cells reduce number and function of CD4+CD25+ cells in cytokine-induced killer cells derived from patients with pancreatic carcinomaCancer Immunol Immunother2004531018.21. Schmidt J, Eisold S, Büchler MW, et al. Dendritic cells reduce number and function of CD4+CD25+ cells in cytokine-induced killer cells derived from patients with pancreatic carcinoma. Cancer Immunol Immunother 2004;53:1018.
22.
Ostrand-Rosenberg S. Myeloid-derived suppressor cells: More mechanisms for inhibiting antitumor immunityCancer Immunol Immunother2010591593.22. Ostrand-Rosenberg S. Myeloid-derived suppressor cells: More mechanisms for inhibiting antitumor immunity. Cancer Immunol Immunother 2010;59:1593.
23.
Finn OJ. Cancer immunologyN Engl J Med20083582704.23. Finn OJ. Cancer immunology. N Engl J Med 2008;358:2704.
24.
Bracci LMoschella FSestili P et al. Cyclophosphamide enhances the antitumor efficacy of adoptively transferred immune cells through the induction of cytokine expression, B-cell and T-cell homeostatic proliferation, and specific tumor infiltrationClin Cancer Res200713644.24. Bracci L, Moschella F, Sestili P, et al. Cyclophosphamide enhances the antitumor efficacy of adoptively transferred immune cells through the induction of cytokine expression, B-cell and T-cell homeostatic proliferation, and specific tumor infiltration. Clin Cancer Res 2007;13:644.
25.
Zhong HHan BTourkova IL et al. Low-dose paclitaxel prior to intratumoral dendritic cell vaccine modulates intratumoral cytokine network and lung cancer growthClin Cancer Res2007135455.25. Zhong H, Han B, Tourkova IL, et al. Low-dose paclitaxel prior to intratumoral dendritic cell vaccine modulates intratumoral cytokine network and lung cancer growth. Clin Cancer Res 2007;13:5455.
26.
Bae SHPark YJPark JB et al. Therapeutic synergy of human papillomavirus E7 subunit vaccines plus cisplatin in an animal tumor model: Causal involvement of increased sensitivity of cisplatin-treated tumors to CTL-mediated killing in therapeutic synergyClin Cancer Res200713341.26. Bae SH, Park YJ, Park JB, et al. Therapeutic synergy of human papillomavirus E7 subunit vaccines plus cisplatin in an animal tumor model: Causal involvement of increased sensitivity of cisplatin-treated tumors to CTL-mediated killing in therapeutic synergy. Clin Cancer Res 2007;13:341.
27.
Schmidt-Wolf IGLefterova PMehta BA et al. Phenotypic characterization and identification of effector cells involved in tumor cell recognition of cytokine-induced killer cellsExp Hematol1993211673.27. Schmidt-Wolf IG, Lefterova P, Mehta BA, et al. Phenotypic characterization and identification of effector cells involved in tumor cell recognition of cytokine-induced killer cells. Exp Hematol 1993;21:1673.
28.
Marincola FMJaffee EMHicklin DJ et al. Escape of human solid tumors from T-cell recognition: Molecular mechanisms and functional significanceAdv Immunol200074181.28. Marincola FM, Jaffee EM, Hicklin DJ, et al. Escape of human solid tumors from T-cell recognition: Molecular mechanisms and functional significance. Adv Immunol 2000;74:181.
29.
Gasser SOrsulic SBrown EJ et al. The DNA damage pathway regulates innate immune system ligands of the NKG2D receptorNature20054361186.29. Gasser S, Orsulic S, Brown EJ, et al. The DNA damage pathway regulates innate immune system ligands of the NKG2D receptor. Nature 2005;436:1186.
30.
Micheau OSolary EHammann A et al. Sensitization of cancer cells treated with cytotoxic drugs to fas-mediated cytotoxicityJ Natl Cancer Inst199789783.30. Micheau O, Solary E, Hammann A, et al. Sensitization of cancer cells treated with cytotoxic drugs to fas-mediated cytotoxicity. J Natl Cancer Inst 1997;89:783.
31.
Huang XChen YSong H et al. Cisplatin pretreatment enhances anti-tumor activity of cytokine-induced killer cellsWorld J Gastroenterol2011173002.31. Huang X, Chen Y, Song H, et al. Cisplatin pretreatment enhances anti-tumor activity of cytokine-induced killer cells. World J Gastroenterol 2011;17:3002.
32.
Bromley SKMempel TRLuster AD. Orchestrating the orchestrators: Chemokines in control of T cell trafficNat Immunol20089970.32. Bromley SK, Mempel TR, Luster AD. Orchestrating the orchestrators: Chemokines in control of T cell traffic. Nat Immunol 2008;9:970.
33.
Zhong RTeng JHan B et al. Dendritic cells combining with cytokine-induced killer cells synergize chemotherapy in patients with late-stage non-small cell lung cancerCancer Immunol Immunother2011601497.33. Zhong R, Teng J, Han B, et al. Dendritic cells combining with cytokine-induced killer cells synergize chemotherapy in patients with late-stage non-small cell lung cancer. Cancer Immunol Immunother 2011;60:1497.
34.
Serafini PBorrello IBronte V. Myeloid suppressor cells in cancer: Recruitment, phenotype, properties, and mechanisms of immune suppressionSemin Cancer Biol20061653.34. Serafini P, Borrello I, Bronte V. Myeloid suppressor cells in cancer: Recruitment, phenotype, properties, and mechanisms of immune suppression. Semin Cancer Biol 2006;16:53.
35.
Ko HJLee JMKim YJ et al. Immunosuppressive myeloid-derived suppressor cells can be converted into immunogenic APCs with the help of activated NKT cells: An alternative cell-based antitumor vaccineJ Immunol20091821818.35. Ko HJ, Lee JM, Kim YJ, et al. Immunosuppressive myeloid-derived suppressor cells can be converted into immunogenic APCs with the help of activated NKT cells: An alternative cell-based antitumor vaccine. J Immunol 2009;182:1818.
36.
Salem MLCole DJ. Dendritic cell recovery post-lymphodepletion: A potential mechanism for anti-cancer adoptive T cell therapy and vaccinationCancer Immunol Immunother201059341.36. Salem ML, Cole DJ. Dendritic cell recovery post-lymphodepletion: A potential mechanism for anti-cancer adoptive T cell therapy and vaccination. Cancer Immunol Immunother 2010;59:341.
37.
Suzuki EKapoor VJassar AS et al. Gemcitabine selectively eliminates splenic Gr-1+/CD11b+ myeloid suppressor cells in tumor-bearing animals and enhances antitumor immune activityClin Cancer Res2005116713.37. Suzuki E, Kapoor V, Jassar AS, et al. Gemcitabine selectively eliminates splenic Gr-1+/CD11b+ myeloid suppressor cells in tumor-bearing animals and enhances antitumor immune activity. Clin Cancer Res 2005;11:6713.
38.
Vincent JMignot GChalmin F et al. 5-Fluorouracil selectively kills tumor-associated myeloid-derived suppressor cells resulting in enhanced T cell-dependent antitumor immunityCancer Res2010703052.38. Vincent J, Mignot G, Chalmin F, et al. 5-Fluorouracil selectively kills tumor-associated myeloid-derived suppressor cells resulting in enhanced T cell-dependent antitumor immunity. Cancer Res 2010;70:3052.

Information & Authors

Information

Published In

cover image Cancer Biotherapy and Radiopharmaceuticals
Cancer Biotherapy and Radiopharmaceuticals
Volume 27Issue Number 3April 2012
Pages: 210 - 220
PubMed: 22440093

History

Published online: 3 April 2012
Published in print: April 2012
Published ahead of print: 22 March 2012

Permissions

Request permissions for this article.

Authors

Affiliations

Jing Chen
*
Department of Medical Oncology, Jinling Hospital, Medical School of Nanjing University, Nanjing, People's Republic of China.
Xiang Huang*
Department of Medical Oncology, Jinling Hospital, Medical School of Nanjing University, Nanjing, People's Republic of China.
Guichun Huang
Department of Medical Oncology, Jinling Hospital, Medical School of Nanjing University, Nanjing, People's Republic of China.
Yitian Chen
Department of Medical Oncology, Jinling Hospital, Medical School of Nanjing University, Nanjing, People's Republic of China.
Longbang Chen
Department of Medical Oncology, Jinling Hospital, Medical School of Nanjing University, Nanjing, People's Republic of China.
Haizhu Song
Department of Medical Oncology, Jinling Hospital, Medical School of Nanjing University, Nanjing, People's Republic of China.

Notes

Address correspondence to: Haizhu Song; Department of Medical Oncology, Jinling Hospital, Medical School of Nanjing University; 305 ZhongShan Eastern Road, Nanjing 210002, People's Republic of China
E-mail: [email protected]

Disclosure Statement

The authors report no conflicts of interest. The authors are responsible for the content and writing of this article.

Metrics & Citations

Metrics

Citations

Export citation

Select the format you want to export the citations of this publication.

View Options

Get Access

Access content

To read the fulltext, please use one of the options below to sign in or purchase access.

Society Access

If you are a member of a society that has access to this content please log in via your society website and then return to this publication.

Restore your content access

Enter your email address to restore your content access:

Note: This functionality works only for purchases done as a guest. If you already have an account, log in to access the content to which you are entitled.

View options

PDF/EPUB

View PDF/ePub

Full Text

View Full Text

Media

Figures

Other

Tables

Share

Share

Copy the content Link

Share on social media

Back to Top