Home LiteratureArticle Details
PMID: 25143233 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

CpG-mediated modulation of MDSC contributes to the efficacy of Ad5-TRAIL therapy against renal cell carcinoma.

Cancer immunology, immunotherapy : CII ·Vol. 63 ·No. 11 ·2014-11-00 ·Pages 1213-27

James BR, Anderson KG, Brincks EL, Kucaba TA, Norian LA, Masopust D, Griffith TS

Abstract

Tumor progression occurs through the modulation of a number of physiological parameters, including the development of immunosuppressive mechanisms to prevent immune detection and response. Among these immune evasion mechanisms, the mobilization of myeloid-derived suppressor cells (MDSC) is a major contributor to the suppression of antitumor T-cell immunity. Patients with renal cell carcinoma (RCC) show increased MDSC, and methods are being explored clinically to reduce the prevalence of MDSC and/or inhibit their function. In the present study, we investigated the relationship between MDSC and the therapeutic potential of a TRAIL-encoding recombinant adenovirus (Ad5-TRAIL) in combination with CpG-containing oligodeoxynucleotides (Ad5-TRAIL/CpG) in an orthotopic mouse model of RCC. This immunotherapy effectively clears renal (Renca) tumors and enhances survival, despite the presence of a high frequency of MDSC in the spleens and primary tumor-bearing kidneys at the time of treatment. Subsequent analyses revealed that the CpG component of the immunotherapy was responsible for decreasing the frequency of MDSC in Renca-bearing mice; further, treatment with CpG modulated the phenotype and function of MDSC that remained after immunotherapy and correlated with an increased T-cell response. Interestingly, the CpG-dependent alterations in MDSC frequency and function did not occur in tumor-bearing mice complicated with diet-induced obesity. Collectively, these data suggest that in addition to its adjuvant properties, CpG also enhances antitumor responses by altering the number and function of MDSC.

MeSH Terms
Adenoviridae/genetics Animals CD8-Positive T-Lymphocytes/immunology Carcinoma, Renal Cell/immunology,therapy Cell Line, Tumor Cell Proliferation Female Immunotherapy/methods Kidney/metabolism Kidney Neoplasms/immunology,therapy Mice Mice, Inbred BALB C Myeloid Cells/cytology Obesity Oligodeoxyribonucleotides/immunology Oligonucleotides Phenotype Spleen/metabolism T-Lymphocytes/cytology TNF-Related Apoptosis-Inducing Ligand/genetics
Chemicals
CPG-oligonucleotide Oligodeoxyribonucleotides Oligonucleotides TNF-Related Apoptosis-Inducing Ligand
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
James Britnie R
Department of Urology, University of Minnesota, 3-125 CCRB, 2231 6th St. SE, Minneapolis, MN, 55455, USA.
Anderson Kristin G
Brincks Erik L
Kucaba Tamara A
Norian Lyse A
Masopust David
Griffith Thomas S
References (60)
60 references, click to expand
  1. Risk factors, classification, and staging of renal cell cancer.
    Med Oncol. 2006;23(4):443-54 PMID: 17303902
  2. Clinical perspectives on targeting of myeloid derived suppressor cells in the treatment of cancer.
    Front Oncol. 2013 Mar 15;3:49 PMID: 23508517
  3. Diet-induced obesity impairs the T cell memory response to influenza virus infection.
    J Immunol. 2010 Mar 15;184(6):3127-33 PMID: 20173021
  4. Myeloid-derived suppressor cell activation by combined LPS and IFN-gamma treatment impairs DC development.
    Eur J Immunol. 2009 Oct;39(10):2865-76 PMID: 19637228
  5. Impairment of dendritic cell functionality and steady-state number in obese mice.
    J Immunol. 2006 Nov 1;177(9):5997-6006 PMID: 17056524
  6. New insights into cancer immunoediting and its three component phases--elimination, equilibrium and escape.
    Curr Opin Immunol. 2014 Apr;27:16-25 PMID: 24531241
  7. STAT1 signaling regulates tumor-associated macrophage-mediated T cell deletion.
    J Immunol. 2005 Apr 15;174(8):4880-91 PMID: 15814715
  8. Arginase I-producing myeloid-derived suppressor cells in renal cell carcinoma are a subpopulation of activated granulocytes.
    Cancer Res. 2009 Feb 15;69(4):1553-60 PMID: 19201693
  9. Impaired toll-like receptor 9 expression in alveolar macrophages with no sensitivity to CpG DNA.
    Am J Respir Crit Care Med. 2005 Apr 1;171(7):707-13 PMID: 15640365
  10. The terminology issue for myeloid-derived suppressor cells.
    Cancer Res. 2007 Jan 1;67(1):425; author reply 426 PMID: 17210725
  11. Investigation of a new renal tumor model.
    J Surg Res. 1973 Nov;15(5):327-36 PMID: 4759685
  12. Diet-induced obesity in mice reduces the maintenance of influenza-specific CD8+ memory T cells.
    J Nutr. 2010 Sep;140(9):1691-7 PMID: 20592105
  13. Eradication of established tumors by CD8+ T cell adoptive immunotherapy.
    Immunity. 2000 Aug;13(2):265-76 PMID: 10981969
  14. Cross-talk between myeloid-derived suppressor cells (MDSC), macrophages, and dendritic cells enhances tumor-induced immune suppression.
    Semin Cancer Biol. 2012 Aug;22(4):275-81 PMID: 22313874
  15. Chemotherapy delivered after viral immunogene therapy augments antitumor efficacy via multiple immune-mediated mechanisms.
    Mol Ther. 2010 Nov;18(11):1947-59 PMID: 20683443
  16. Lipoic acid attenuates high-fat-diet-induced oxidative stress and B-cell-related immune depression.
    Nutrition. 2012 Mar;28(3):275-80 PMID: 22305006
  17. Selective impairment in dendritic cell function and altered antigen-specific CD8+ T-cell responses in diet-induced obese mice infected with influenza virus.
    Immunology. 2009 Feb;126(2):268-79 PMID: 18754811
  18. Reduced inflammation in the tumor microenvironment delays the accumulation of myeloid-derived suppressor cells and limits tumor progression.
    Cancer Res. 2007 Oct 15;67(20):10019-26 PMID: 17942936
  19. Successful treatment of advanced murine renal cell cancer by bicompartmental adoptive chemoimmunotherapy.
    J Immunol. 1987 Jan 15;138(2):641-7 PMID: 3491854
  20. Interferon alpha/beta and interleukin 12 responses to viral infections: pathways regulating dendritic cell cytokine expression in vivo.
    J Exp Med. 2002 Feb 18;195(4):517-28 PMID: 11854364
  21. Activation of tumor-specific CD8+ T Cells after intratumoral Ad5-TRAIL/CpG oligodeoxynucleotide combination therapy.
    Cancer Res. 2007 Dec 15;67(24):11980-90 PMID: 18089829
  22. Intratumoral injection of CpG oligonucleotides induces the differentiation and reduces the immunosuppressive activity of myeloid-derived suppressor cells.
    J Immunol. 2012 Feb 15;188(4):1592-9 PMID: 22231700
  23. CpG still rocks! Update on an accidental drug.
    Nucleic Acid Ther. 2012 Apr;22(2):77-89 PMID: 22352814
  24. Role of immature myeloid cells in mechanisms of immune evasion in cancer.
    Cancer Immunol Immunother. 2006 Mar;55(3):237-45 PMID: 16047143
  25. Identification of discrete tumor-induced myeloid-derived suppressor cell subpopulations with distinct T cell-suppressive activity.
    Blood. 2008 Apr 15;111(8):4233-44 PMID: 18272812
  26. Diet-induced obesity alters dendritic cell function in the presence and absence of tumor growth.
    J Immunol. 2012 Aug 1;189(3):1311-21 PMID: 22745381
  27. Oxidative stress regulates expression of VEGFR1 in myeloid cells: link to tumor-induced immune suppression in renal cell carcinoma.
    J Immunol. 2008 Jul 1;181(1):346-53 PMID: 18566400
  28. Subsets of myeloid-derived suppressor cells in tumor-bearing mice.
    J Immunol. 2008 Oct 15;181(8):5791-802 PMID: 18832739
  29. Impaired natural killer (NK) cell activity in leptin receptor deficient mice: leptin as a critical regulator in NK cell development and activation.
    Biochem Biophys Res Commun. 2002 Nov 1;298(3):297-302 PMID: 12413939
  30. Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance.
    J Clin Invest. 2003 Dec;112(12):1821-30 PMID: 14679177
  31. Diet-induced adiposity alters the serum profile of inflammation in C57BL/6N mice as measured by antibody array.
    Diabetes Obes Metab. 2009 Apr;11(4):343-54 PMID: 19267713
  32. NK-cell and T-cell functions in patients with breast cancer: effects of surgery and adjuvant chemo- and radiotherapy.
    Br J Cancer. 2007 Jul 2;97(1):105-11 PMID: 17551492
  33. Visceral fat accumulation induced by a high-fat diet causes the atrophy of mesenteric lymph nodes in obese mice.
    Obesity (Silver Spring). 2008 Jun;16(6):1261-9 PMID: 18369345
  34. Sunitinib mediates reversal of myeloid-derived suppressor cell accumulation in renal cell carcinoma patients.
    Clin Cancer Res. 2009 Mar 15;15(6):2148-57 PMID: 19276286
  35. Successful elimination of memory-type CD8+ T cell subsets by the administration of anti-Gr-1 monoclonal antibody in vivo.
    Cell Immunol. 2003 Aug;224(2):98-105 PMID: 14609575
  36. Cytokeratin 18 expression pattern correlates with renal cell carcinoma progression: relationship with Snail.
    Int J Oncol. 2010 May;36(5):1145-54 PMID: 20372788
  37. Phenotypic switching of adipose tissue macrophages with obesity is generated by spatiotemporal differences in macrophage subtypes.
    Diabetes. 2008 Dec;57(12):3239-46 PMID: 18829989
  38. Induction of necrotic tumor cell death by TRAIL/Apo-2L.
    Apoptosis. 2003 Dec;8(6):587-99 PMID: 14739604
  39. Influence of high-fat feeding on both naive and antigen-experienced T-cell immune response in DO10.11 mice.
    Scand J Immunol. 2006 Nov;64(5):457-66 PMID: 17032237
  40. Leptin: a critical regulator of CD4+ T-cell polarization in vitro and in vivo.
    Endocrinology. 2010 Jan;151(1):56-62 PMID: 19966187
  41. Arginase, prostaglandins, and myeloid-derived suppressor cells in renal cell carcinoma.
    Clin Cancer Res. 2007 Jan 15;13(2 Pt 2):721s-726s PMID: 17255300
  42. Effective TRAIL-based immunotherapy requires both plasmacytoid and CD8α dendritic cells.
    Cancer Immunol Immunother. 2014 Jul;63(7):685-97 PMID: 24711083
  43. Intravascular staining for discrimination of vascular and tissue leukocytes.
    Nat Protoc. 2014 Jan;9(1):209-22 PMID: 24385150
  44. Gr-1+ CD11b+ myeloid-derived suppressor cells suppress inflammation and promote insulin sensitivity in obesity.
    J Biol Chem. 2011 Jul 1;286(26):23591-9 PMID: 21592961
  45. CpG blocks immunosuppression by myeloid-derived suppressor cells in tumor-bearing mice.
    Clin Cancer Res. 2011 Apr 1;17(7):1765-75 PMID: 21233400
  46. 5-Fluorouracil selectively kills tumor-associated myeloid-derived suppressor cells resulting in enhanced T cell-dependent antitumor immunity.
    Cancer Res. 2010 Apr 15;70(8):3052-61 PMID: 20388795
  47. Adipokines in inflammation and metabolic disease.
    Nat Rev Immunol. 2011 Feb;11(2):85-97 PMID: 21252989
  48. Systemic immune effects of adjuvant chemotherapy with 5-fluorouracil, epirubicin and cyclophosphamide and/or radiotherapy in breast cancer: a longitudinal study.
    Cancer Immunol Immunother. 2009 Jan;58(1):111-20 PMID: 18488220
  49. Direct and differential suppression of myeloid-derived suppressor cell subsets by sunitinib is compartmentally constrained.
    Cancer Res. 2010 May 1;70(9):3526-36 PMID: 20406969
  50. Effect of high fat diet on NKT cell function and NKT cell-mediated regulation of Th1 responses.
    Scand J Immunol. 2008 Mar;67(3):230-7 PMID: 18226013
  51. Obesity-driven inflammation and cancer risk: role of myeloid derived suppressor cells and alternately activated macrophages.
    Am J Cancer Res. 2013;3(1):21-33 PMID: 23359288
  52. Profound impairment of adaptive immune responses by alkylating chemotherapy.
    J Immunol. 2013 Jun 15;190(12):6259-68 PMID: 23686484
  53. Myeloid cell population dynamics in healthy and tumor-bearing mice.
    Int Immunopharmacol. 2011 Jul;11(7):783-8 PMID: 21406269
  54. Oral-tolerance induction in diet-induced obese mice.
    Life Sci. 2006 Aug 8;79(11):1056-61 PMID: 16650442
  55. Endostatin gene therapy enhances the efficacy of IL-2 in suppressing metastatic renal cell carcinoma in mice.
    Cancer Immunol Immunother. 2010 Sep;59(9):1357-65 PMID: 20490489
  56. Shifts in diet from high fat to high carbohydrate improved levels of adipokines and pro-inflammatory cytokines in mice fed a high-fat diet.
    Endocr J. 2010;57(1):39-50 PMID: 19822999
  57. Targeting immune suppressing myeloid-derived suppressor cells in oncology.
    Crit Rev Oncol Hematol. 2011 Jan;77(1):12-9 PMID: 20304669
  58. Mechanisms of immune evasion by tumors.
    Adv Immunol. 2006;90:51-81 PMID: 16730261
  59. Eradication of metastatic renal cell carcinoma after adenovirus-encoded TNF-related apoptosis-inducing ligand (TRAIL)/CpG immunotherapy.
    PLoS One. 2012;7(2):e31085 PMID: 22312440
  60. Myeloid-derived suppressor cells: more mechanisms for inhibiting antitumor immunity.
    Cancer Immunol Immunother. 2010 Oct;59(10):1593-600 PMID: 20414655
Article Info
Journal
Cancer immunology, immunotherapy : CII
Abbr.
Cancer Immunol Immunother
ISSN
1432-0851
DOI
10.1007/s00262-014-1598-8
Published
2014-11-00
Epub
2014-00-21
Pages
1213-27
Language
English
Region
Germany
NLM ID
8605732
PMCID
PMC4412276
Subset
IM
Grants
NIDCR NIH HHS · T90 DE022732 · United States
NIDCR NIH HHS · T90DE022732 · United States
NCI NIH HHS · R01 CA109446 · United States
NIAID NIH HHS · AI084913 · United States
NCI NIH HHS · R01 CA181088 · United States
NIAID NIH HHS · R01 AI084913 · United States
NCI NIH HHS · CA109446 · United States
External Links
PubMed source DOI: 10.1007/s00262-014-1598-8 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: product@genelibs.com

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2