Skip to main content

Advertisement

SpringerLink
Log in

The immunomodulatory, antitumor and antimetastatic responses of melanoma-bearing normal and alcoholic mice to sunitinib and ALT-803: a combinatorial treatment approach

  • Original Article
  • Published:
Cancer Immunology, Immunotherapy Aims and scope Submit manuscript

Abstract

ALT-803, a novel IL-15/IL-15 receptor alpha complex, and the tyrosine kinase inhibitor, sunitinib, were examined for their single and combined effects on the growth of subcutaneous B16BL6 melanoma and on lymph node and lung metastasis. The study was conducted in immunocompetent C57BL/6 mice drinking water (Water mice) and in mice that chronically consumed alcohol (Alcohol mice), which are deficient in CD8+ T cells. Sunitinib inhibited melanoma growth and was more effective in Alcohol mice. ALT-803 did not alter tumor growth or survival in Water or Alcohol mice. Combined ALT-803 and sunitinib inhibited melanoma growth and increased survival, and these effects were greater than sunitinib alone in Water mice. ALT-803 and alcohol independently suppressed lymph node and lung metastasis, whereas sunitinib alone or in combination with ALT-803 increased lymph node and lung metastasis in Water and Alcohol mice. Initially, ALT-803 increased IFN-γ-producing CD8+CD44hi memory T cells and CD8+CD44hiCD62Llo effector memory T cells and sunitinib decreased immunosuppressive MDSC and T regulatory cells (Treg). However, the impact of these treatments diminished with time. Subcutaneous tumors from Water mice showed increased numbers of CD8+ T cells, CD8+CD44hi T cells, NK cells, and MDSC cells and decreased Treg cells after ALT-803 treatment.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

Abbreviations

Cy5.5:

Cyanine 5.5

IL-15Rα:

IL-15 receptor alpha

Treg:

Regulatory T cells

References

  1. Wu J (2013) IL-15 agonists: the cancer cure cytokine. J Mol Genet Med 7:85

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Xu W, Jones M, Liu B, Zhu X, Johnson CB, Edwards AC et al (2013) Efficacy and mechanism-of-action of a novel superagonist interleukin-15: interleukin-15 receptor alphaSu/Fc fusion complex in syngeneic murine models of multiple myeloma. Cancer Res 73(10):3075–3086

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Gomes-Giacoia E, Miyake M, Goodison S, Sriharan A, Zhang G, You L et al (2014) Intravesical ALT-803 and BCG treatment reduces tumor burden in a carcinogen induced bladder cancer rat model; a role for cytokine production and NK cell expansion. PLoS One 9(6):e96705

    Article  PubMed  PubMed Central  Google Scholar 

  4. Kakuta S, Tagawa Y, Shibata S, Nanno M, Iwakura Y (2002) Inhibition of B16 melanoma experimental metastasis by interferon-gamma through direct inhibition of cell proliferation and activation of antitumour host mechanisms. Immunology 105(1):92–100

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Zhang H, Zhu Z, McKinley JM, Meadows GG (2011) IFN-gamma is essential for the inhibition of B16BL6 melanoma lung metastasis in chronic alcohol drinking mice. Clin Exp Metastasis 28(3):301–307

    Article  PubMed  PubMed Central  Google Scholar 

  6. Eyles J, Puaux AL, Wang X, Toh B, Prakash C, Hong M et al (2010) Tumor cells disseminate early, but immunosurveillance limits metastatic outgrowth, in a mouse model of melanoma. J Clin Invest 120(6):2030–2039

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Rosenberg SA, Dudley ME (2009) Adoptive cell therapy for the treatment of patients with metastatic melanoma. Curr Opin Immunol 21(2):233–240

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Erdag G, Schaefer JT, Smolkin ME, Deacon DH, Shea SM, Dengel LT et al (2012) Immunotype and immunohistologic characteristics of tumor-infiltrating immune cells are associated with clinical outcome in metastatic melanoma. Cancer Res 72(5):1070–1080

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Fridman WH, Pages F, Sautes-Fridman C, Galon J (2012) The immune contexture in human tumours: impact on clinical outcome. Nat Rev Cancer 12(4):298–306

    Article  CAS  PubMed  Google Scholar 

  10. Epardaud M, Elpek KG, Rubinstein MP, Yonekura AR, Bellemare-Pelletier A, Bronson R et al (2008) Interleukin-15/interleukin-15R alpha complexes promote destruction of established tumors by reviving tumor-resident CD8+ T cells. Cancer Res 68(8):2972–2983

    Article  CAS  PubMed  Google Scholar 

  11. Dubois S, Patel HJ, Zhang M, Waldmann TA, Muller JR (2008) Preassociation of IL-15 with IL-15R alpha-IgG1-Fc enhances its activity on proliferation of NK and CD8+/CD44high T cells and its antitumor action. J Immunol 180(4):2099–2106

    Article  CAS  PubMed  Google Scholar 

  12. Umansky V, Sevko A, Gebhardt C, Utikal J (2014) Myeloid-derived suppressor cells in malignant melanoma. J Dtsch Dermatol Ges 12(11):1021–1027

    PubMed  Google Scholar 

  13. Weide B, Martens A, Zelba H, Stutz C, Derhovanessian E, Di Giacomo AM et al (2014) Myeloid-derived suppressor cells predict survival of patients with advanced melanoma: comparison with regulatory T cells and NY-ESO-1- or melan-A-specific T cells. Clin Cancer Res 20(6):1601–1609

    Article  CAS  PubMed  Google Scholar 

  14. Jordan KR, Amaria RN, Ramirez O, Callihan EB, Gao D, Borakove M et al (2013) Myeloid-derived suppressor cells are associated with disease progression and decreased overall survival in advanced-stage melanoma patients. Cancer Immunol Immunother 62(11):1711–1722

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Messmer MN, Netherby CS, Banik D, Abrams SI (2015) Tumor-induced myeloid dysfunction and its implications for cancer immunotherapy. Cancer Immunol Immunother 64(1):1–13

    Article  CAS  PubMed  Google Scholar 

  16. Najjar YG, Finke JH (2013) Clinical perspectives on targeting of myeloid derived suppressor cells in the treatment of cancer. Front Oncol 3:49

    Article  PubMed  PubMed Central  Google Scholar 

  17. Albeituni SH, Ding C, Yan J (2013) Hampering immune suppressors: therapeutic targeting of myeloid-derived suppressor cells in cancer. Cancer J 19(6):490–501

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Ko JS, Rayman P, Ireland J, Swaidani S, Li G, Bunting KD et al (2010) Direct and differential suppression of myeloid-derived suppressor cell subsets by sunitinib is compartmentally constrained. Cancer Res 70(9):3526–3536

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Ozao-Choy J, Ma G, Kao J, Wang GX, Meseck M, Sung M et al (2009) The novel role of tyrosine kinase inhibitor in the reversal of immune suppression and modulation of tumor microenvironment for immune-based cancer therapies. Cancer Res 69(6):2514–2522

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Kao J, Ko EC, Eisenstein S, Sikora AG, Fu S, Chen SH (2011) Targeting immune suppressing myeloid-derived suppressor cells in oncology. Crit Rev Oncol Hematol 77(1):12–19

    Article  PubMed  Google Scholar 

  21. Ugel S, Delpozzo F, Desantis G, Papalini F, Simonato F, Sonda N et al (2009) Therapeutic targeting of myeloid-derived suppressor cells. Curr Opin Pharmacol 9(4):470–481

    Article  CAS  PubMed  Google Scholar 

  22. Ko JS, Zea AH, Rini BI, Ireland JL, Elson P, Cohen P et al (2009) Sunitinib mediates reversal of myeloid-derived suppressor cell accumulation in renal cell carcinoma patients. Clin Cancer Res 15(6):2148–2157

    Article  CAS  PubMed  Google Scholar 

  23. Kujawski M, Zhang C, Herrmann A, Reckamp K, Scuto A, Jensen M et al (2010) Targeting STAT3 in adoptively transferred T cells promotes their in vivo expansion and antitumor effects. Cancer Res 70(23):9599–9610

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Roskoski R Jr (2007) Sunitinib: a VEGF and PDGF receptor protein kinase and angiogenesis inhibitor. Biochem Biophys Res Commun 356(2):323–328

    Article  CAS  PubMed  Google Scholar 

  25. Imamichi H, Sereti I, Lane HC (2008) IL-15 acts as a potent inducer of CD4(+)CD25(hi) cells expressing FOXP3. Eur J Immunol 38(6):1621–1630

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Bagnardi V, Rota M, Botteri E, Tramacere I, Islami F, Fedirko V et al (2014) Alcohol consumption and site-specific cancer risk: a comprehensive dose–response meta-analysis. Br J Cancer 112(3):580–593

    Article  PubMed  PubMed Central  Google Scholar 

  27. Zhang H, Meadows GG (2005) Chronic alcohol consumption in mice increases the proportion of peripheral memory T cells by homeostatic proliferation. J Leukoc Biol 78(5):1070–1080

    CAS  PubMed  Google Scholar 

  28. Zhang H, Meadows GG (2010) Chronic alcohol consumption enhances myeloid-derived suppressor cells in B16BL6 melanoma-bearing mice. Cancer Immunol Immunother 59(8):1151–1159

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Zhang H, Meadows GG (2009) Exogenous IL-15 in combination with IL-15R alpha rescues natural killer cells from apoptosis induced by chronic alcohol consumption. Alcohol Clin Exp Res 33(3):419–427

    Article  CAS  PubMed  Google Scholar 

  30. D’Souza El-Guindy NB, Kovacs EJ, De Witte P, Spies C, Littleton JM, de Villiers WJ et al (2010) Laboratory models available to study alcohol-induced organ damage and immune variations: choosing the appropriate model. Alcohol Clin Exp Res 34(9):1489–1511

    Article  PubMed  PubMed Central  Google Scholar 

  31. Feldman JP, Goldwasser R, Mark S, Schwartz J, Orion I (2009) A mathematical model for tumor volume evaluation using two-dimensions. JAQM 4(4):455–462

    Google Scholar 

  32. Meadows GG, Elstad CA, Blank SE, Gallucci RM, Pfister LJ (1993) Alcohol consumption suppresses metastasis of B16-BL6 melanoma in mice. Clin Exp Metastasis 11(2):191–199

    Article  CAS  PubMed  Google Scholar 

  33. Zhang H, Zhu Z, Meadows GG (2011) Chronic alcohol consumption decreases the percentage and number of NK cells in the peripheral lymph nodes and exacerbates B16BL6 melanoma metastasis into the draining lymph nodes. Cell Immunol 266(2):172–179

    Article  CAS  PubMed  Google Scholar 

  34. Sallusto F, Lenig D, Forster R, Lipp M, Lanzavecchia A (1999) Two subsets of memory T lymphocytes with distinct homing potentials and effector functions. Nature 401(6754):708–712

    Article  CAS  PubMed  Google Scholar 

  35. Hamilton SE, Jameson SC (2012) CD8 T cell memory: it takes all kinds. Front Immunol 3:353

    Article  PubMed  Google Scholar 

  36. Klebanoff CA, Gattinoni L, Restifo NP (2012) Sorting through subsets: which T-cell populations mediate highly effective adoptive immunotherapy? J Immunother 35(9):651–660

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Wong HC, Jeng EK, Rhode PR (2013) The IL-15-based superagonist ALT-803 promotes the antigen-independent conversion of memory CD8 T cells into innate-like effector cells with antitumor activity. Oncoimmunology 2(11):e26442

    Article  PubMed  PubMed Central  Google Scholar 

  38. Kwilas AR, Donahue RN, Tsang KY, Hodge JW (2015) Immune consequences of tyrosine kinase inhibitors that synergize with cancer immunotherapy. Cancer Cell Microenviron 2(1):e677

    PubMed  PubMed Central  Google Scholar 

  39. Tamzalit F, Barbieux I, Plet A, Heim J, Nedellec S, Morisseau S et al (2014) IL-15.IL-15Ralpha complex shedding following trans-presentation is essential for the survival of IL-15 responding NK and T cells. Proc Natl Acad Sci U S A 111(23):8565–8570

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Zhang D, Hedlund EM, Lim S, Chen F, Zhang Y, Sun B et al (2011) Antiangiogenic agents significantly improve survival in tumor-bearing mice by increasing tolerance to chemotherapy-induced toxicity. Proc Natl Acad Sci U S A 108(10):4117–4122

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Passarella RJ, Zhou L, Phillips JG, Wu H, Hallahan DE, Diaz R (2009) Recombinant peptides as biomarkers for tumor response to molecular targeted therapy. Clin Cancer Res 15(20):6421–6429

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Ebos JM, Lee CR, Cruz-Munoz W, Bjarnason GA, Christensen JG, Kerbel RS (2009) Accelerated metastasis after short-term treatment with a potent inhibitor of tumor angiogenesis. Cancer Cell 15(3):232–239

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Paez-Ribes M, Allen E, Hudock J, Takeda T, Okuyama H, Vinals F et al (2009) Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis. Cancer Cell 15(3):220–231

    Article  CAS  PubMed Central  Google Scholar 

  44. Stewart GD, O’Mahony FC, Laird A, Eory L, Lubbock AL, Mackay A et al (2015) Sunitinib treatment exacerbates intratumoral heterogeneity in metastatic renal cancer. Clin Cancer Res 21(18):4212–4223

    Article  CAS  PubMed  Google Scholar 

  45. Barsoum IB, Koti M, Siemens DR, Graham CH (2014) Mechanisms of hypoxia-mediated immune escape in cancer. Cancer Res 74(24):7185–7190

    Article  CAS  PubMed  Google Scholar 

  46. Mitrus I, Bryndza E, Kazura M, Smagur A, Sochanik A, Cichon T et al (2012) Properties of B16-F10 murine melanoma cells subjected to metabolic stress conditions. Acta Biochim Pol 59(3):363–366

    CAS  PubMed  Google Scholar 

  47. Almendros I, Montserrat JM, Torres M, Dalmases M, Cabanas ML, Campos-Rodriguez F et al (2013) Intermittent hypoxia increases melanoma metastasis to the lung in a mouse model of sleep apnea. Respir Physiol Neurobiol 186(3):303–307

    Article  CAS  PubMed  Google Scholar 

  48. Ebos JM, Mastri M, Lee CR, Tracz A, Hudson JM, Attwood K et al (2014) Neoadjuvant antiangiogenic therapy reveals contrasts in primary and metastatic tumor efficacy. EMBO Mol Med 6(12):1561–1576

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors greatly appreciate Dr. Hing C. Wong and Altor BioScience for the generous gift of ALT-803. They also thank and appreciate the guidance provided by Dr. Sterling McPherson regarding statistical analysis. The authors also acknowledge the technical contributions of Dung Luong to the collection of data for the manuscript. This work was supported by the following grants: National Institutes of Health (NIH) Grants K05AA017149 to Gary G. Meadows, and R21AA022098 to Hui Zhang and Gary G. Meadows; Research Assistantships for Diverse Scholars Program, Washington State University, to Alexander A. Little; and National Science Foundation (NSF) Graduate Research Fellowship DGE-1347973 to Kari A. Gaither.

Author information

Author notes

    Authors and Affiliations

    1. Department of Pharmaceutical Sciences and the Pharmaceutical Sciences Graduate Program, College of Pharmacy, Washington State University Spokane, PBS 323, P. O. Box 1495, Spokane, WA, 99210-1495, USA

      Kari A. Gaither, Alexander A. Little, Alisha A. McBride, Savanna R. Garcia, Kiranjot K. Brar, Zhaohui Zhu, Amity Platt, Faya Zhang, Gary G. Meadows & Hui Zhang

    Authors
    1. Kari A. Gaither
      View author publications

      You can also search for this author in PubMed Google Scholar

    2. Alexander A. Little
      View author publications

      You can also search for this author in PubMed Google Scholar

    3. Alisha A. McBride
      View author publications

      You can also search for this author in PubMed Google Scholar

    4. Savanna R. Garcia
      View author publications

      You can also search for this author in PubMed Google Scholar

    5. Kiranjot K. Brar
      View author publications

      You can also search for this author in PubMed Google Scholar

    6. Zhaohui Zhu
      View author publications

      You can also search for this author in PubMed Google Scholar

    7. Amity Platt
      View author publications

      You can also search for this author in PubMed Google Scholar

    8. Faya Zhang
      View author publications

      You can also search for this author in PubMed Google Scholar

    9. Gary G. Meadows
      View author publications

      You can also search for this author in PubMed Google Scholar

    10. Hui Zhang
      View author publications

      You can also search for this author in PubMed Google Scholar

    Corresponding authors

    Correspondence to Gary G. Meadows or Hui Zhang.

    Ethics declarations

    Conflict of interest

    The authors declare that they have no conflict of interest.

    Additional information

    K. A. Gaither and A. A. Little have contributed equally in this paper.

    G. G. Meadows and H. Zhang are co-corresponding authors in this paper.

    Rights and permissions

    Reprints and permissions

    About this article

    Check for updates. Verify currency and authenticity via CrossMark

    Cite this article

    Gaither, K.A., Little, A.A., McBride, A.A. et al. The immunomodulatory, antitumor and antimetastatic responses of melanoma-bearing normal and alcoholic mice to sunitinib and ALT-803: a combinatorial treatment approach. Cancer Immunol Immunother 65, 1123–1134 (2016). https://doi.org/10.1007/s00262-016-1876-8

    Download citation

    • Received:

    • Accepted:

    • Published:

    • Issue Date:

    • DOI: https://doi.org/10.1007/s00262-016-1876-8

    Keywords

    Search

    Navigation