Cancer Immunology, Immunotherapy

, Volume 60, Issue 9, pp 1281–1288

Enhanced anti-tumor activity of interferon-alpha in SOCS1-deficient mice is mediated by CD4+ and CD8+ T cells

  • Kristan D. Guenterberg
  • Gregory B. Lesinski
  • Bethany L. Mundy-Bosse
  • Volodymyr I. Karpa
  • Alena Cristina Jaime-Ramirez
  • Lai Wei
  • William E. CarsonIII
Original article

Abstract

Interferon-alpha (IFN-α) is an immunomodulatory cytokine that is used clinically for the treatment of melanoma in the adjuvant setting. The cellular actions of IFN-α are regulated by the suppressors of cytokine signaling (SOCS) family of proteins. We hypothesized that the anti-tumor activity of exogenous IFN-α would be enhanced in SOCS1-deficient mice. SOCS1-deficient (SOCS1−/−) or control (SOCS1+/+) mice on an IFN-γ−/− C57BL/6 background bearing intraperitoneal (i.p.) JB/MS murine melanoma cells were treated for 30 days with i.p. injections of IFN-A/D or PBS (vehicle). Log-rank Kaplan-Meier survival curves were used to evaluate survival. Tumor-bearing control SOCS1+/+ mice receiving IFN-A/D had significantly enhanced survival versus PBS–treated mice (P = 0.0048). The anti-tumor effects of IFN-A/D therapy were significantly enhanced in tumor-bearing SOCS1−/− mice; 75% of these mice survived tumor challenge, whereas PBS-treated SOCS1−/− mice all died at 13-16 days (P = 0.00038). Antibody (Ab) depletion of CD8+ T cells abrogated the anti-tumor effects of IFN-A/D in SOCS1−/− mice as compared with mice receiving a control antibody (P = 0.0021). CD4+ T-cell depletion from SOCS1−/− mice also inhibited the effects of IFN-A/D (P = 0.0003). IFN-A/D did not alter expression of CD80 or CD86 on splenocytes of SOCS1+/+ or SOCS1−/− mice, or the proportion of T regulatory cells or myeloid-derived suppressor cells in SOCS1+/+ or SOCS1−/− mice. An analysis of T-cell function did reveal increased proliferation of SOCS1-deficient splenocytes at baseline and in response to mitogenic stimuli. These data suggest that modulation of SOCS1 function in T-cell subsets could enhance the anti-tumor effects of IFN-α in the setting of melanoma.

Keywords

Interferon-alpha Suppressors of cytokine signaling T cell Interferon 

References

  1. 1.
    Lens MB, Dawes M (2004) Global perspectives of contemporary epidemiological trends of cutaneous malignant melanoma. Br J Dermatol 150(2):179–185PubMedCrossRefGoogle Scholar
  2. 2.
    Atkins MB (1998) Immunotherapy and experimental approaches for metastatic melanoma. Hematol Oncol Clin North Am 12(4):877–902 viiiPubMedCrossRefGoogle Scholar
  3. 3.
    Saleh FH, Crotty KA, Hersey P, Menzies SW, Rahman W (2003) Autonomous histopathological regression of primary tumours associated with specific immune responses to cancer antigens. J Pathol 200(3):383–395PubMedCrossRefGoogle Scholar
  4. 4.
    Darnell JE Jr (1998) Studies of IFN-induced transcriptional activation uncover the Jak-Stat pathway. J Interferon Cytokine Res 18(8):549–554PubMedCrossRefGoogle Scholar
  5. 5.
    Darnell JE Jr, Kerr IM, Stark GR (1994) Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins. Science 264(5164):1415–1421PubMedCrossRefGoogle Scholar
  6. 6.
    Haque SJ, Williams BR (1998) Signal transduction in the interferon system. Semin Oncol 25(Suppl 1):14–22PubMedGoogle Scholar
  7. 7.
    Ransohoff RM (1998) Cellular responses to interferon’s and other cytokines: the JAK-STAT paradigm. N Engl J Med 338(9):616–618PubMedCrossRefGoogle Scholar
  8. 8.
    Lesinski GB, Anghelina M, Zimmerer J, Bakalakos T, Badgwell B, Parihar R, Hu Y, Becknell B, Abood G, Chaudhury AR, Magro C, Durbin J, Carson WE III (2003) The antitumor effects of IFN-alpha are abrogated in a STAT1-deficient mouse. J Clin Invest 112(2):170–180PubMedGoogle Scholar
  9. 9.
    Lesinski GB, Valentino D, Hade EM, Jones S, Magro C, Chaudhury AR, Walker MJ, Carson WE III (2005) Expression of STAT1 and STAT2 in malignant melanoma does not correlate with response to interferon-alpha adjuvant therapy. Cancer Immunol Immunother 54(9):815–825PubMedCrossRefGoogle Scholar
  10. 10.
    Alexander WS (2002) Suppressors of cytokine signalling (SOCS) in the immune system. Nat Rev Immunol 2(6):410–416PubMedGoogle Scholar
  11. 11.
    Nicholson SE, Willson TA, Farley A, Starr R, Zhang JG, Baca M, Alexander WS, Metcalf D, Hilton DJ, Nicola NA (1999) Mutational analyses of the SOCS proteins suggest a dual domain requirement but distinct mechanisms for inhibition of LIF and IL-6 signal transduction. EMBO J 18(2):375–385PubMedCrossRefGoogle Scholar
  12. 12.
    Yasukawa H, Misawa H, Sakamoto H, Masuhara M, Sasaki A, Wakioka T, Ohtsuka S, Imaizumi T, Matsuda T, Ihle JN, Yoshimura A (1999) The JAK-binding protein JAB inhibits Janus tyrosine kinase activity through binding in the activation loop. EMBO J 18(5):1309–1320PubMedCrossRefGoogle Scholar
  13. 13.
    Marine JC, Topham DJ, McKay C, Wang D, Parganas E, Stravopodis D, Yoshimura A, Ihle JN (1999) SOCS1 deficiency causes a lymphocyte-dependent perinatal lethality. Cell 98(5):609–616PubMedCrossRefGoogle Scholar
  14. 14.
    Starr R, Metcalf D, Elefanty AG, Brysha M, Willson TA, Nicola NA, Hilton DJ, Alexander WS (1998) Liver degeneration and lymphoid deficiencies in mice lacking suppressor of cytokine signaling-1. Proc Natl Acad Sci U S A 95(24):14395–14399PubMedCrossRefGoogle Scholar
  15. 15.
    Berkelhammer J, Oxenhandler RW, Hook RR Jr, Hennessy JM (1982) Development of a new melanoma model in C57BL/6 mice. Cancer Res 42(8):3157–3163PubMedGoogle Scholar
  16. 16.
    Gagnon J, Ramanathan S, Leblanc C, Ilangumaran S (2007) Regulation of IL-21 signaling by suppressor of cytokine signaling-1 (SOCS1) in CD8(+) T lymphocytes. Cell Signal 19(4):806–816PubMedCrossRefGoogle Scholar
  17. 17.
    Zimmerer JM, Lesinski GB, Kondadasula SV, Karpa VI, Lehman A, Raychaudhury A, Becknell B, Carson WE III (2007) IFN-alpha-induced signal transduction, gene expression, and antitumor activity of immune effector cells are negatively regulated by suppressor of cytokine signaling proteins. J Immunol 178(8):4832–4845. doi:178/8/4832[pii] PubMedGoogle Scholar
  18. 18.
    Lesinski GB, Kondadasula SV, Crespin T, Shen L, Kendra K, Walker M, Carson WE III (2004) Multiparametric flow cytometric analysis of inter-patient variation in STAT1 phosphorylation following interferon Alfa immunotherapy. J Natl Cancer Inst 96(17):1331–1342PubMedCrossRefGoogle Scholar
  19. 19.
    Movahedi K, Guilliams M, Van den Bossche J, Van den Bergh R, Gysemans C, Beschin A, De Baetselier P, Van Ginderachter JA (2008) Identification of discrete tumor-induced myeloid-derived suppressor cell subpopulations with distinct T cell-suppressive activity. Blood 111(8):4233–4244PubMedCrossRefGoogle Scholar
  20. 20.
    Mazzoni A, Bronte V, Visintin A, Spitzer JH, Apolloni E, Serafini P, Zanovello P, Segal DM (2002) Myeloid suppressor lines inhibit T cell responses by an NO-dependent mechanism. J Immunol 168(2):689–695PubMedGoogle Scholar
  21. 21.
    Gogas H, Ioannovich J, Dafni U, Stavropoulou-Giokas C, Frangia K, Tsoutsos D, Panagiotou P, Polyzos A, Papadopoulos O, Stratigos A, Markopoulos C, Bafaloukos D, Pectasides D, Fountzilas G, Kirkwood JM (2006) Prognostic significance of autoimmunity during treatment of melanoma with interferon. N Engl J Med 354(7):709–718PubMedCrossRefGoogle Scholar
  22. 22.
    Moschos SJ, Kirkwood JM, Konstantinopoulos PA (2004) Present status and future prospects for adjuvant therapy of melanoma: time to build upon the foundation of high-dose interferon alfa-2b. J Clin Oncol 22(1):11–14PubMedCrossRefGoogle Scholar
  23. 23.
    Catlett IM, Hedrick SM (2005) Suppressor of cytokine signaling 1 is required for the differentiation of CD4 + T cells. Nat Immunol 6(7):715–721PubMedCrossRefGoogle Scholar
  24. 24.
    Chong MM, Cornish AL, Darwiche R, Stanley EG, Purton JF, Godfrey DI, Hilton DJ, Starr R, Alexander WS, Kay TW (2003) Suppressor of cytokine signaling-1 is a critical regulator of interleukin-7-dependent CD8 + T cell differentiation. Immunity 18(4):475–487PubMedCrossRefGoogle Scholar
  25. 25.
    Tanaka K, Ichiyama K, Hashimoto M, Yoshida H, Takimoto T, Takaesu G, Torisu T, Hanada T, Yasukawa H, Fukuyama S, Inoue H, Nakanishi Y, Kobayashi T, Yoshimura A (2008) Loss of suppressor of cytokine signaling 1 in helper T cells leads to defective Th17 differentiation by enhancing antagonistic effects of IFN-gamma on STAT3 and Smads. J Immunol 180(6):3746–3756PubMedGoogle Scholar
  26. 26.
    Evel-Kabler K, Song XT, Aldrich M, Huang XF, Chen SY (2006) SOCS1 restricts dendritic cells’ ability to break self tolerance and induce antitumor immunity by regulating IL-12 production and signaling. J Clin Invest 116(1):90–100PubMedCrossRefGoogle Scholar
  27. 27.
    Hashimoto M, Ayada T, Kinjyo I, Hiwatashi K, Yoshida H, Okada Y, Kobayashi T, Yoshimura A (2009) Silencing of SOCS1 in macrophages suppresses tumor development by enhancing antitumor inflammation. Cancer Sci 100(4):730–736PubMedCrossRefGoogle Scholar
  28. 28.
    Hanada T, Kobayashi T, Chinen T, Saeki K, Takaki H, Koga K, Minoda Y, Sanada T, Yoshioka T, Mimata H, Kato S, Yoshimura A (2006) IFNgamma-dependent, spontaneous development of colorectal carcinomas in SOCS1-deficient mice. J Exp Med 203(6):1391–1397PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Kristan D. Guenterberg
    • 1
  • Gregory B. Lesinski
    • 2
  • Bethany L. Mundy-Bosse
    • 3
  • Volodymyr I. Karpa
    • 1
  • Alena Cristina Jaime-Ramirez
    • 3
  • Lai Wei
    • 4
  • William E. CarsonIII
    • 1
  1. 1.Department of SurgeryColumbus, OH 3210, Ohio State University, Arthur G. James Cancer Hospital and Richard J. Solove Research InstituteColumbusUSA
  2. 2.Department of Internal Medicine, Division of Medical OncologyOhio State University, Arthur G. James Cancer Hospital and Richard J. Solove Research InstituteColumbusUSA
  3. 3.Department of Integrated Biomedical SciencesOhio State University, Arthur G. James Cancer Hospital and Richard J. Solove Research InstituteColumbusUSA
  4. 4.Center for Biostatistics, Ohio State University, Arthur G. James Cancer Hospital and Richard J. Solove Research InstituteColumbusUSA

Personalised recommendations