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

DOI: 10.1007/s00262-011-1034-2

Cite this article as:
Guenterberg, K.D., Lesinski, G.B., Mundy-Bosse, B.L. et al. Cancer Immunol Immunother (2011) 60: 1281. doi:10.1007/s00262-011-1034-2

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-alphaSuppressors of cytokine signalingT cellInterferon

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