Enhanced anti-tumor activity of interferon-alpha in SOCS1-deficient mice is mediated by CD4 + and CD8 + T cells Kristan D. GuenterbergGregory B. LesinskiBethany L. Mundy-Bosse • Volodymyr I. KarpaAlena Cristina Jaime-RamirezLai WeiWilliam E. Carson III

Interferon-alpha (IFN-a) is an immunomodu- latory cytokine that is used clinically for the treatment of melanoma in the adjuvant setting. The cellular actions of IFN-a are regulated by the suppressors of cytokine sig- naling (SOCS) family of proteins. We hypothesized that the anti-tumor activity of exogenous IFN-a would be enhanced in SOCS1-deficient mice. SOCS1-deficient (SOCS1 -/- ) or control (SOCS1 ?/? ) mice on an IFN-c -/- 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 chal- lenge, 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 prolifera- tion 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-a in the setting of melanoma.