The interaction between murine melanoma and the immune system reveals that prolonged responses predispose for autoimmunity

Abstract

An assessment of antitumor immunity versus autoimmunity as provoked by the specific depletion of FOXP3(+) Tregs is now possible with the development of Foxp3-diphtheria toxin receptor-like transgenic mouse models. We have used the poorly immunogenic B16F10 melanoma model to characterize a very heterogeneous antitumor effect of the immune response induced by Treg depletion. Depletion and neutralization studies demonstrated the importance of host T cells and interferon gamma (IFN gamma) in mediating the antitumor response developing in Treg-depleted mice. Such a response correlated with increased proliferation of granzyme B-and IFN.-producing T cells in the tumor. Furthermore, enhanced antitumor immunity modulated the expression of MHC Class I molecules by B16F10 melanoma cells in Treg-depleted mice. Since Foxp3(+) Treg depletion induced a significantly heterogeneous antitumor response, for the first time we were able to assess antitumor immunity and autoimmunity across different groups of responding mice. Strikingly, the duration of the tumor-immune system interaction provoked in individual Treg-depleted mice positively correlated with their propensity to develop vitiligo. A rapid complete tumor rejection was not associated with the development of autoimmunity, however, a proportion of mice that suppressed, but did not effectively clear, B16F10 melanoma did develop vitiligo. The significant implication is that approaches that combine with Treg depletion to rapidly reject tumors may also diminish autoimmune toxicities.