A dual role for IFN-γ in resolving the balance between tumor progression and regression

Tumor-reactive T lymphocytes can direct the progression of tumor immunity through the secretion of cytokines such as IFN-γ. IFN-γ often displays a decisive function in tilting the balance between tumor progression and immune attack in the favor of the immune system. However, several human tumors display a resistance to IFN-γ suggesting that this may serve as a mechanism to circumvent recognition and elimination by the immune system. In this work, we investigate the function of tumor responsiveness to IFN-γ in resolving the balance between tumor progression and regression. Although IFN-γ has generally been thought to be an essential component of effective tumor immunity, we have found that IFN-γ has the potential to both discourage tumor outgrowth by inhibiting tumor angiogenesis and promote tumor escape through a reduction in tumor immunogenicity due to the downregulation of an endogenous tumor antigen. The clinical outcome of tumor challenge in the animal models described here is, therefore, dependent on a delicate balance of anti- and pro-tumor activities that is defined by IFN-γ secreted by tumor-infiltrating T cells. Using the CT26 murine colon carcinoma model, we demonstrate a critical role for IFN-γ secreted by CD4+ T cells in restraining initial tumor development through the inhibition of tumor angiogenesis. However, despite an initial slowing of tumor growth, the inevitable downregulation of the immunodominant tumor antigen by IFN-γ promotes a decrease in tumor immunogenicity that is correlated with tumor growth. We compare the findings obtained in the CT26 model to the human papilloma virus (HPV) E6/E7 expressing TC1 tumor model. In this system, we demonstrate a requirement for tumor sensitivity to IFN-γ for the efficacy of antigen-based immunotherapy. We find that tumor sensitivity to IFN-γ is not required for inhibition of tumor angiogenesis, but is required for facilitating T cell infiltration into the tumor mass. These results identify a novel role for tumor sensitivity to IFN-γ and suggest that loss of tumor responsiveness to IFN-γ may pose an impediment to antigen-based immunotherapy. Nonetheless, these results underscore the importance of communication between T cells and tumor cells in defining the effectiveness of tumor immunity