Demonstration of an interferon γ-dependent tumor surveillance system in immunocompetent mice

TLDR

This study demonstrates that endogenously produced interferon‑gamma (IFN‑γ) forms the basis of a tumor surveillance system that controls development of both chemically induced and spontaneously arising tumors in mice. The authors used tumor cells from methylcholanthrene‑treated IFN‑γ‑insensitive mice and found that IFN‑γ enhances tumor cell immunogenicity by acting directly on the tumor cells. Mice lacking IFN‑γ signaling or all IFN family members developed tumors more rapidly and frequently than wild‑type mice, and IFN‑γ‑insensitive p53‑deficient mice showed accelerated tumor onset and a broader tumor spectrum; additionally, IFN‑γ directly increases tumor cell immunogenicity, and certain human tumors become selectively unresponsive to IFN‑γ, underscoring its role as an extrinsic tumor‑suppressor mechanism.

Abstract

This study demonstrates that endogenously produced interferon gamma (IFN-gamma) forms the basis of a tumor surveillance system that controls development of both chemically induced and spontaneously arising tumors in mice. Compared with wild-type mice, mice lacking sensitivity to either IFN-gamma (i.e., IFN-gamma receptor-deficient mice) or all IFN family members (i.e., Stat1-deficient mice) developed tumors more rapidly and with greater frequency when challenged with different doses of the chemical carcinogen methylcholanthrene. In addition, IFN-gamma-insensitive mice developed tumors more rapidly than wild-type mice when bred onto a background deficient in the p53 tumor-suppressor gene. IFN-gamma-insensitive p53(-/-) mice also developed a broader spectrum of tumors compared with mice lacking p53 alone. Using tumor cells derived from methylcholanthrene-treated IFN-gamma-insensitive mice, we found IFN-gamma's actions to be mediated at least partly through its direct effects on the tumor cell leading to enhanced tumor cell immunogenicity. The importance and generality of this system is evidenced by the finding that certain types of human tumors become selectively unresponsive to IFN-gamma. Thus, IFN-gamma forms the basis of an extrinsic tumor-suppressor mechanism in immunocompetent hosts.