Progression of cancer from indolent to aggressive despite antigen retention and increased expression of interferon-gamma inducible genes

Terry H. Wu1*, Karin Schreiber1*, Ainhoa Arina1, Nikolai N. Khodarev2, Elena V. Efimova2, Donald A. Rowley1, Ralph R. Weichselbaum2 and Hans Schreiber1

1Department of Pathology, The University of Chicago, Chicago, IL 60637, USA

2Department of Radiation and Cellular Oncology, The University of Chicago, Chicago, IL 60637, USA

*These authors contributed equally to this work

Communicated by: PK Srivastava

Keywords: mice, cultured tumor cells, melanoma, MHC, IFN-gamma, cytotoxic T lymphocytes, immunoproteasome


Many cancers escape host immunity without losing tumor-specific rejection antigens or MHC class I expression. This study tracks the evolution of one such cancer that developed in a mouse following exposure to ultraviolet light. The primary autochthonous tumor was not highly malignant and was rejected when transplanted into naïve immunocompetent mice. Neoplastic cells isolated from the primary tumor were susceptible to the growth-inhibitory effects of IFNγ in vitro, but expressed very low levels of MHC I antigen and were resistant to tumor-specific T cells unless they were first exposed to IFNγ. Serial passage of the primary tumor cells in vivo led to a highly aggressive variant that caused fast-growing tumors in normal mice. In vitro, the variant tumor cells showed increased resistance to the growth-inhibitory effects of IFNγ but expressed high levels of immunoproteasomes and MHC I molecules and were susceptible to tumor-specific T cells even without prior exposure to IFNγ.