DECREASED TUMOR SURVEILLANCE IN PERFORIN-DEFICIENT MICE

Immune surveillance against tumors usually depends on T cell recogniti on of tumor antigens presented by major histocompatibility complex (MH C) molecules, whereas MHC class I- tumors may be controlled by natural killer (NK) cells. Perforin-dependent cytotoxicity is a major effecto r function of CD8(+) MHC class I-restricted T cells and of NK cells. H ere, we used perforin-deficient C57BL/6 (PKO) mice to study involvemen t of perforin and Fas ligand in tumor surveillance in vivo. We induced tumors in PKO and normal C57BL/6 mice by (a) injection of different s yngeneic tumor cell, lines of different tissue origin in naive and pri med mice; (b) administration of the chemical carcinogens methylcholant hrene (MCA) or 12-O-tetradecanoylphorbol-13-acetate (TPA) plus 7,12-di methylbenzanthracene (DMBA), or (c) by injection of acutely oncogenic Moloney sarcoma virus. The first set of models analyzes the defense ag ainst a tumor load given at once, whereas the last two sets give infor mation on immune defense against tumors at the very moment of their ge neration. Most of the tumor cell lines tested were eliminated 10-100-f old better by C57BL/6 mice in an unprimed situation; after priming, th e differences were more pronounced. Lymphoma cells transfected with Fa s were controlled 10-fold better by PKO and C57BL/6 mice when compared to untransfected control cells, indicating some role for Fast in tumo r control. MCA-induced tumors arose more rapidly and with a higher inc idence in PKO mice compared to C57BL/6 or CD8-deficient mice. DMBA+TPA -induced skin papillomas arose with similar high incidence and compara ble kinetics in both mouse strains. C57BL/6 and PKO mice have a simila r incidence of Moloney murine sarcoma and leukemia virus-induced sarco mas, but tumors are larger and regression is retarded in PKO mice. Thu s, perforin-dependent cytotoxicity is not only a crucial mechanism of both cytotoxic T lymphocyte- and NK-dependent resistance to injected t umor cell lines, but also operates during viral and chemical carcinoge nesis in vivo. Experiments addressing the role of Fas-dependent cytoto xicity by studying resistance to tumor cell lines that were stably tra nsfected with Fas neither provided evidence for a major role of Fas no r excluded a minor contribution of Fas in tumor surveillance.