Decreased tumor surveillance in perforin-deficient mice.

Abstract

SummaryImmune surveillance against tumors usually depends on T cell recognition of tumor antigens presented by major histocompatibility complex (MHC) molecules, whereas MHC class I tumors may be controlled by natural killer (NK) cells. Perforin-dependent cytotoxicity is a major effector function ofCD8 + MHC class I-restricted T cells and of NK cells. Here, we used perforin-deficient C57BL/6 (PKO) mice to study involvement 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 syngeneic tumor cell lines of different tissue origin in naive and primed mice; (b) administration of the chemical carcinogens methylcholanthrene (MCA) or 12-O-tetradecanoylphorbol-13-acetare (TPA) plus 7,12-dimethylbenzanthracene (DMBA), or (c) by injection of acutely oncogenic Moloney sarcoma virus. The first set of models analyzes the defense against a tumor load given at once, whereas the last two sets give information on immune defense against tumors at the very moment of their generation. Most of the tumor cell lines tested were eliminated 10-100-fold better by C57BL/6 mice in an unprimed situation; after priming, the differences were more pronounced. Lymphoma cells transfected with Fas were controlled 10-fold better by PKO and C57BL/6 mice when compared to untransfected control cells, indicating some role for FasL in tumor control. MCA-induced tumors arose more rapidly and with a higher incidence in PKO mice compared to C57BL/6 or CDS-deficient mice. DMBA+TPA-induced skin papillomas arose with similar high incidence and comparable kinetics in both mouse strains. C57BL/6 and PKO mice have a similar incidence ofMoloney murine sarcoma and leukemia virus-induced sarcomas, but tumors are larger and regression is retarded in PKO mice.Thus, perform-dependent cytotoxicity is not only a crucial mechanism of both cytotoxic T lymphocyte-and NK-dependent resistance to injected tumor cell lines, but also operates during viral and chemical carcinogenesis in vivo. Experiments addressing the role of Fasdependent cytotoxlcity by studying resistance to tumor cell lines that were stably transfected with Fas neither provided evidence for a major role of Fas nor excluded a minor contribution of Fas in tumor surveillance.

The Fas/Fas Ligand Pathway Is Important for Optimal Tumor Regression in a Mouse Model of CTL Adoptive Immunotherapy of Experimental CMS4 Lung Metastases

“…Although the identity of the FasL-independent mechanisms of tumor regression remains to be fully defined in this model, one possibility includes perforin, based in part on our CMA blocking studies (Figs. 1 and 3) and extrapolation of work by others (6,7,18).…”

“…The contribution of each effector mechanism to the overall lytic response probably reflects or depends upon intrinsic characteristics of the given target cell population. Although the prevailing view, particularly in mouse studies, is that perforin/granzyme-mediated lysis is a dominant pathway (6,7,18), it is unclear whether FasLmediated cytotoxicity is additionally required for optimal tumor regression. Accordingly, we investigated here the role of the FasL pathway in Ag-specific CTL-mediated tumor regression by adoptive immunotherapy using this CTL/CMS4 model.…”

Tumor stress, cell death and the ensuing immune response

“…3 About 50 years later, the seminal work brought up by Burnet and Thomas supported the concept of tumor immunosurveillance. 4,5 Later, gene targeting, 6 transgenic mouse technologies 7 and highly specific neutralizing monoclonal antibodies targeting particular immune components 8 have allowed to formally identify the key components of anticancer immune responses.…”

Tumor-Specific CTL Kill Murine Renal Cancer Cells Using Both Perforin and Fas Ligand-Mediated Lysis In Vitro, But Cause Tumor Regression In Vivo in the Absence of Perforin

“…Similarly, studies in tumor-bearing, perforin-deficient mice have also shown a major contribution of perforin to regression of established tumors (12,13). However, many of the tumors used in these previous studies were intrinsically resistant to Fas-mediated killing (9), and some of these experimental models used xenotransplantation of human tumors into mice (12,13). In such experimental systems, the species-specific activities of some cytokines and the strength of xenogeneic immune responses may mask relevant biological roles for cytokines and FasL-mediated effects.…”