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Antigen Presented by Tumors In vivo Determines the Nature of CD8⁺ T-Cell Cytotoxicity

¹ Laboratory of Experimental Immunology, Cancer and Inflammation Program; and ² Science Applications International Corporation-Frederick, Inc., National Cancer Institute-Frederick, Frederick, Maryland; and ³ Department of Immunology, Juntendo University School of Medicine, Bunkyo-ku, Tokyo, Japan

Requests for reprints: Anil Shanker or Thomas Sayers, Laboratory of Experimental Immunology, Building 560/31-33, National Cancer Institute-Frederick, Frederick, MD 21702. Phone: 301-846-6551; Fax: 301-846-1673; E-mail: shankera{at}mail.nih.gov or sayerst{at}mail.nih.gov.

Key Words: CTL • perforin • Fas ligand • cytotoxicity • cancer immunotherapy

The biological relevance of the perforin and Fas ligand (FasL) cytolytic pathways of CD8⁺ T lymphocytes (CTL) for cancer immunotherapy is controversial. We investigated the importance of these pathways in a murine renal cell carcinoma expressing influenza viral hemagglutinin as a defined surrogate antigen (Renca-HA). Following Renca-HA injection, all FasL-dysfunctional FasL^gld/gld mice (n = 54) died from Renca-HA tumors by day 62. By contrast, perforin^–/– (51%; n = 45) and Fas^lpr/lpr (55%; n = 51) mice remained tumor-free at day 360. Blocking FasL in vivo inhibited tumor rejection in these mice. Moreover, established Renca-HA tumors were cleared more efficiently by adoptively transferred HA_518-526–specific T-cell receptor–transgenic CTL using FasL rather than perforin. Strikingly, a range of mouse tumor cells presenting low concentrations of immunogenic peptide were all preferentially lysed by the FasL but not the Pfp-mediated effector pathway of CTL, whereas at higher peptide concentrations, the preference in effector pathway usage by CTL was lost. Interestingly, a number of human renal cancer lines were also susceptible to FasL-mediated cytotoxicity. Therefore, the FasL cytolytic pathway may be particularly important for eradicating Fas-sensitive tumors presenting low levels of MHC class I–associated antigens following adoptive T-cell therapy. [Cancer Res 2009;69(16):6615–23]