Data from Antigen Presented by Tumors <i>In vivo</i> Determines the Nature of CD8<sup>+</sup> T-Cell Cytotoxicity

Abstract

<div>Abstract<p>The biological relevance of the perforin and Fas ligand (FasL) cytolytic pathways of CD8<sup>+</sup> 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<sup><i>gld/gld</i></sup> mice (<i>n</i> = 54) died from Renca-HA tumors by day 62. By contrast, perforin<sup>−/−</sup> (51%; <i>n</i> = 45) and Fas<sup><i>lpr/lpr</i></sup> (55%; <i>n</i> = 51) mice remained tumor-free at day 360. Blocking FasL <i>in vivo</i> inhibited tumor rejection in these mice. Moreover, established Renca-HA tumors were cleared more efficiently by adoptively transferred HA<sub>518-526</sub>–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]</p></div>