Antigen presented by tumors in vivo determines the nature of CD8+ T-cell cytotoxicity.
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.
Shanker
Anil
A
Laboratory of Experimental Immunology, Cancer and Inflammation Program, National Cancer Institute-Frederick, Maryland 21702, USA. shankera@mail.nih.gov
Brooks
Alan D
AD
Jacobsen
Kristen M
KM
Wine
John W
JW
Wiltrout
Robert H
RH
Yagita
Hideo
H
Sayers
Thomas J
TJ
D000818:Animals; D017951:Antigen Presentation / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002292:Carcinoma, Renal Cell / Q000276:immunology / Q000628:therapy; D003602:Cytotoxicity, Immunologic / Q000276:immunology / Q000502:physiology*; D053222:Fas Ligand Protein / Q000502:physiology; D016219:Immunotherapy, Adoptive; D007680:Kidney Neoplasms / Q000276:immunology / Q000628:therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D008822:Mice, Transgenic; D009369:Neoplasms / Q000276:immunology* / Q000628:therapy
D053222:Fas Ligand Protein