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The Journal of Immunology, 2002, 168: 3484-3492.
Copyright © 2002 by The American Association of Immunologists

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 Perforin1

Naoko Seki*, Alan D. Brooks{dagger}, Clive R. D. Carter2,*, Timothy C. Back{dagger}, Erin M. Parsoneault{dagger}, Mark J. Smyth{ddagger}, Robert H. Wiltrout* and Thomas J. Sayers3,{dagger}

* Laboratory of Experimental Immunology, Center for Cancer Research, National Cancer Institute, and {dagger} Intramural Research Support Program, Science Applications International Corporation, Frederick, MD 21702; and {ddagger} Cancer Immunology, Peter MacCallum Cancer Institute, East Melbourne, Victoria, Australia

Kidney cancer is a devastating disease; however, biological therapies have achieved some limited success. The murine renal cancer Renca has been used as a model for developing new preclinical approaches to the treatment of renal cell carcinoma. Successful cytokine-based approaches require CD8+ T cells, but the exact mechanisms by which T cells mediate therapeutic benefit have not been completely identified. After successful biological therapy of Renca in BALB/c mice, we generated CTLs in vitro using mixed lymphocyte tumor cultures. These CTL mediated tumor-specific H-2Kd-restricted lysis and production of IFN-{gamma}, TNF-{alpha}, and Fas ligand (FasL) in response to Renca. CTL used both granule- and FasL-mediated mechanisms to lyse Renca, although granule-mediated killing was the predominant lytic mechanism in vitro. The cytokines IFN-{gamma} and TNF-{alpha} increased the sensitivity of Renca cells to CTL lysis by both granule- and FasL-mediated death pathways. Adoptive transfer of these anti-Renca CTL into tumor-bearing mice cured most mice of established experimental pulmonary metastases, and successfully treated mice were immune to tumor rechallenge. Interestingly, we were able to establish Renca-specific CTL from mice gene targeted for perforin (pfp-/-) mice. Although these pfp-/- CTL showed reduced cytotoxic activity against Renca, their IFN-{gamma} production in the presence of Renca targets was equivalent to that of wild-type CTL, and adoptive transfer of pfp-/- CTL was as efficient as wild-type CTL in causing regression of established Renca pulmonary metastases. Therefore, although granule-mediated killing is of paramount importance for CTL-mediated lysis in vitro, some major in vivo effector mechanisms clearly are independent of perforin.




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