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

• Published in: The Journal of immunology (1950) Vol. 168; no. 7; pp. 3484 - 3492
• Main Authors: Seki, Naoko, Brooks, Alan D, Carter, Clive R. D, Back, Timothy C, Parsoneault, Erin M, Smyth, Mark J, Wiltrout, Robert H, Sayers, Thomas J
• Format: Journal Article
• Language: English
• Published: United States Am Assoc Immnol 01.04.2002
• Subjects: Animals; Antineoplastic Agents - toxicity; Apoptosis - genetics; Apoptosis - immunology; Apoptosis Regulatory Proteins; Carcinoma, Renal Cell - immunology; Carcinoma, Renal Cell - pathology; Carcinoma, Renal Cell - therapy; Cell Line, Transformed; Cytotoxicity, Immunologic - genetics; Epitopes, T-Lymphocyte - administration & dosage; Epitopes, T-Lymphocyte - immunology; Fas Ligand Protein; fas Receptor - metabolism; FasL protein; g-Interferon; Immunotherapy, Adoptive - methods; Intercellular Adhesion Molecule-1 - metabolism; Intercellular Adhesion Molecule-1 - physiology; Kidney Neoplasms - immunology; Kidney Neoplasms - pathology; Kidney Neoplasms - therapy; Ligands; Lung Neoplasms - immunology; Lung Neoplasms - pathology; Lung Neoplasms - secondary; Lung Neoplasms - therapy; Lymphocyte Activation - genetics; Lymphocyte Function-Associated Antigen-1 - metabolism; Lymphocyte Function-Associated Antigen-1 - physiology; Melanoma, Experimental - immunology; Membrane Glycoproteins - biosynthesis; Membrane Glycoproteins - deficiency; Membrane Glycoproteins - genetics; Membrane Glycoproteins - metabolism; Membrane Glycoproteins - toxicity; Mice; Mice, Inbred BALB C; Mice, Inbred C3H; Mice, Inbred C57BL; Mice, Inbred DBA; Mice, Knockout; Neoplasm Transplantation; Perforin; Pore Forming Cytotoxic Proteins; renal cell carcinoma; T-Lymphocytes, Cytotoxic - immunology; T-Lymphocytes, Cytotoxic - transplantation; TNF-Related Apoptosis-Inducing Ligand; Tumor Cells, Cultured; Tumor Necrosis Factor-alpha - toxicity
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.168.7.3484

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-2K(d)-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.