Influence of CD80, interleukin-2, and interleukin-7 expression in human renal cell carcinoma on the expansion, function, and survival of tumor-specific CTLs.
OBJECTIVE
A renal cell carcinoma (RCC) line, RCC-26, has been identified as a suitable candidate for development of an allogeneic tumor cell vaccine based on its expression of a variety of tumor-associated antigens (TAA). To improve immunogenicity, RCC-26 cells were genetically engineered to express CD80 alone or in combination with interleukin (IL)-2 or IL-7. The effect of these modifications on proliferation, function, and survival of autologous and allogeneic tumor-specific CTLs was assessed.


METHODS
RCC-26 sublines expressing different transgenes were tested for their capacity to reactivate cytokine secretion and cytotoxicity in autologous tumor-infiltrating lymphocytes, to improve proliferation and survival of tumor-associated T cells present in autologous peripheral blood, and to induce tumor-associated responses in naive allogeneic lymphocytes. The expression of several common TAA was quantitated in the RCC-26 sublines using reverse transcription-PCR to identify surrogate markers for immune monitoring in clinical trials.


RESULTS
Gene-modified RCC-26 cells showed enhanced immunogenicity. CD80 expression was necessary to induce RCC-associated CTL in blood of healthy allogeneic donors. It also improved proliferation of autologous effector-memory T cells. Further enhancement was achieved with IL-2 through induction of the antiapoptosis protein Bcl-x(L). The candidate vaccine lines overexpressed several common TAA that are suitable markers for immune monitoring.


CONCLUSIONS
RCC-26 cells coexpressing CD80 and cytokine transgenes display improved immunogenic characteristics, supporting their use as allogeneic tumor cell vaccines for HLA-A2-matched patients with metastatic RCC.
Frankenberger
Bernhard
B
Institute of Molecular Immunology, Forschungszentrum für Umwelt und Gesundheit-National Research Center for Environment and Health, Marchioninistrasse 25, 81377 Munich, Germany. b.frankenberger@gsf.de
Pohla
Heike
H
Noessner
Elfriede
E
Willimsky
Gerald
G
Papier
Britta
B
Pezzutto
Antonio
A
Kopp
Joachim
J
Oberneder
Ralph
R
Blankenstein
Thomas
T
Schendel
Dolores J
DJ
D000951:Antigens, Neoplasm / Q000096:biosynthesis / Q000276:immunology; D018122:B7-1 Antigen / Q000096:biosynthesis* / Q000494:pharmacology; D019496:Cancer Vaccines / Q000276:immunology; D002292:Carcinoma, Renal Cell / Q000276:immunology*; D049109:Cell Proliferation; D002470:Cell Survival; D016207:Cytokines / Q000096:biosynthesis; D020869:Gene Expression Profiling; D015789:HLA-A2 Antigen / Q000276:immunology; D006801:Humans; D007376:Interleukin-2 / Q000096:biosynthesis* / Q000494:pharmacology; D015851:Interleukin-7 / Q000096:biosynthesis* / Q000494:pharmacology; D007680:Kidney Neoplasms / Q000276:immunology*; D009362:Neoplasm Metastasis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D019076:Transgenes; D014407:Tumor Cells, Cultured
D000951:Antigens, Neoplasm; D018122:B7-1 Antigen; D019496:Cancer Vaccines; D016207:Cytokines; D015789:HLA-A2 Antigen; D007376:Interleukin-2; D015851:Interleukin-7