Dendritic cell-mediated cross-presentation of antigens derived from colon carcinoma cells exposed to a highly cytotoxic multidrug regimen with gemcitabine, oxaliplatin, 5-fluorouracil, and leucovorin, elicits a powerful human antigen-specific CTL response with antitumor activity in vitro.
Gemcitabine, oxaliplatin, leucovorin, and 5-fluorouracil (GOLF) is a novel multidrug regimen inducing high levels of necrosis and apoptosis in colon carcinoma cells. This regimen is also able to promote a process of Ag remodeling including up-regulation of immunotherapy targets like carcinoembryonic Ag (CEA), thymidylate synthase (TS). We have conducted a preclinical study aimed to investigate whether these drug-induced modifications would also enhance colon cancer cell immunogenicity. Several CTL lines were thus generated by in vitro stimulating human HLA-A(*)02.01(+) PBMCs, from normal donors and colon cancer patients, with autologous dendritic cells cross-primed with cell lysates of colon cancer cells untreated, irradiated, or previously exposed to different drug treatments including the GOLF regimen. Class I HLA-restricted cytolytic activity of these CTL lines was tested against colon cancer cells and CEA and TS gene transfected target cells. These experiments revealed that CTLs sensitized with GOLF-treated cancer cells were much more effective than those sensitized with the untreated colon carcinoma cells or those exposed to the other treatments. CTL lines sensitized against the GOLF-treated colon cancer cells, also expressed a greater percentage of T-lymphocyte precursors able to recognize TS- and CEA-derived peptides. These results suggest that GOLF regimen is a powerful antitumor and immunomodulating regimen that can make the tumor cells a suitable means to induce an Ag-specific CTL response. These results suggest that a rationale combination of GOLF chemotherapy with cytokine-based immunotherapy could generate a chemotherapy-modulated Ag-specific T-lymphocyte response in cancer patients able to destroy the residual disease survived to the cytotoxic drugs.
Section of Oncology, Department of Human Pathology and Oncology, Siena University School of Medicine, Viale Bracci 11, 53100 Siena, Italy. correale@unisi.it
Pierpaolo
P
Correale
Maria Grazia
MG
Cusi
Maria Teresa
MT
Del Vecchio
Angelo
A
Aquino
Salvatore Pasquale
SP
Prete
Salvatore
S
Prete
Kwong Y
KY
Tsang
Lucia
L
Micheli
Cristina
C
Nencini
Marco
M
La Placa
Francesco
F
Montagnani
Chiara
C
Terrosi
Michele
M
Caraglia
Vincenzo
V
Formica
Giorgio
G
Giorgi
Enzo
E
Bonmassar
Guido
G
Francini
D000951:Antigens, Neoplasm / Q000276:immunology / Q000378:metabolism*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use* / Q000633:toxicity; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000276:immunology* / Q000473:pathology; D045142:Cross-Priming / Q000187:drug effects / Q000276:immunology*; D003602:Cytotoxicity, Immunologic / Q000187:drug effects*; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000627:therapeutic use / Q000633:toxicity; D004353:Drug Evaluation, Preclinical; D005472:Fluorouracil / Q000008:administration & dosage / Q000627:therapeutic use / Q000633:toxicity; D015234:HLA-A Antigens / Q000096:biosynthesis / Q000235:genetics; D015789:HLA-A2 Antigen; D019073:HT29 Cells; D006801:Humans; D002955:Leucovorin / Q000008:administration & dosage / Q000627:therapeutic use / Q000633:toxicity; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D009944:Organoplatinum Compounds / Q000008:administration & dosage / Q000627:therapeutic use / Q000633:toxicity; D000077150:Oxaliplatin; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects / Q000276:immunology*; D000093542:Gemcitabine
D000951:Antigens, Neoplasm; D015234:HLA-A Antigens; C435939:HLA-A*02:01 antigen; D015789:HLA-A2 Antigen; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D003841:Deoxycytidine; D002955:Leucovorin; D005472:Fluorouracil; D000093542:Gemcitabine