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.
Correale
Pierpaolo
P
Section of Oncology, Department of Human Pathology and Oncology, Siena University School of Medicine, Viale Bracci 11, 53100 Siena, Italy. correale@unisi.it
Cusi
Maria Grazia
MG
Del Vecchio
Maria Teresa
MT
Aquino
Angelo
A
Prete
Salvatore Pasquale
SP
Prete
Salvatore
S
Tsang
Kwong Y
KY
Micheli
Lucia
L
Nencini
Cristina
C
La Placa
Marco
M
Montagnani
Francesco
F
Terrosi
Chiara
C
Caraglia
Michele
M
Formica
Vincenzo
V
Giorgi
Giorgio
G
Bonmassar
Enzo
E
Francini
Guido
G
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