Antitumor activity of expanded human tumor-infiltrating gammadelta T lymphocytes.
BACKGROUND
The objective of this study was to investigate the antitumor activity of selectively expanded gammadelta T cells in tumor-infiltrating lymphocytes (gammadeltaTILs) or tumor ascites lymphocytes (gammadeltaTALs) from patients with colorectal and ovarian epithelial carcinoma (OEC) in vitro and in vivo.


METHODS
gammadeltaTILs/TALs were expanded by the solid-phase antibody method; their cytolytic and proliferative activities in vitro were detected by the MTT method and 3H-TdR incorporation and their effect in vivo was evaluated by the nude mice model.


RESULTS
Expanded gammadeltaTILs from colorectal tumors demonstrated marked cytotoxicities to allogeneic human colon adenocarcinoma HR8348 and lymphoma Daudi cells, as well as xenogeneic murine thymoma EL-4 cell lines. Cytokines, including IL-2, IL-4, IL-12, IL-15, TNF-alpha and INF-gamma, could promote the cytotoxicities of gammadeltaTILs to tumor cells, whereas IL-10, GM-CSF and TFG-beta had no effect on such killing activities. Rested gammadeltaTILs could proliferate strongly in response to mitomycin C-treated Daudi and EL-4 tumor cells, but not to HR8348 tumor cells, suggesting that the latter might possess only cytotoxicity-related antigen recognized by gammadeltaTILs. Either alphabetaTILs or gammadeltaTILs from patients with OEC displayed cytotoxicities to allogeneic or autologous OEC cell lines at a similar strength in vitro. Transferring gammadeltaTILs into Daudi cell-bearing BALB/c nude mice with an injection of IL-2 was able to maintain a high survival rate of the mice for 30 days, when compared with mice treated with alphabetaTILs or without any treatment (p < 0.05). Without coinjection of IL-2, after 3 months of Daudi tumor inoculation, a high survival rate was observed in gammadeltaTIL-treated mice. Similarly, adoptive gammadeltaTALs from the ascites of patients with OEC transferred into nude mice displayed a stronger antitumor response to OEC SKOV3 cells than alphabetaTALs in vivo. Tumor volumes in gammadeltaTAL-treated mice were smaller than in alphabetaTAL-treated or non-TAL-treated mice within the period from day 23 to day 50 after tumor inoculation (p < 0.05). Fifty days after SKOV3 tumor inoculation, a decreasing trend of carcinogenic rate was observed in gammadeltaTAL-treated nude mice.


CONCLUSIONS
Taken together, our results suggest that gammadeltaT cells could be a new candidate for adoptive immunotherapy in the future treatment of patients with cancer.
Chen
J
J
Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, Beijing, People's Republic of China.
Niu
H
H
He
W
W
Ba
D
D
D000230:Adenocarcinoma / Q000276:immunology*; D000328:Adult; D000368:Aged; D000818:Animals; D016207:Cytokines / Q000494:pharmacology; D003601:Cytotoxicity Tests, Immunologic; D005260:Female; D006801:Humans; D016219:Immunotherapy, Adoptive; D008213:Lymphocyte Activation / Q000187:drug effects; D016246:Lymphocytes, Tumor-Infiltrating / Q000187:drug effects / Q000276:immunology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008875:Middle Aged; D016685:Mitomycin / Q000494:pharmacology; D010051:Ovarian Neoplasms / Q000276:immunology*; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000276:immunology; D012004:Rectal Neoplasms / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects / Q000276:immunology*; D014407:Tumor Cells, Cultured
D016207:Cytokines; D016692:Receptors, Antigen, T-Cell, gamma-delta; D016685:Mitomycin