Adoptively transferred human lung tumor specific cytotoxic T cells can control autologous tumor growth and shape tumor phenotype in a SCID mouse xenograft model.
BACKGROUND
The anti-tumor efficacy of human immune effector cells, such as cytolytic T lymphocytes (CTLs), has been difficult to study in lung cancer patients in the clinical setting. Improved experimental models for the study of lung tumor-immune cell interaction as well as for evaluating the efficacy of adoptive transfer of immune effector cells are needed.


METHODS
To address questions related to the in vivo interaction of human lung tumor cells and immune effector cells, we obtained an HLA class I (+) lung tumor cell line from a fresh surgical specimen, and using the infiltrating immune cells, isolated and characterized tumor antigen-specific, CD8(+) CTLs. We then established a SCID mouse-human tumor xenograft model with the tumor cell line and used it to study the function of the autologous CTLs provided via adoptive transfer.


RESULTS
The tumor antigen specific CTLs isolated from the tumor were found to have an activated memory phenotype and able to kill tumor cells in an antigen specific manner in vitro. Additionally, the tumor antigen-specific CTLs were fully capable of homing to and killing autologous tumors in vivo, and expressing IFN-gamma, each in an antigen-dependent manner. A single injection of these CTLs was able to provide significant but temporary control of the growth of autologous tumors in vivo without the need for IL-2. The timing of injection of CTLs played an essential role in the outcome of tumor growth control. Moreover, immunohistochemical analysis of surviving tumor cells following CTL treatment indicated that the surviving tumor cells expressed reduced MHC class I antigens on their surface.


CONCLUSIONS
These studies confirm and extend previous studies and provide additional information regarding the characteristics of CTLs which can be found within a patient's tumor. Moreover, the in vivo model described here provides a unique window for observing events that may also occur in patients undergoing adoptive cellular immunotherapy as effector cells seek and destroy areas of tumor growth and for testing strategies to improve clinical effectiveness.
Oflazoglu
Ezogelin
E
Department of Immunology Roswell Park Cancer Institute, Buffalo, NY 14263, USA. eoflazoglu@seagen.com
Elliott
Mark
M
Takita
Hiroshi
H
Ferrone
Soldano
S
Henderson
Robert A
RA
Repasky
Elizabeth A
EA
D019264:Adoptive Transfer; D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology; D049109:Cell Proliferation; D016207:Cytokines / Q000378:metabolism; D003602:Cytotoxicity, Immunologic; D000939:Epitopes / Q000276:immunology; D015395:Histocompatibility Antigens Class I / Q000276:immunology; D006801:Humans; D007156:Immunologic Memory; D008175:Lung Neoplasms / Q000276:immunology* / Q000473:pathology*; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology; D008297:Male; D051379:Mice; D016513:Mice, SCID; D009928:Organ Specificity; D010641:Phenotype; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D013997:Time Factors; D023041:Xenograft Model Antitumor Assays
D000951:Antigens, Neoplasm; D016207:Cytokines; D000939:Epitopes; D015395:Histocompatibility Antigens Class I