A GM-CSF/CD40L producing cell augments anti-tumor T cell responses.
BACKGROUND
Tumors evade T cell-mediated rejection despite the presence of tumor associated antigens (TAAs) and T cells specific for these TAAs in cancer patients. Therapeutic tumor vaccines are being developed to prevent this evasion. Previous reports revealed that anti-tumor T cell responses could be activated in mice when granulocyte macrophage-colony stimulating factor (GM-CSF) or CD40L are produced at tumor vaccine sites. We sought to test the hypothesis that production of GM-CSF and CD40L by a bystander cell line could induce an anti-tumor T cell response in an in vitro human model.


METHODS
The K562 cell line was stably transfected with the human GM-CSF and CD40L genes. The effect of this cell line on T cell responses was tested in a human autologous mixed tumor cell/lymph node cell model using tissue from a series of cancer patients.


RESULTS
There was no significant anti-tumor T cell response when human lymphocytes derived from tumor-draining lymph nodes were stimulated with autologous tumor cells in vitro. However, significant anti-tumor T cell responses were observed when bystander cells transfected with CD40L and GM-CSF were added to the cultures.


CONCLUSIONS
A fully autologous human model consisting of tumor cells as stimulator cells and tumor-draining lymph nodes as responder cells can be used to test immunotherapeutic strategies. T cells in these lymph nodes are unresponsive to autologous tumor cells, but this lack of responsiveness can be reversed in the presence of GM-CSF and CD40L. These data provide a rationale for testing tumor cell vaccines incorporating GM-CSF- and CD40L-expressing bystanders in clinical trials.
Dessureault
Sophie
S
Department of Interdisciplinary Oncology, H. Lee Moffitt Cancer Center & Research Institute at the University of South Florida, Tampa, Florida 33612, USA.
Alsarraj
Marwan
M
McCarthy
Susan
S
Hunter
Terri
T
Noyes
David
D
Lee
David
D
Harkins
Jennifer
J
Seigne
John
J
Jennings
Ron
R
Antonia
Scott J
SJ
D024201:Bystander Effect; D023201:CD40 Ligand / Q000378:metabolism*; D019496:Cancer Vaccines; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism*; D006801:Humans; D007167:Immunotherapy; D066298:In Vitro Techniques; D020014:K562 Cells / Q000378:metabolism*; D008198:Lymph Nodes / Q000378:metabolism*; D008213:Lymphocyte Activation; D009369:Neoplasms / Q000378:metabolism / Q000628:therapy; D013601:T-Lymphocytes / Q000378:metabolism*; D014162:Transfection
D019496:Cancer Vaccines; D023201:CD40 Ligand; D016178:Granulocyte-Macrophage Colony-Stimulating Factor