Essential complicity of perforin-granzyme and FAS-L mechanisms to achieve tumor rejection following treatment with anti-CD137 mAb.
BACKGROUND
Treatment with agonist anti-CD137 (4-1BB) immunostimulatory monoclonal antibodies elicits complete tumor regressions in a number of transplanted hematological and solid malignancies in mice. Rejection is mainly dependent on cytotoxic T lymphocytes (CTL) and IFNγ, although a role for NK cells and dendritic cells has been observed in some tumor models. Rejection of EG7-derived thymomas has been shown to be CTL-dependent but not NK-dependent.


RESULTS
In this therapeutic setting, we show that both the perforin-granzyme and FasL effector systems are readily expressed by CD8(+) T lymphocytes infiltrating the EG7 lymphomas which are undergoing rejection. Using knock-out mice, we demonstrate that both effector cytolytic systems are involved in the execution of complete immune rejections against EG7 established tumors. In accordance, EG7 tumor cells were susceptible in vitro to both killing mechanisms acting in a synergistic fashion.


CONCLUSIONS
CD137-elicited rejection of EG7-derived tumors involves the interplay of at least two final effector cytolytic mechanisms that act in cooperation.
CIMA, Gene therapy and Hepatology Unit, University of Navarra, Pamplona, Navarra, Spain.
Aizea
A
Morales-Kastresana
Departamento de Bioquímica y Biología Molecular y Celular, Universidad de Zaragoza, Zaragoza, Spain.
Elena
E
Catalán
CIMA, Gene therapy and Hepatology Unit, University of Navarra, Pamplona, Navarra, Spain.
Sandra
S
Hervás-Stubbs
CIMA, Gene therapy and Hepatology Unit, University of Navarra, Pamplona, Navarra, Spain.
Asis
A
Palazón
CIMA, Gene therapy and Hepatology Unit, University of Navarra, Pamplona, Navarra, Spain.
Arantza
A
Azpilikueta
CIMA, Gene therapy and Hepatology Unit, University of Navarra, Pamplona, Navarra, Spain.
Elixabet
E
Bolaños
Departamento de Bioquímica y Biología Molecular y Celular, Universidad de Zaragoza, Zaragoza, Spain.
Alberto
A
Anel
Instituto de Investigaciones Sanitarias de Aragón. Departamento de Bioquímica y Biología Molecular y Celular, Fac. Ciencias, Instituto de Nanociencia de Aragón (INA). Fundación Aragón I+D (ARAID) Universidad de Zaragoza, Zaragoza, Spain.
Julián
J
Pardo
CIMA, Gene therapy and Hepatology Unit, University of Navarra, Pamplona, Navarra, Spain.
Ignacio
I
Melero