Abstract
BackgroundTreatment 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.FindingsIn 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.ConclusionsCD137-elicited rejection of EG7-derived tumors involves the interplay of at least two final effector cytolytic mechanisms that act in cooperation.
Highlights
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
CD137-elicited rejection of EG7-derived tumors involves the interplay of at least two final effector cytolytic mechanisms that act in cooperation
Granzymes A and B and FasL are involved in tumor rejection elicited by anti-CD137 Monoclonal antibody (mAb) As previously published, tumors derived from the EG7 cell line (EL4 stably transfected with ovalbumin [15]) are readily rejected following treatment with anti-CD137 mAb [5]
Summary
CD137 agonists hold promise to augment antitumor immune responses in a clinically significant fashion [1] and two fully human monoclonal antibodies (mAbs) are currently undergoing clinical development (BMS-663513 and PFZ-05082566). Hematological malignancies are not exception to the therapeutic effects of anti-CD137 mAbs and activity has been reported on experimental models of lymphoma, myeloma and mastocytomas [2,3,4]. The mechanism of action depends mainly on cytolytic T lymphocytes (CTLs) since depletion of CD8β T cells completely abrogates the therapeutic effect [5]. Evidence has been reported showing that activated CD8+ tumor infiltrating lymphocytes (TILs) express CD137 [9] and are amenable to receive artificial costimulation by agonist anti-CD137 mAbs within the malignant tissue microenvironment. Little is known about the final effector mechanisms that mediate tumor cell killing. Granule and the FasL-mediated killing mechanisms were synergistically involved in achieving complete rejections of these lymphomas
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