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Essential complicity of perforin-granzyme and FAS-L mechanisms to achieve tumor rejection following treatment with anti-CD137 mAb.

Morales-Kastresana A, Catalán E, Hervás-Stubbs S, Palazón A, Azpilikueta A, Bolaños E, Anel A, Pardo J, Melero I - J Immunother Cancer (2013)

Bottom Line: Rejection of EG7-derived thymomas has been shown to be CTL-dependent but not NK-dependent.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: CIMA, Gene therapy and Hepatology Unit, University of Navarra, Pamplona, Navarra, Spain.

ABSTRACT

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.

Findings: 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.

No MeSH data available.


Related in: MedlinePlus

Both perforin-granzyme and FasL pathways contribute to rejection of EG7 tumors upon treatment with anti-CD137 mAbs. Wild type (A), perforin and granzyme A and B knockout (PAB-/-) (B) and FasL-mutant gld (C) mice were injected s.c. with 5 × 105 EG7 tumor cells and treated i.p. with 100 μg of control Rat IgG or anti-CD137 mAb on days 8, 10, 12 and 14 after tumor cell challenge. Mean tumor diameters were sequentially measured 2-3 times per week. 6 mice per group were included. Statistical comparisons were performed using a nonlinear regression statistical method (Y= (MaxVol * exp(X-TimeO))/( 1 + exp((X-TimeO)/RateGrowth)) with GraphPad software. ***, P<0.001 were considered statistically significant.
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Figure 1: Both perforin-granzyme and FasL pathways contribute to rejection of EG7 tumors upon treatment with anti-CD137 mAbs. Wild type (A), perforin and granzyme A and B knockout (PAB-/-) (B) and FasL-mutant gld (C) mice were injected s.c. with 5 × 105 EG7 tumor cells and treated i.p. with 100 μg of control Rat IgG or anti-CD137 mAb on days 8, 10, 12 and 14 after tumor cell challenge. Mean tumor diameters were sequentially measured 2-3 times per week. 6 mice per group were included. Statistical comparisons were performed using a nonlinear regression statistical method (Y= (MaxVol * exp(X-TimeO))/( 1 + exp((X-TimeO)/RateGrowth)) with GraphPad software. ***, P<0.001 were considered statistically significant.

Mentions: 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]. Treatment of 8-day established tumors with 1D8 mAb achieved complete rejections in six out of six tumors, while the tumors in the control group lethally progressed upon treatment with irrelevant rat IgG (Figure 1A).


Essential complicity of perforin-granzyme and FAS-L mechanisms to achieve tumor rejection following treatment with anti-CD137 mAb.

Morales-Kastresana A, Catalán E, Hervás-Stubbs S, Palazón A, Azpilikueta A, Bolaños E, Anel A, Pardo J, Melero I - J Immunother Cancer (2013)

Both perforin-granzyme and FasL pathways contribute to rejection of EG7 tumors upon treatment with anti-CD137 mAbs. Wild type (A), perforin and granzyme A and B knockout (PAB-/-) (B) and FasL-mutant gld (C) mice were injected s.c. with 5 × 105 EG7 tumor cells and treated i.p. with 100 μg of control Rat IgG or anti-CD137 mAb on days 8, 10, 12 and 14 after tumor cell challenge. Mean tumor diameters were sequentially measured 2-3 times per week. 6 mice per group were included. Statistical comparisons were performed using a nonlinear regression statistical method (Y= (MaxVol * exp(X-TimeO))/( 1 + exp((X-TimeO)/RateGrowth)) with GraphPad software. ***, P<0.001 were considered statistically significant.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3987045&req=5

Figure 1: Both perforin-granzyme and FasL pathways contribute to rejection of EG7 tumors upon treatment with anti-CD137 mAbs. Wild type (A), perforin and granzyme A and B knockout (PAB-/-) (B) and FasL-mutant gld (C) mice were injected s.c. with 5 × 105 EG7 tumor cells and treated i.p. with 100 μg of control Rat IgG or anti-CD137 mAb on days 8, 10, 12 and 14 after tumor cell challenge. Mean tumor diameters were sequentially measured 2-3 times per week. 6 mice per group were included. Statistical comparisons were performed using a nonlinear regression statistical method (Y= (MaxVol * exp(X-TimeO))/( 1 + exp((X-TimeO)/RateGrowth)) with GraphPad software. ***, P<0.001 were considered statistically significant.
Mentions: 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]. Treatment of 8-day established tumors with 1D8 mAb achieved complete rejections in six out of six tumors, while the tumors in the control group lethally progressed upon treatment with irrelevant rat IgG (Figure 1A).

Bottom Line: Rejection of EG7-derived thymomas has been shown to be CTL-dependent but not NK-dependent.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: CIMA, Gene therapy and Hepatology Unit, University of Navarra, Pamplona, Navarra, Spain.

ABSTRACT

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.

Findings: 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.

No MeSH data available.


Related in: MedlinePlus