THE IMMUNE SURVEILLANCE CONSTRAINTS B CELL LYMPHOMAS WITH CONTINUOUS CD40 SIGNALING TO AN INDOLENT PHENOTYPE
(Abstract release date: 05/19/16)
EHA Library. VINCENT-FABERT C. 06/09/16; 132937; E1388
Dr. Christelle VINCENT-FABERT
Contributions
Contributions
Abstract
Abstract: E1388
Type: Eposter Presentation
Background
LMP1/CD40 transgenic mice, with specific expression of the chimeric protein composed of the transmembrane domain of LMP1, the main Epstein Barr Virus oncoprotein, and intracellular signaling domain of CD40 in B cells, develop indolent lymphomas after one year in 60% cases. LMP1/CD40 expressing B cells are characterized by constitutive activation of the MAPK JNK and ERK as well as the non-canonical NF-kappa B signaling pathway (Hömig-Hölzel et al., 2008). Since (i) NF-kappa B can induce a strong immune surveillance of the tumor when activated by LMP1, such as in transgenic LMP1 mice (Zhang et al., 2012) or in EBV immortalized human B cells (Le Clorennec et al., 2006, 2008) and (ii) not all LMP1/CD40 transgenic mice will develop a tumor, we supposed that the LMP1/CD40 activation signal could also favor some immuno-surveillance of B cells.
Aims
We asked the question of the control by the immune system on B-cell lymphoproliferation related to the constitutive activation of CD40 since the activation signal is very similar to that of the EBV protein LMP1.
Methods
In order to test the effect of immunosuppression on the kinetics of tumor emergence, we injected every day for 3 months the immunosuppressive Cyclosporin A molecule (CsA) at a dose of 10 mg/kg to 8 months-old wild type (WT) or LMP1/CD40 mice.
Results
While cyclosporin A was toxic in vitro on B cells, in vivo lymphomagenesis B was accelerated with a greater splenomegaly and increased number of tumor cells in the blood in LMP1/CD40 mice treated with CsA in comparison to untreated mice. Morphologically, tumor B cells of mice treated with CsA were larger with a more immunoblastic phenotype, both on blood smears and spleen tissue sections. Proliferation was increased both ex vivo and in vivo (Ki67 and BrdU labeling). Similarly, the number of cells with an activated phenotype was increased in CsA treated LMP1/CD40 mice. Finally, we noted that the injection of CsA increases the expression of PDL -1/B7 -H1 and decreases the expression of CD95.
Conclusion
Despite direct toxic effect on B-cells in vitro, immunosuppressive treatment with CsA accelerates CD40 signal dependent B-cell lymphomagenesis in vivo by inducing the transformation of an indolent tumor into a tumor morphologically and phenotypically resembling to a Richter syndrome. This suggests that B-cell lymphomagenesis related to constitutive CD40 signaling is under partial control of the immune microenvironment, which may influence tumor morphology. This may give some clues explaining why indolent B-cells lymphomas may transform in aggressive form.
Session topic: E-poster
Keyword(s): Cyclosporin A, EBV, NF- B, Non-Hodgkin's lymphoma
Type: Eposter Presentation
Background
LMP1/CD40 transgenic mice, with specific expression of the chimeric protein composed of the transmembrane domain of LMP1, the main Epstein Barr Virus oncoprotein, and intracellular signaling domain of CD40 in B cells, develop indolent lymphomas after one year in 60% cases. LMP1/CD40 expressing B cells are characterized by constitutive activation of the MAPK JNK and ERK as well as the non-canonical NF-kappa B signaling pathway (Hömig-Hölzel et al., 2008). Since (i) NF-kappa B can induce a strong immune surveillance of the tumor when activated by LMP1, such as in transgenic LMP1 mice (Zhang et al., 2012) or in EBV immortalized human B cells (Le Clorennec et al., 2006, 2008) and (ii) not all LMP1/CD40 transgenic mice will develop a tumor, we supposed that the LMP1/CD40 activation signal could also favor some immuno-surveillance of B cells.
Aims
We asked the question of the control by the immune system on B-cell lymphoproliferation related to the constitutive activation of CD40 since the activation signal is very similar to that of the EBV protein LMP1.
Methods
In order to test the effect of immunosuppression on the kinetics of tumor emergence, we injected every day for 3 months the immunosuppressive Cyclosporin A molecule (CsA) at a dose of 10 mg/kg to 8 months-old wild type (WT) or LMP1/CD40 mice.
Results
While cyclosporin A was toxic in vitro on B cells, in vivo lymphomagenesis B was accelerated with a greater splenomegaly and increased number of tumor cells in the blood in LMP1/CD40 mice treated with CsA in comparison to untreated mice. Morphologically, tumor B cells of mice treated with CsA were larger with a more immunoblastic phenotype, both on blood smears and spleen tissue sections. Proliferation was increased both ex vivo and in vivo (Ki67 and BrdU labeling). Similarly, the number of cells with an activated phenotype was increased in CsA treated LMP1/CD40 mice. Finally, we noted that the injection of CsA increases the expression of PDL -1/B7 -H1 and decreases the expression of CD95.
Conclusion
Despite direct toxic effect on B-cells in vitro, immunosuppressive treatment with CsA accelerates CD40 signal dependent B-cell lymphomagenesis in vivo by inducing the transformation of an indolent tumor into a tumor morphologically and phenotypically resembling to a Richter syndrome. This suggests that B-cell lymphomagenesis related to constitutive CD40 signaling is under partial control of the immune microenvironment, which may influence tumor morphology. This may give some clues explaining why indolent B-cells lymphomas may transform in aggressive form.
Session topic: E-poster
Keyword(s): Cyclosporin A, EBV, NF- B, Non-Hodgkin's lymphoma
Abstract: E1388
Type: Eposter Presentation
Background
LMP1/CD40 transgenic mice, with specific expression of the chimeric protein composed of the transmembrane domain of LMP1, the main Epstein Barr Virus oncoprotein, and intracellular signaling domain of CD40 in B cells, develop indolent lymphomas after one year in 60% cases. LMP1/CD40 expressing B cells are characterized by constitutive activation of the MAPK JNK and ERK as well as the non-canonical NF-kappa B signaling pathway (Hömig-Hölzel et al., 2008). Since (i) NF-kappa B can induce a strong immune surveillance of the tumor when activated by LMP1, such as in transgenic LMP1 mice (Zhang et al., 2012) or in EBV immortalized human B cells (Le Clorennec et al., 2006, 2008) and (ii) not all LMP1/CD40 transgenic mice will develop a tumor, we supposed that the LMP1/CD40 activation signal could also favor some immuno-surveillance of B cells.
Aims
We asked the question of the control by the immune system on B-cell lymphoproliferation related to the constitutive activation of CD40 since the activation signal is very similar to that of the EBV protein LMP1.
Methods
In order to test the effect of immunosuppression on the kinetics of tumor emergence, we injected every day for 3 months the immunosuppressive Cyclosporin A molecule (CsA) at a dose of 10 mg/kg to 8 months-old wild type (WT) or LMP1/CD40 mice.
Results
While cyclosporin A was toxic in vitro on B cells, in vivo lymphomagenesis B was accelerated with a greater splenomegaly and increased number of tumor cells in the blood in LMP1/CD40 mice treated with CsA in comparison to untreated mice. Morphologically, tumor B cells of mice treated with CsA were larger with a more immunoblastic phenotype, both on blood smears and spleen tissue sections. Proliferation was increased both ex vivo and in vivo (Ki67 and BrdU labeling). Similarly, the number of cells with an activated phenotype was increased in CsA treated LMP1/CD40 mice. Finally, we noted that the injection of CsA increases the expression of PDL -1/B7 -H1 and decreases the expression of CD95.
Conclusion
Despite direct toxic effect on B-cells in vitro, immunosuppressive treatment with CsA accelerates CD40 signal dependent B-cell lymphomagenesis in vivo by inducing the transformation of an indolent tumor into a tumor morphologically and phenotypically resembling to a Richter syndrome. This suggests that B-cell lymphomagenesis related to constitutive CD40 signaling is under partial control of the immune microenvironment, which may influence tumor morphology. This may give some clues explaining why indolent B-cells lymphomas may transform in aggressive form.
Session topic: E-poster
Keyword(s): Cyclosporin A, EBV, NF- B, Non-Hodgkin's lymphoma
Type: Eposter Presentation
Background
LMP1/CD40 transgenic mice, with specific expression of the chimeric protein composed of the transmembrane domain of LMP1, the main Epstein Barr Virus oncoprotein, and intracellular signaling domain of CD40 in B cells, develop indolent lymphomas after one year in 60% cases. LMP1/CD40 expressing B cells are characterized by constitutive activation of the MAPK JNK and ERK as well as the non-canonical NF-kappa B signaling pathway (Hömig-Hölzel et al., 2008). Since (i) NF-kappa B can induce a strong immune surveillance of the tumor when activated by LMP1, such as in transgenic LMP1 mice (Zhang et al., 2012) or in EBV immortalized human B cells (Le Clorennec et al., 2006, 2008) and (ii) not all LMP1/CD40 transgenic mice will develop a tumor, we supposed that the LMP1/CD40 activation signal could also favor some immuno-surveillance of B cells.
Aims
We asked the question of the control by the immune system on B-cell lymphoproliferation related to the constitutive activation of CD40 since the activation signal is very similar to that of the EBV protein LMP1.
Methods
In order to test the effect of immunosuppression on the kinetics of tumor emergence, we injected every day for 3 months the immunosuppressive Cyclosporin A molecule (CsA) at a dose of 10 mg/kg to 8 months-old wild type (WT) or LMP1/CD40 mice.
Results
While cyclosporin A was toxic in vitro on B cells, in vivo lymphomagenesis B was accelerated with a greater splenomegaly and increased number of tumor cells in the blood in LMP1/CD40 mice treated with CsA in comparison to untreated mice. Morphologically, tumor B cells of mice treated with CsA were larger with a more immunoblastic phenotype, both on blood smears and spleen tissue sections. Proliferation was increased both ex vivo and in vivo (Ki67 and BrdU labeling). Similarly, the number of cells with an activated phenotype was increased in CsA treated LMP1/CD40 mice. Finally, we noted that the injection of CsA increases the expression of PDL -1/B7 -H1 and decreases the expression of CD95.
Conclusion
Despite direct toxic effect on B-cells in vitro, immunosuppressive treatment with CsA accelerates CD40 signal dependent B-cell lymphomagenesis in vivo by inducing the transformation of an indolent tumor into a tumor morphologically and phenotypically resembling to a Richter syndrome. This suggests that B-cell lymphomagenesis related to constitutive CD40 signaling is under partial control of the immune microenvironment, which may influence tumor morphology. This may give some clues explaining why indolent B-cells lymphomas may transform in aggressive form.
Session topic: E-poster
Keyword(s): Cyclosporin A, EBV, NF- B, Non-Hodgkin's lymphoma
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