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T cell-NF-κB activation is required for tumor control in vivo.

Barnes SE, Wang Y, Chen L, Molinero LL, Gajewski TF, Evaristo C, Alegre ML - J Immunother Cancer (2015)

Bottom Line: However, it is not clear if this is causal for an inability to reject transformed cells, or if it is a consequence of tumor growth.Tumor antigen-specific T cell-IFN-γ and TNF-α production, as well as cytotoxic ability, were all reduced in mice with impaired T cell-NF-κB, suggesting an important role for this transcription factor in the effector differentiation of tumor-specific effector T cells.Maintaining or enhancing T cell-NF-κB activity may be a promising avenue for anti-tumor immunotherapy.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, The University of Chicago, 924 E. 57th St. JFK-R312, Chicago, IL 60637 USA.

ABSTRACT

Background: T cells have the capacity to eliminate tumors but the signaling pathways by which they do so are incompletely understood. T cell priming requires activation of the transcription factors AP-1, NFAT and NF-κB downstream of the TCR, but whether activation of T cell-NF-κB in vivo is required for tumor control has not been addressed. In humans and mice with progressively growing tumors, the activity of T cell-intrinsic NF-κB is often reduced. However, it is not clear if this is causal for an inability to reject transformed cells, or if it is a consequence of tumor growth. T cell-NF-κB is important for T cell survival and effector differentiation and plays an important role in enabling T cells to reject cardiac and islet allografts, suggesting the possibility that it may also be required for tumor elimination. In this study, we tested whether normal T cell-NF-κB activation is necessary for the rejection of tumors whose growth is normally controlled by the immune system.

Methods: Mice with genetically impaired T cell-NF-κB activity were subcutaneously injected with MC57-SIY tumor cells. Tumor growth was measured over time, and the anti-tumor immune response was evaluated using flow cytometry and cytokine detection assays.

Results: Mice with impaired T cell-NF-κB activity were unable to reject tumors that were otherwise eliminated by wildtype mice, despite equal accumulation of tumor-reactive T cells. In addition, specific impairment of NF-κB signaling downstream of the TCR was sufficient to prevent tumor rejection. Tumor antigen-specific T cell-IFN-γ and TNF-α production, as well as cytotoxic ability, were all reduced in mice with impaired T cell-NF-κB, suggesting an important role for this transcription factor in the effector differentiation of tumor-specific effector T cells.

Conclusions: Our results have identified the NF-κB pathway as an important signaling axis in T cells, required for the elimination of growing tumors in vivo. Maintaining or enhancing T cell-NF-κB activity may be a promising avenue for anti-tumor immunotherapy.

No MeSH data available.


Related in: MedlinePlus

IKKβ expression in T cells is required for MC57-SIY tumor rejection. a) One million MC57-SIY tumor cells were subcutaneously injected into CD4-cre x IKKβfl/fl mice, and tumor growth was measured over time. b) Fully mismatched skin from wildtype BALB/c mice (H-2d) was transplanted into CD4-cre x IKKβfl/fl mice (H-2b). Results are representative of at least 2 experiments. ***p < 0.001.
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Fig1: IKKβ expression in T cells is required for MC57-SIY tumor rejection. a) One million MC57-SIY tumor cells were subcutaneously injected into CD4-cre x IKKβfl/fl mice, and tumor growth was measured over time. b) Fully mismatched skin from wildtype BALB/c mice (H-2d) was transplanted into CD4-cre x IKKβfl/fl mice (H-2b). Results are representative of at least 2 experiments. ***p < 0.001.

Mentions: To determine whether T cell-NF-κB signaling was required for tumor rejection, we examined the ability of T cell-NF-κB-impaired mice to reject a transplantable tumor. To this end, we utilized CD4-cre x IKKβfl/fl mice, the T cells from which lack the kinase IKKβ that is required for the phosphorylation of IκB and consequent nuclear translocation of NF-κB molecules. In these mice, cre-mediated deletion of IKKβ occurs at the double positive stage of thymocyte development, resulting in absence of IKKβ from all peripheral CD4+ and CD8+ αβT cells. CD4-cre x IKKβfl/fl mice have been previously described [14,31], and their T cells displayed normal survival and activation by polyclonal stimuli in vitro, expanded efficiently in response to superantigen administration in vivo, but were deficient in recall responses, help for germinal center formation, and lymphopenia-induced homeostatic proliferation [31,32]. CD4-cre x IKKβfl/fl mice and littermate controls (CD4-cre x IKKβ+/fl) were subcutaneously injected with 106 MC57-SIY tumor cells, a mouse fibrosarcoma cell line engineered to express the model peptide antigen SIYRYYGL (SIY). This transplantable tumor is spontaneously rejected by wildtype mice [33]. While littermate controls successfully rejected the MC57-SIY tumors, CD4-cre x IKKβfl/fl mice did not (Figure 1a). To determine if this was due to an inability of CD4-cre x IKKβfl/fl mice to mount any kind of immune response when antigens were present in a cutaneous location, we examined whether they could reject skin grafts. CD4-cre x IKKβfl/fl mice (C57BL/6 background, H-2b) successfully rejected a fully mismatched BALB/c (H-2d) skin allograft, albeit with slower kinetics than wildtype mice (Figure 1b). Therefore, T cell-IKKβ was necessary for elimination of MC57-SIY tumors but was not required for the complete destruction of skin allografts.Figure 1


T cell-NF-κB activation is required for tumor control in vivo.

Barnes SE, Wang Y, Chen L, Molinero LL, Gajewski TF, Evaristo C, Alegre ML - J Immunother Cancer (2015)

IKKβ expression in T cells is required for MC57-SIY tumor rejection. a) One million MC57-SIY tumor cells were subcutaneously injected into CD4-cre x IKKβfl/fl mice, and tumor growth was measured over time. b) Fully mismatched skin from wildtype BALB/c mice (H-2d) was transplanted into CD4-cre x IKKβfl/fl mice (H-2b). Results are representative of at least 2 experiments. ***p < 0.001.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4308877&req=5

Fig1: IKKβ expression in T cells is required for MC57-SIY tumor rejection. a) One million MC57-SIY tumor cells were subcutaneously injected into CD4-cre x IKKβfl/fl mice, and tumor growth was measured over time. b) Fully mismatched skin from wildtype BALB/c mice (H-2d) was transplanted into CD4-cre x IKKβfl/fl mice (H-2b). Results are representative of at least 2 experiments. ***p < 0.001.
Mentions: To determine whether T cell-NF-κB signaling was required for tumor rejection, we examined the ability of T cell-NF-κB-impaired mice to reject a transplantable tumor. To this end, we utilized CD4-cre x IKKβfl/fl mice, the T cells from which lack the kinase IKKβ that is required for the phosphorylation of IκB and consequent nuclear translocation of NF-κB molecules. In these mice, cre-mediated deletion of IKKβ occurs at the double positive stage of thymocyte development, resulting in absence of IKKβ from all peripheral CD4+ and CD8+ αβT cells. CD4-cre x IKKβfl/fl mice have been previously described [14,31], and their T cells displayed normal survival and activation by polyclonal stimuli in vitro, expanded efficiently in response to superantigen administration in vivo, but were deficient in recall responses, help for germinal center formation, and lymphopenia-induced homeostatic proliferation [31,32]. CD4-cre x IKKβfl/fl mice and littermate controls (CD4-cre x IKKβ+/fl) were subcutaneously injected with 106 MC57-SIY tumor cells, a mouse fibrosarcoma cell line engineered to express the model peptide antigen SIYRYYGL (SIY). This transplantable tumor is spontaneously rejected by wildtype mice [33]. While littermate controls successfully rejected the MC57-SIY tumors, CD4-cre x IKKβfl/fl mice did not (Figure 1a). To determine if this was due to an inability of CD4-cre x IKKβfl/fl mice to mount any kind of immune response when antigens were present in a cutaneous location, we examined whether they could reject skin grafts. CD4-cre x IKKβfl/fl mice (C57BL/6 background, H-2b) successfully rejected a fully mismatched BALB/c (H-2d) skin allograft, albeit with slower kinetics than wildtype mice (Figure 1b). Therefore, T cell-IKKβ was necessary for elimination of MC57-SIY tumors but was not required for the complete destruction of skin allografts.Figure 1

Bottom Line: However, it is not clear if this is causal for an inability to reject transformed cells, or if it is a consequence of tumor growth.Tumor antigen-specific T cell-IFN-γ and TNF-α production, as well as cytotoxic ability, were all reduced in mice with impaired T cell-NF-κB, suggesting an important role for this transcription factor in the effector differentiation of tumor-specific effector T cells.Maintaining or enhancing T cell-NF-κB activity may be a promising avenue for anti-tumor immunotherapy.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, The University of Chicago, 924 E. 57th St. JFK-R312, Chicago, IL 60637 USA.

ABSTRACT

Background: T cells have the capacity to eliminate tumors but the signaling pathways by which they do so are incompletely understood. T cell priming requires activation of the transcription factors AP-1, NFAT and NF-κB downstream of the TCR, but whether activation of T cell-NF-κB in vivo is required for tumor control has not been addressed. In humans and mice with progressively growing tumors, the activity of T cell-intrinsic NF-κB is often reduced. However, it is not clear if this is causal for an inability to reject transformed cells, or if it is a consequence of tumor growth. T cell-NF-κB is important for T cell survival and effector differentiation and plays an important role in enabling T cells to reject cardiac and islet allografts, suggesting the possibility that it may also be required for tumor elimination. In this study, we tested whether normal T cell-NF-κB activation is necessary for the rejection of tumors whose growth is normally controlled by the immune system.

Methods: Mice with genetically impaired T cell-NF-κB activity were subcutaneously injected with MC57-SIY tumor cells. Tumor growth was measured over time, and the anti-tumor immune response was evaluated using flow cytometry and cytokine detection assays.

Results: Mice with impaired T cell-NF-κB activity were unable to reject tumors that were otherwise eliminated by wildtype mice, despite equal accumulation of tumor-reactive T cells. In addition, specific impairment of NF-κB signaling downstream of the TCR was sufficient to prevent tumor rejection. Tumor antigen-specific T cell-IFN-γ and TNF-α production, as well as cytotoxic ability, were all reduced in mice with impaired T cell-NF-κB, suggesting an important role for this transcription factor in the effector differentiation of tumor-specific effector T cells.

Conclusions: Our results have identified the NF-κB pathway as an important signaling axis in T cells, required for the elimination of growing tumors in vivo. Maintaining or enhancing T cell-NF-κB activity may be a promising avenue for anti-tumor immunotherapy.

No MeSH data available.


Related in: MedlinePlus