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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

Normal T cell priming in CD4-cre x IKKβfl/flmice. CD4-cre x IKKβfl/fl mice were subcutaneously injected with 106 MC57-SIY tumor cells, were sacrificed on day 7 and splenocytes were prepared for flow cytometry. Graphical representation (a and c) and absolute numbers (b and d) of SYI:Kb+ tumor-specific CD8+ T cells (a and b) and of Ki67+ proliferating CD8+CD44hi cells (c and d). Results are representative of at least 2 independent experiments. NS = not significant.
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Fig2: Normal T cell priming in CD4-cre x IKKβfl/flmice. CD4-cre x IKKβfl/fl mice were subcutaneously injected with 106 MC57-SIY tumor cells, were sacrificed on day 7 and splenocytes were prepared for flow cytometry. Graphical representation (a and c) and absolute numbers (b and d) of SYI:Kb+ tumor-specific CD8+ T cells (a and b) and of Ki67+ proliferating CD8+CD44hi cells (c and d). Results are representative of at least 2 independent experiments. NS = not significant.

Mentions: Lack of tumor rejection in CD4-cre x IKKβfl/fl mice may depend on impaired survival, proliferation, differentiation, migration or effector function of tumor-reactive T cells in vivo. To investigate the fate of anti-tumor T cells, we used fluorescently labeled pentamers of the MHC class I Kb molecule coupled to the SIY peptide to identify SIY-reactive T cells. Mice inoculated with MC57-SIY tumor cells were sacrificed on day 7, which was determined to be the height of the anti-tumor response [33], and splenocytes were analyzed by flow cytometry. Frequencies (Figure 2a) and absolute numbers (Figure 2b) of SIY-specific T cells were similar between CD4-cre x IKKβfl/fl mice and littermate controls, suggesting similar expansion and survival of SIY-specific CD8+ T cells following tumor exposure regardless of the presence or absence of IKKβ.Figure 2


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)

Normal T cell priming in CD4-cre x IKKβfl/flmice. CD4-cre x IKKβfl/fl mice were subcutaneously injected with 106 MC57-SIY tumor cells, were sacrificed on day 7 and splenocytes were prepared for flow cytometry. Graphical representation (a and c) and absolute numbers (b and d) of SYI:Kb+ tumor-specific CD8+ T cells (a and b) and of Ki67+ proliferating CD8+CD44hi cells (c and d). Results are representative of at least 2 independent experiments. NS = not significant.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Fig2: Normal T cell priming in CD4-cre x IKKβfl/flmice. CD4-cre x IKKβfl/fl mice were subcutaneously injected with 106 MC57-SIY tumor cells, were sacrificed on day 7 and splenocytes were prepared for flow cytometry. Graphical representation (a and c) and absolute numbers (b and d) of SYI:Kb+ tumor-specific CD8+ T cells (a and b) and of Ki67+ proliferating CD8+CD44hi cells (c and d). Results are representative of at least 2 independent experiments. NS = not significant.
Mentions: Lack of tumor rejection in CD4-cre x IKKβfl/fl mice may depend on impaired survival, proliferation, differentiation, migration or effector function of tumor-reactive T cells in vivo. To investigate the fate of anti-tumor T cells, we used fluorescently labeled pentamers of the MHC class I Kb molecule coupled to the SIY peptide to identify SIY-reactive T cells. Mice inoculated with MC57-SIY tumor cells were sacrificed on day 7, which was determined to be the height of the anti-tumor response [33], and splenocytes were analyzed by flow cytometry. Frequencies (Figure 2a) and absolute numbers (Figure 2b) of SIY-specific T cells were similar between CD4-cre x IKKβfl/fl mice and littermate controls, suggesting similar expansion and survival of SIY-specific CD8+ T cells following tumor exposure regardless of the presence or absence of IKKβ.Figure 2

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