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Deficiency of AMPK in CD8+ T cells suppresses their anti-tumor function by inducing protein phosphatase-mediated cell death.

Rao E, Zhang Y, Zhu G, Hao J, Persson XM, Egilmez NK, Suttles J, Li B - Oncotarget (2015)

Bottom Line: A number of studies have linked AMPK, a major metabolic sensor coordinating of multiple cellular functions, to tumor development and progression.Here we report that activation of AMPK promotes survival and anti-tumor function of T cells, in particular CD8+ T cells, resulting in superior tumor suppression in vivo.Moreover, we demonstrate that protein phosphatases are the key mediators of AMPK-dependent effects on T cell death, and inhibition of phosphatase activity by okadaic acid successfully restores T cell survival and function.

View Article: PubMed Central - PubMed

Affiliation: The Hormel Institute, University of Minnesota, Austin, MN, USA.

ABSTRACT
A number of studies have linked AMPK, a major metabolic sensor coordinating of multiple cellular functions, to tumor development and progression. However, the exact role of AMPK in tumor development is still controversial. Here we report that activation of AMPK promotes survival and anti-tumor function of T cells, in particular CD8+ T cells, resulting in superior tumor suppression in vivo. While AMPK expression is dispensable for T cell development, genetic deletion of AMPK promotes T cell death during in vitro activation and in vivo tumor development. Moreover, we demonstrate that protein phosphatases are the key mediators of AMPK-dependent effects on T cell death, and inhibition of phosphatase activity by okadaic acid successfully restores T cell survival and function. Altogether, our data suggest a novel mechanism by which AMPK regulates protein phosphatase activity in control of survival and function of CD8+ T cells, thereby enhancing their role in tumor immunosurveillance.

No MeSH data available.


Related in: MedlinePlus

AMPK deficiency increases T cell death in tumor-bearing miceSinge cells were prepared from E0771 tumors from WT and KO mice. Cell death of tumor infiltrating CD8+ (A) or CD4+ T cells (B) was analyzed by 7-AAD staining. C, splenocytes from tumor-bearing mice were analyzed for cell death in CD8+ cells, CD4+ T cells, or non-T cell populations. D, splenocytes from naïve mice were analyzed for cell death in CD8+ cells, CD4+ T cells, or non-T cell populations. (*, p<0.05; **, p<0.01).
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Figure 7: AMPK deficiency increases T cell death in tumor-bearing miceSinge cells were prepared from E0771 tumors from WT and KO mice. Cell death of tumor infiltrating CD8+ (A) or CD4+ T cells (B) was analyzed by 7-AAD staining. C, splenocytes from tumor-bearing mice were analyzed for cell death in CD8+ cells, CD4+ T cells, or non-T cell populations. D, splenocytes from naïve mice were analyzed for cell death in CD8+ cells, CD4+ T cells, or non-T cell populations. (*, p<0.05; **, p<0.01).

Mentions: On the basis of the above in vitro results, we reasoned that the decreased percentage and function of T cells in tumors from AMPK KO mice (Figure 3) may be due to the increased cell death induced by AMPK deficiency. To that end, we directly measured tumor-infiltrating T cell death in tumor-bearing mice without any in vitro stimulation. Indeed, we found that ~20% of the CD8+ T cells died in the tumor stroma of AMPK KO mice, whereas only ~6% CD8+ T cells died in tumors of WT mice (Figure 7A). Similarly, tumors from AMPK KO mice exhibited 2 fold increase of CD4+ T cell death as compared to tumors from WT mice (Figure 7B). Furthermore, splenic T-cell populations from AMPK KO tumor-bearing mice also displayed enhanced cell death demonstrating that the loss of viability was not limited to the tumor microenvironment (Figure 7C). In contrast, the non-T populations exhibited a similar death ratio between WT and KO, further indicating the essential role of AMPK in mediating the observed effect (Figure 7C). It is worth noting that splenic cell death in naïve mice was much lower when compared to tumor-bearing mice, and AMPK deficiency showed no effect on T cell death in these mice (Figure 7D). In addition, we also measured the expression of CCR4, CCR5 and CXCR3 receptors on tumor infiltrating CD8+ and CD4+ T cells from both WT and KO mice and found AMPK deficiency had no overt impact on the expression of these major chemokine receptors (Supplementary Figure 6A-6D). Consistently, expression levels of these chemokine receptors on T cells from peripheral lymph organs were also similar in WT and KO mice (Supplementary Figure 6E-6H). Taken together, these data suggest that AMPK deficiency does not affect T cell recruitment, but promotes T cell death, thereby leading to reduced percentage and function of effector T cells in the tumor microenvironment.


Deficiency of AMPK in CD8+ T cells suppresses their anti-tumor function by inducing protein phosphatase-mediated cell death.

Rao E, Zhang Y, Zhu G, Hao J, Persson XM, Egilmez NK, Suttles J, Li B - Oncotarget (2015)

AMPK deficiency increases T cell death in tumor-bearing miceSinge cells were prepared from E0771 tumors from WT and KO mice. Cell death of tumor infiltrating CD8+ (A) or CD4+ T cells (B) was analyzed by 7-AAD staining. C, splenocytes from tumor-bearing mice were analyzed for cell death in CD8+ cells, CD4+ T cells, or non-T cell populations. D, splenocytes from naïve mice were analyzed for cell death in CD8+ cells, CD4+ T cells, or non-T cell populations. (*, p<0.05; **, p<0.01).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4480727&req=5

Figure 7: AMPK deficiency increases T cell death in tumor-bearing miceSinge cells were prepared from E0771 tumors from WT and KO mice. Cell death of tumor infiltrating CD8+ (A) or CD4+ T cells (B) was analyzed by 7-AAD staining. C, splenocytes from tumor-bearing mice were analyzed for cell death in CD8+ cells, CD4+ T cells, or non-T cell populations. D, splenocytes from naïve mice were analyzed for cell death in CD8+ cells, CD4+ T cells, or non-T cell populations. (*, p<0.05; **, p<0.01).
Mentions: On the basis of the above in vitro results, we reasoned that the decreased percentage and function of T cells in tumors from AMPK KO mice (Figure 3) may be due to the increased cell death induced by AMPK deficiency. To that end, we directly measured tumor-infiltrating T cell death in tumor-bearing mice without any in vitro stimulation. Indeed, we found that ~20% of the CD8+ T cells died in the tumor stroma of AMPK KO mice, whereas only ~6% CD8+ T cells died in tumors of WT mice (Figure 7A). Similarly, tumors from AMPK KO mice exhibited 2 fold increase of CD4+ T cell death as compared to tumors from WT mice (Figure 7B). Furthermore, splenic T-cell populations from AMPK KO tumor-bearing mice also displayed enhanced cell death demonstrating that the loss of viability was not limited to the tumor microenvironment (Figure 7C). In contrast, the non-T populations exhibited a similar death ratio between WT and KO, further indicating the essential role of AMPK in mediating the observed effect (Figure 7C). It is worth noting that splenic cell death in naïve mice was much lower when compared to tumor-bearing mice, and AMPK deficiency showed no effect on T cell death in these mice (Figure 7D). In addition, we also measured the expression of CCR4, CCR5 and CXCR3 receptors on tumor infiltrating CD8+ and CD4+ T cells from both WT and KO mice and found AMPK deficiency had no overt impact on the expression of these major chemokine receptors (Supplementary Figure 6A-6D). Consistently, expression levels of these chemokine receptors on T cells from peripheral lymph organs were also similar in WT and KO mice (Supplementary Figure 6E-6H). Taken together, these data suggest that AMPK deficiency does not affect T cell recruitment, but promotes T cell death, thereby leading to reduced percentage and function of effector T cells in the tumor microenvironment.

Bottom Line: A number of studies have linked AMPK, a major metabolic sensor coordinating of multiple cellular functions, to tumor development and progression.Here we report that activation of AMPK promotes survival and anti-tumor function of T cells, in particular CD8+ T cells, resulting in superior tumor suppression in vivo.Moreover, we demonstrate that protein phosphatases are the key mediators of AMPK-dependent effects on T cell death, and inhibition of phosphatase activity by okadaic acid successfully restores T cell survival and function.

View Article: PubMed Central - PubMed

Affiliation: The Hormel Institute, University of Minnesota, Austin, MN, USA.

ABSTRACT
A number of studies have linked AMPK, a major metabolic sensor coordinating of multiple cellular functions, to tumor development and progression. However, the exact role of AMPK in tumor development is still controversial. Here we report that activation of AMPK promotes survival and anti-tumor function of T cells, in particular CD8+ T cells, resulting in superior tumor suppression in vivo. While AMPK expression is dispensable for T cell development, genetic deletion of AMPK promotes T cell death during in vitro activation and in vivo tumor development. Moreover, we demonstrate that protein phosphatases are the key mediators of AMPK-dependent effects on T cell death, and inhibition of phosphatase activity by okadaic acid successfully restores T cell survival and function. Altogether, our data suggest a novel mechanism by which AMPK regulates protein phosphatase activity in control of survival and function of CD8+ T cells, thereby enhancing their role in tumor immunosurveillance.

No MeSH data available.


Related in: MedlinePlus