Publication Highlights: October 2017-January 2018 CFATG
Publication Highlights: October 2017-January 2018

Publication Highlights: Articles on autophagy research published by french laboratories and selected by CFATG.

Solid tumors are able to develop a hostile microenvironment preventing the infiltration of cytotoxic immune cells such as NK (Natural Killer) cells and cytotoxic T lymphocytes (CTL). One of the major challenge of tumor immunotherapy is to define strategies capable of redirecting these cytotoxic immune cells to the tumor bed and thus switch the immunosuppressive tumor microenvironment into a microenvironment capable of attracting cytotoxic immune cells. The tumor microenvironment research team of Dr. Janji, at Luxembourg Institute of Health (LIH), has investigated the impact of targeting Beclin1 gene on the immune landscape of murine melanoma tumors. They reported that targeting Beclin1 induces a significant decrease in tumor volume which is associated with a massive infiltration of NK cells into tumors. They also revealed that this infiltration is strikingly related to the ability of Beclin1-deficient tumor cells to overexpress and secrete the CCL5 cytokine in the tumor microenvironment of melanoma since the deletion of CCL5 in these tumors completely blocks NK cell infiltration. Clinically, the study demonstrated a strong positive correlation between CCL5 expression and NK cell infiltration in human melanoma biopsies. Mechanistically, the results revealed that the overexpression of CCL5 in Beclin1-deficient melanoma cells is related to the activation of the JNK / c-Jun pathway involved in the transcriptional activation of CCL5.
Although the effect of targeting autophagy on the inhibition of tumor growth in several experimental models is currently well established, this study reveals for the first time its major impact on immune cell infiltration, notably NK cells, in the tumor microenvironment.

Proc Natl Acad Sci U S A. 2017 Oct 31;114(44):E9271-E9279

Atherosclerotic lesions develop in curvatures or branch points of the vasculature due to low shear stress (SS) exerted by the blood flow, while high SS areas are devoid of plaques. Endothelial inflammation, apoptosis and senescence are involved, but the mechanisms remain elusive. Our aim was to understand the role of autophagy in athero-protective effects of high SS.
We first demonstrated in human and murine arteries that atheroprotective high SS activates endothelial autophagic flux. On the opposite, endothelial cells exposed to atheroprone low SS displayed inefficient autophagy. In vitro, low SS activated mTOR, inhibited AMPKα and blocked the autophagic flux, thus contributing to the decrease in autophagy.
Interestingly, in ApoE-/- hypercholesterolemic mice, a murine model prone to atherosclerosis development, deficiency in endothelial autophagy led to increased plaque burden in areas usually atheroresistant, highlighting an anti-atherogenic protective effect of high SS-induced autophagy. Both in cultured endothelial cells and in transgenic mice, deficiency in endothelial autophagy was associated with a misalignment of endothelial cells with flow direction under high SS, a hallmark of endothelial cell health. Cultured endothelial cells deficient in autophagy presented a senescent profile under high SS and displayed an enhanced inflammatory response when stimulated with TNFα. In transgenic mice, high SS areas of aortas exhibited increased endothelial senescence and apoptosis, with increased nuclear translocation of their effectors, p16 and p53.
Altogether, these results show that adequate endothelial autophagic flux under high SS limits atherosclerotic plaque formation by preventing inflammation, senescence and apoptosis.

Proc Natl Acad Sci U S A. 2017 Oct 10;114(41):E8675-E8684.

Although it is now clear autophagy that proteins play an essential role in cell-autonomous innate immunity and antigen presentation, their contribution to CD4 T cell differentiation, an essential event that shapes adaptive immune responses, remains to be fully understood. Recently, autophagy has been shown to be required for the survival and stability of regulatory CD4 T cells, which mediate immunosuppression and self-tolerance. In our study, we demonstrate that while autophagy does not impact the differentiation of naïve CD4 T cells into Th1, Th2 and Th17 effector cells in vitro, it markedly represses IL-9 secretion from CD4 T cells cultured in Th9-polarizing conditions. Exploration of the underlying molecular mechanisms revealed that ubiquitination of PU.1, the master transcription factor of Th9 cells, leads to its specific recruitment by the autophagy receptor p62 and its subsequent degradation in autophagosomes. Thus, p62-dependent selective autophagy restrains the differentiation of Th9 cells. Given the potent anticancer functions previously ascribed to Th9 cells by us and others, we evaluated the effect of autophagy inhibition on Th9 cell anticancer properties in vivo. Chloroquine-treated Th9 cells display enhanced suppressive activity against tumor growth upon adoptive transfer than untreated Th9 cells, suggesting that this lysosome inhibitor may be considered in the context of adoptive T-cell therapy of cancer. Furthermore, the T-cell-specific deletion of Atg5 in mice leads to the reduction of tumor growth in an IL-9-dependent manner. Our study reveals a new function for autophagy in modulating Th9 cell differentiation and suggests that autophagy in tumor microenvironment might restrain Th9 cell development and functions. These findings, which lend further support to the anticancer activity of Th9 cells, could be exploited for the design of new anticancer immunotherapies based on autophagy modulation.

Nat Commun. 2017 Sep 15;8(1):559.

Written by Elise Jacquin, Post-doc (

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