Altered metabolism and functions of Natural Killer cells in acute myeloid leukemia : role of the IL-15 signaling

Les cellules Natural Killer (NK) sont des effecteurs immuns anti-leucémiques. Toutefois, elles sont altérées chez les patients atteints de la leucémie aigüe myéloïde (LAM). Ceci entraîne une réduction de leurs fonctions anti-tumorales et un mauvais pronostique chez les patients. Jusqu’à présent, les mécanismes responsables des altérations des cellules NK dans la LAM demeurent peu connus. L'objectif de ma thèse est d'étudier ces mécanismes dans des modèles murins de leucémie récapitulant les principales caractéristiques de la LAM humaine. Nous avons montré qu’au début du développement leucémique, les cellules NK s’enrichissent à proximité des amas de cellules de la LAM dans la moelle osseuse. Les cellules NK baignent ainsi dans un microenvironnement leucémique riche en cytokines proinflammatoires, ce qui induit l’activation persistante des voies de signalisation cytokinique, et au moins en partie de la voie IL-15. Ceci entraîne, in fine, l’épuisement des cellules NK révélé par une hyporéponse à la stimulation par l’IL-15 et une réduction de leurs capacités métaboliques et fonctionnelles. De plus, nous avons montré que les cellules NK du microenvironnement leucémique sont également inhibées par la cytokine immunosuppressive TGF-β. Toutefois, il n'y avait aucune évidence de l'implication de cette cytokine dans les altérations des cellules NK dans la LAM. En somme, mes travaux de thèse contribuent à la compréhension de l’effet du développement leucémique sur la biologie des cellules NK et pourraient servir de base pour des études ultérieures visant à restaurer le potentiel des cellules NK pour le traitement de la LAM.Natural Killer (NK) cells are potent anti-leukemic immune effector cells. However, they are altered in patients with Acute Myeloid Leukemia (AML). These alterations lead to reduced anti-tumor functions and poor clinical outcomes in AML patients. The mechanisms underlying the defects of NK cells in AML remain poorly understood. The objective of my thesis is to investigate these mechanisms in mouse models of AML recapitulating the major characteristics of the human pathology. At early stages of AML development, we showed that NK cells are enriched near to the clusters of leukemic cells in the bone marrow. Hence, NK cells bath in a microenvironment filled with pro-inflammatory cytokines, which induces persistent activation of the cytokine signaling pathways, and at least in part the IL-15 pathway. This leads, in fine, to the exhaustion of NK cells revealed by a hyporesponse to the stimulation with IL-15 and a reduction of their metabolic and functional capacities. Moreover, we showed that NK cells of leukemic microenvironment are also inhibited by the immunosuppressive cytokine TGF-β. However, there was no evidence of the implication of this cytokine in the alterations of NK cell in AML. To conclude, our study contributes to the understanding of the effect of AML development on the biology of NK cells and can serve as a basis for future studies aimed at restoring the potential of NK cells for the treatment of leukemic patients

Vitamin D Controls Tumor Growth and CD8+ T Cell Infiltration in Breast Cancer

International audienceWomen with low levels of vitamin D have a higher risk of developing breast cancer. Numerous studies associated the presence of a CD8+ T cell infiltration with a good prognosis. As vitamin D may play a key role in the modulation of the immune system, the objective of this work was to evaluate the impact of vitamin D on the breast cancer progression and mammary tumor microenvironment. We show that vitamin D decreases breast cancer tumor growth. Immunomonitoring of the different immune subsets in dissociated tumors revealed an increase in tumor infiltrating CD8+ T cells in the vitamin D-treated group. Interestingly, these CD8+ T cells exhibited a more active T cell (TEM/CM) phenotype. However, in high-fat diet conditions, we observed an opposite effect of vitamin D on breast cancer tumor growth, associated with a reduction of CD8+ T cell infiltration. Our data show that vitamin D is able to modulate breast cancer tumor growth and inflammation in the tumor microenvironment in vivo. Unexpectedly, this effect is reversed in high-fat diet conditions, revealing the importance of diet on tumor growth. We believe that supplementation with vitamin D can in certain conditions represent a new adjuvant in the treatment of breast cancers

Chronic IL-15 Stimulation and Impaired mTOR Signaling and Metabolism in Natural Killer Cells During Acute Myeloid Leukemia

International audienceNatural Killer (NK) cells are potent anti-leukemic immune effectors. However, they display multiple defects in acute myeloid leukemia (AML) patients leading to reduced anti-tumor potential. Our limited understanding of the mechanisms underlying these defects hampers the development of strategies to restore NK cell potential. Here, we have used a mouse model of AML to gain insight into these mechanisms. We found that leukemia progression resulted in NK cell maturation defects and functional alterations. Next, we assessed NK cell cytokine signaling governing their behavior. We showed that NK cells from leukemic mice exhibit constitutive IL-15/mTOR signaling and type I IFN signaling. However, these cells failed to respond to IL-15 stimulation in vitro as illustrated by reduced activation of the mTOR pathway. Moreover, our data suggest that mTOR-mediated metabolic responses were reduced in NK cells from AML-bearing mice. Noteworthy, the reduction of mTOR-mediated activation of NK cells during AML development partially rescued NK cell metabolic and functional defects. Altogether, our data strongly suggest that NK cells from leukemic mice are metabolically and functionally exhausted as a result of a chronic cytokine activation, at least partially IL-15/mTOR signaling. NK cells from AML patients also displayed reduced IL-2/15Rβ expression and showed cues of reduced metabolic response to IL-15 stimulation in vitro , suggesting that a similar mechanism might occur in AML patients. Our study pinpoints the dysregulation of cytokine stimulation pathways as a new mechanism leading to NK cell defects in AML

Downregulation of stromal syntenin sustains AML development

Abstract The crosstalk between cancer and stromal cells plays a critical role in tumor progression. Syntenin is a small scaffold protein involved in the regulation of intercellular communication that is emerging as a target for cancer therapy. Here, we show that certain aggressive forms of acute myeloid leukemia (AML) reduce the expression of syntenin in bone marrow stromal cells (BMSC). Stromal syntenin deficiency, in turn, generates a pro‐tumoral microenvironment. From serial transplantations in mice and co‐culture experiments, we conclude that syntenin‐deficient BMSC stimulate AML aggressiveness by promoting AML cell survival and protein synthesis. This pro‐tumoral activity is supported by increased expression of endoglin, a classical marker of BMSC, which in trans stimulates AML translational activity. In short, our study reveals a vicious signaling loop potentially at the heart of AML–stroma crosstalk and unsuspected tumor‐suppressive effects of syntenin that need to be considered during systemic targeting of syntenin in cancer therapy