The metabolism of cells regulates their sensitivity to NK cells depending on p53 status

Leukemic cells proliferate faster than non-transformed counterparts. This requires them to change their metabolism to adapt to their high growth. This change can stress cells and facilitate recognition by immune cells such as cytotoxic lymphocytes, which express the activating receptor Natural Killer G2-D (NKG2D). The tumor suppressor gene p53 regulates cell metabolism, but its role in the expression of metabolism-induced ligands, and subsequent recognition by cytotoxic lymphocytes, is unknown. We show here that dichloroacetate (DCA), which induces oxidative phosphorylation (OXPHOS) in tumor cells, induces the expression of such ligands, e.g. MICA/B, ULBP1 and ICAM-I, by a wtp53-dependent mechanism. Mutant or null p53 have the opposite effect. Conversely, DCA sensitizes only wtp53-expressing cells to cytotoxic lymphocytes, i.e. cytotoxic T lymphocytes and NK cells. In xenograft in vivo models, DCA slows down the growth of tumors with low proliferation. Treatment with DCA, monoclonal antibodies and NK cells also decreased tumors with high proliferation. Treatment of patients with DCA, or a biosimilar drug, could be a clinical option to increase the effectiveness of CAR T cell or allogeneic NK cell therapies

Generación de nuevos derivados de macrólidos por glicosilación en Streptomyces

Basándonos en la cierta flexibilidad de sustrato de las glicosiltransferasas (GTFs) de macrólidos se han generado cepas de Streptomyces lividans potencialmente capaces de generar nuevos derivados de macrólidos que presente distintos azúcares unidos a su estructura. Estas cepas se caracterizan por contener integrados en su cromosoma los genes oleG2 y eryBV que codifican GTFs de macrólidos. Dichos genes fueron clonados bajo el control del promotor del gen de resistencia de eritromicina. Las cepas recombinantes fueron transformadas con diferentes plásmidos de azúcares capaces de dirigir la biosíntesis de diferentes deoxiazúcares (DOHs) y posteriormente fueron incubadas en presencia de eritronólido B. Los productos de la biotransformación fueron analizados por TLC, HPLC y HPLC-MS, comprobando que OleG2 transfiere eficientemente los DOHs: L-olivosa y con peor eficiencia L-digitoxosa y L-ramnosa mientras que EryBV fue mucho más flexible transfiriendo con mayor eficiencia los DOHs: L-olivosa, L-digitoxosa y L-rodinosa, además de un D-azúcar, la D-olivosa. Todos estos DOHs fueron transferidos a la posición 3 del eritronólido B y no presentan actividad antibacteriana. Con la finalidad de obtener nuevos compuestos activos, era necesario una segunda glicosilación en posición 5 del aglicón, para ello los extractos obtenidos de la cepa S. lividans conteniendo el gen eryBV fueron empleados en una segunda biotransformación utilizando una cepa mutante de Saccharopolyspora erythraea capaz de dirigir y transferir el D-azúcar, D-desosamina a la posición 5. Como resultado se obtuvieron nuevos derivados de eritromicinas que presentaban diferentes azúcares neutros y con cierta actividad antibiótica ensayada frente Bacillus subtillis

Metabolic stress controls mutant p53 R248Q stability in acute myeloid leukemia cells

Abstract Eliminating mutant p53 (mt p53) protein could be a useful strategy to treat mt p53 tumors and potentially improve the prognosis of cancer patients. In this study, we unveil different mechanisms that eliminate p53-R248Q, one of the most frequent mutants found in human cancers. We show that the Hsp90 inhibitor 17-AAG eliminates R248Q by stimulating macroautophagy under normal growth conditions. Metabolic stress induced by the pyruvate dehydrogenase kinase-1 (PDK1) inhibitor dichloroacetate (DCA) inhibits the macroautophagy pathway. This induces the accumulation of R248Q, which in addition further inhibits macroautophagy. Combination of DCA and 17-AAG further decreases the autophagy flux compared to DCA alone. Despite this, this co-treatment strongly decreases R248Q levels. In this situation of metabolic stress, 17-AAG induces the binding of p53-R248Q to Hsc70 and the activation of Chaperone-Mediated Autophagy (CMA), leading to higher R248Q degradation than in non-stress conditions. Thus, different metabolic contexts induce diverse autophagy mechanisms that degrade p53-R248Q, and under metabolic stress, its degradation is CMA-mediated. Hence, we present different strategies to eliminate this mutant and provide new evidence of the crosstalk between macroautophagy and CMA and their potential use to target mutant p53

From tumor cell metabolism to tumor immune escape.

International audienceTumorigenesis implies adaptation of tumor cells to an adverse environment. First, developing tumors must acquire nutrients to ensure their rapid growth. Second, they must escape the attack from the host immune system. Recent studies suggest that these phenomena could be related and that tumor cell metabolism may propel tumor immune escape. Tumor cell metabolism tends to avoid mitochondrial activity and oxidative phosphorylation (OXPHOS), and largely relies on glycolysis to produce energy. This specific metabolism helps tumor cells to avoid the immune attack from the host by blocking or avoiding the immune attack. By changing their metabolism, tumor cells produce or sequester a variety of amino acids, lipids and chemical compounds that directly alter immune function therefore promoting immune evasion. A second group of metabolism-related modification targets the major histocompatibility complex-I (MHC-I) and related molecules. Tumor MHC-I presents tumor-associated antigens (TAAs) to cytotoxic T-cells (CTLs) and hence, sensitizes cancer cells to the cytolytic actions of the anti-tumor adaptive immune response. Blocking tumor mitochondrial activity decreases expression of MHC-I molecules at the tumor cell surface. And peroxynitrite (PNT), produced by tumor-infiltrating myeloid cells, chemically modifies MHC-I avoiding TAA expression in the plasma membrane. These evidences on the role of tumor cell metabolism on tumor immune escape open the possibility of combining drugs designed to control tumor cell metabolism with new procedures of anti-tumor immunotherapy. This article is part of a Directed Issue entitled: Bioenergetic dysfunction, adaptation and therapy

Dissecting the NK cell population in hematological cancers confirms the presence of tumor cells and their impact on NK population function

International audienceAbstract: The lymphocyte lineage natural killer (NK) cell is part of the innate immune system and protects against pathogens and tumor cells. NK cells are the main cell effectors of the monoclonal antibodies (mAbs) that mediates antibody-dependent cell cytotoxicity (ADCC). Hence it is relevant to understand NK physiology and status to investigate the biological effect of mAbs in the clinic. NK cells are heterogeneous with multiple subsets that may have specific activity against different attacks. The presence of viral-sculpted NK cell populations has already been described, but the presence of cancer-sculpted NK cells remains unknown. Cancer induces a broad NK cell dysfunction, which has not been linked to a specific population. Here we investigated the NK cell population by Uniform Manifold Approximation and Projection (UMAP) embed maps in Hodgkin lymphoma (HL) and acute myeloid leukemia (AML) patients at diagnosis and at least 30 days after treatment, which correlates with tumor cell clearance. We found that the NK lineage largely responded to the tumor by generating antitumor NK cells and renewing the population with a subset of immature NK cells. However, we failed to identify a specific “memory-like” subset with the NK cell markers used. Moreover, in patients in relapse we found essentially the same NK populations as those found at diagnosis, suggesting that NK cells equally respond to the first or second tumor rise. Finally, we observed that previous CMV infection largely affects the tumor-associated changes in NK population, but the CMV-associated CD57+NKG2C+ NK cell population does not appear to play any role in tumor immunity

Chemical Metabolic Inhibitors For The Treatment Of Blood-Borne Cancers.

International audience: Tumor cells, including leukemic cells, remodel their bioenergetic system in favor of aerobic glycolysis. This process is called "the Warburg effect" and offers an attractive pharmacological target to preferentially eliminate malignant cells. In addition, recent results show that metabolic changes can be linked to tumor immune evasion. Mouse models demonstrate the importance of this metabolic remodeling in leukemogenesis. Some leukemias, although treatable, remain incurable and resistance to chemotherapy produces an elevated percentage of relapse in most leukemia cases. Several groups have targeted the specific metabolism of leukemia cells in preclinical and clinical studies to improve the prognosis of these patients, i.e. using L-asparaginase to treat pediatric acute lymphocytic leukemia (ALL). Additional metabolic drugs that are currently being used to treat other diseases or tumors could also be exploited for leukemia, based on preclinical studies. Finally, we discuss the potential use of several metabolic drugs in combination therapies, including immunomodulatory drugs (IMiDs) or immune cell-based therapies, to increase their efficacy and reduce side effects in the treatment of hematological cancers