Guido Kroemer

Bio: Guido Kroemer is an academic researcher from Institut Gustave Roussy. The author has contributed to research in topics: Programmed cell death & Autophagy. The author has an hindex of 236, co-authored 1404 publications receiving 246571 citations. Previous affiliations of Guido Kroemer include Karolinska Institutet & Spanish National Research Council.

Comprehensive analysis of current approaches to inhibit regulatory T cells in cancer.

Abstract: CD4+CD25+Foxp3+ regulatory T cells (Treg) have emerged as a dominant T cell population inhibiting anti-tumor effector T cells. Initial strategies used for Treg-depletion (cyclophosphamide, anti-CD25 mAb…) also targeted activated T cells, as they share many phenotypic markers. Current, ameliorated approaches to inhibit Treg aim to either block their function or their migration to lymph nodes and the tumor microenvironment. Various drugs originally developed for other therapeutic indications (anti-angiogenic molecules, tyrosine kinase inhibitors,etc) have recently been discovered to inhibit Treg. These approaches are expected to be rapidly translated to clinical applications for therapeutic use in combination with immunomodulators.

Adenine nucleotide translocase: a component of the phylogenetically conserved cell death machinery.

Abstract: Lethal mitochondrial membrane permeabilization has been depicted as the result of two fundamentally distinct processes, namely primary mitochondrial outer membrane permeabilization (MOMP) versus permeability transition (PT) ignited at the level of the mitochondrial inner membrane. MOMP and PT have been connected to apoptosis and necrosis, respectively. Moreover, it has been thought that MOMP was mediated by pro-apoptotic multidomain proteins of the Bcl-2 family (Bax and Bak), which would operate near-to-independently from the permeability transition pore complex (PTPC) composed by voltage-dependent anion channel (VDAC), adenine nucleotide translocase (ANT) and cyclophilin D. A recent paper in Molecular and Cellular Biology now reveals the obligate contribution of one particular ANT isoform to the execution of developmental and homeostatic cell death in Caenorhabditis elegans. The physical and functional interaction between CED-9, the sole multidomain Bcl-2 protein of C. elegans, and ANT emphasizes the existence of an intricate, phylogenetically conserved crosstalk between Bcl-2 family proteins and constituents of the PTPC. In this issue of Cell Death and Differentiation, Malorni et al. further corroborate this notion by showing that type 2 transglutaminase (TG2) is essential for the correct assembly/function of ANT1, and that, at least in some experimental settings, TG2 might be required to enable and/or stabilize the pro-apoptotic association of Bax with ANT1.

Disruption of the hexokinase-VDAC complex for tumor therapy.

Abstract: Unlike mitochondria from most normal tissues, cancer cell mitochondria demonstrate an association between the glycolytic enzyme hexokinase (HK) and the voltage-dependent anion channel (VDAC). This provides a therapeutic opportunity, as the association appears to protect tumor cells from mitochondrial outer membrane permeabilization (MOMP), an event that marks the point of no return in multiple pathways leading to cell death. In this issue of Oncogene, the plant hormone methyl jasmonate (MJ) is shown to disrupt the interaction between human HK and VDAC, causing the inhibition of glycolysis and the induction of MOMP. MJ has already been shown to have selective anticancer activity in preclinical studies, and this finding may stimulate the development of a novel class of small anticancer compounds that inhibit the HK-VDAC interaction.

Inhibition of autophagy by TAB2 and TAB3

Abstract: Autophagic responses are coupled to the activation of the inhibitor of NF-κB kinase (IKK). Here, we report that the essential autophagy mediator Beclin 1 and TGFβ-activated kinase 1 (TAK1)-binding proteins 2 and 3 (TAB2 and TAB3), two upstream activators of the TAK1-IKK signalling axis, constitutively interact with each other via their coiled-coil domains (CCDs). Upon autophagy induction, TAB2 and TAB3 dissociate from Beclin 1 and bind TAK1. Moreover, overexpression of TAB2 and TAB3 suppresses, while their depletion triggers, autophagy. The expression of the C-terminal domain of TAB2 or TAB3 or that of the CCD of Beclin 1 competitively disrupts the interaction between endogenous Beclin 1, TAB2 and TAB3, hence stimulating autophagy through a pathway that requires endogenous Beclin 1, TAK1 and IKK to be optimally efficient. These results point to the existence of an autophagy-stimulatory ‘switch' whereby TAB2 and TAB3 abandon inhibitory interactions with Beclin 1 to engage in a stimulatory liaison with TAK1.

Trial watch: Cardiac glycosides and cancer therapy.

Abstract: Cardiac glycosides (CGs) are natural compounds sharing the ability to operate as potent inhibitors of the plasma membrane Na+/K+-ATPase, hence promoting-via an indirect mechanism-the intracellular accumulation of Ca2+ ions. In cardiomyocytes, increased intracellular Ca2+ concentrations exert prominent positive inotropic effects, that is, they increase myocardial contractility. Owing to this feature, two CGs, namely digoxin and digitoxin, have extensively been used in the past for the treatment of several cardiac conditions, including distinct types of arrhythmia as well as contractility disorders. Nowadays, digoxin is approved by the FDA and indicated for the treatment of congestive heart failure, atrial fibrillation and atrial flutter with rapid ventricular response, whereas the use of digitoxin has been discontinued in several Western countries. Recently, CGs have been suggested to exert potent antineoplastic effects, notably as they appear to increase the immunogenicity of dying cancer cells. In this Trial Watch, we summarize the mechanisms that underpin the unsuspected anticancer potential of CGs and discuss the progress of clinical studies that have evaluated/are evaluating the safety and efficacy of CGs for oncological indications.

疟原虫var基因转换速率变化导致抗原变异[英]／Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A

Abstract: 抗原变异可使得多种致病微生物易于逃避宿主免疫应答。表达在感染红细胞表面的恶性疟原虫红细胞表面蛋白1（PfPMP1）与感染红细胞、内皮细胞、树突状细胞以及胎盘的单个或多个受体作用，在黏附及免疫逃避中起关键的作用。每个单倍体基因组var基因家族编码约60种成员，通过启动转录不同的var基因变异体为抗原变异提供了分子基础。

Apoptosis: A Review of Programmed Cell Death

Abstract: The process of programmed cell death, or apoptosis, is generally characterized by distinct morphological characteristics and energy-dependent biochemical mechanisms. Apoptosis is considered a vital component of various processes including normal cell turnover, proper development and functioning of the immune system, hormone-dependent atrophy, embryonic development and chemical-induced cell death. Inappropriate apoptosis (either too little or too much) is a factor in many human conditions including neurodegenerative diseases, ischemic damage, autoimmune disorders and many types of cancer. The ability to modulate the life or death of a cell is recognized for its immense therapeutic potential. Therefore, research continues to focus on the elucidation and analysis of the cell cycle machinery and signaling pathways that control cell cycle arrest and apoptosis. To that end, the field of apoptosis research has been moving forward at an alarmingly rapid rate. Although many of the key apoptotic proteins have been identified, the molecular mechanisms of action or inaction of these proteins remain to be elucidated. The goal of this review is to provide a general overview of current knowledge on the process of apoptosis including morphology, biochemistry, the role of apoptosis in health and disease, detection methods, as well as a discussion of potential alternative forms of apoptosis.

The blockade of immune checkpoints in cancer immunotherapy

Abstract: Immune checkpoints refer to the plethora of inhibitory pathways that are crucial to maintaining self-tolerance. Tumour cells induce immune checkpoints to evade immunosurveillance. This Review discusses the progress in targeting immune checkpoints, the considerations for combinatorial therapy and the potential for additional immune-checkpoint targets.