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.

BH3 mimetics reveal the network properties of autophagy-regulatory signaling cascades.

Abstract: Beclin 1 usually interacts with several autophagy-inhibitory proteins including the anti-apoptotic proteins from the Bcl-2 family (Bcl-2, Bcl-XL and Mcl-1) and the inositol-1,4,5 trisphosphate (IP3) receptor, which interacts with Beclin 1 indirectly, via Bcl-2. Beclin 1 possesses a BH3 domain that usually interacts with a hydrophobic cleft, the BH3 receptor domain, contained within Bcl-2 and its homologues. Dissociation of this interaction can be induced by phosphorylation or ubiquitination of the BH3 domain, by post-transcriptional modifications affecting the Bcl-2 protein, as well as by other BH3 domain-containing proteins that have a high affinity for Bcl-2 (or its homologues), and hence liberate Beclin 1 from its restraint. As a result, it has been thought that so-called BH3 mimetics, that is the pharmacological agents that occupy the hydrophobic cleft of Bcl-2, Bcl-XL and Mcl-1, would induce autophagy solely by disrupting the interaction between Beclin 1 and its inhibitors. Unexpectedly, we found tha...

Cancer: Antibodies regulate antitumour immunity

Abstract: Boosting the T cells that mediate anticancer immune responses is a therapeutic goal. But T cells do not work alone — B cells and the antibodies they produce can both trigger and suppress the response. See Letters p.94 & p.99 Oxaliplatin, an immunogenic chemotherapeutic, is effective in aggressive prostate cancer, but as with most other known therapeutics, castration-resistant forms of the cancer become refractory to continued treatment. This study shows that IgA plasmocytes promote resistance to oxaliplatin in prostate cancer mouse models by inhibiting immunogenic tumour cell death and through activation of cytotoxic lymphocytes. Immunosuppressive plasma cells are generated in response to TGFβ, and their functionality depends on the expression of programmed death ligand 1 and interleukin 10. Elimination of these IgA plasmocytes, which also infiltrate human-therapy-resistant prostate cancer, allows cytotoxic-T-cell-dependent eradication of oxaliplatin-treated tumours. Cancers generally evade host immune responses yet tumours are not transmissible between individuals, suggesting that the immune system does have the ability to recognize and kill tumour cells. This study of the fate of transplanted allogeneic tumours in mice shows that their rejection is initiated by naturally occurring tumour-binding IgG antibodies. Fcγ-receptor-mediated uptake of tumour immune complexes into dendritic cells activates tumour-reactive T cells, and intra-tumoral injection of allogeneic IgG together with dendritic cell adjuvants induces systemic T-cell-mediated antitumour responses. This work reveals a novel mechanism of tumour rejection that might be exploited clinically.

Apaf-1 Deficiency Causes Chromosomal Instability.

Abstract: Apaf-1 is an essential component of the apoptosome, the molecular complex assembled in response to mitochondrial cytochrome c release that promotes caspase activation. Apaf-1 expression is suppressed in some malignant tumors, in particular melanoma as well as cervical and colorectal carcinoma, in which the loss of Apaf-1 expression marks tumor progression and poor prognosis. Recent results from our laboratory demonstrate that Apaf-1 has an apoptosis-unrelated function that may well account for its role as a tumor suppressor. The knockout of apaf-1 (in mice), the knockdown of Apaf-1 (in human cells) and loss of function mutations of ced-4 (the Caenorhabditis elegans ortholog of Apaf-1) compromise the arrest of DNA synthesis in response to DNA damage, in a context in which apoptosis does not occur. Here, we show that the depletion of Apaf-1 also sensitizes cells to chromosomalinstability induced by different types of DNA damage such as cisplatin, UVC light and γ-irradiation. These results unravel a hi...

Contagious apoptosis facilitated by the HIV-1 envelope: fusion-induced cell-to-cell transmission of a lethal signal.

Abstract: Cells expressing the human immunodeficiency virus (HIV-1) envelope glycoprotein complex (Env) can fuse with CD4+ cells. When the apoptotic pathway is initiated in Env+ cells (`donor cells9), co-culture with a healthy CD4+ fusion partner (`acceptor cells9) results in apoptosis of the syncytium and thus is `contagious9. The cell-to-cell transmission of the lethal signal was only observed when the nuclei from donor cells exhibited pre-apoptotic chromatin condensation (PACC), correlating with comet assay-detectable DNA strand breaks, which precede caspase activation, as well as the loss of the mitochondrial transmembrane potential. Transmission of the lethal signal resulted into mitochondrial alterations, and caspase-dependent nuclear pyknosis with chromatinolysis affecting both the donor and the acceptor nuclei. In the presence of caspase inhibitors, all nuclei of the syncytium formed by fusion of the pre-apoptotic and the healthy cell manifested PACC, exhibited DNA lesions and lost transcriptional activity. Transmission of the lethal signal did not require donor cells to contain a nucleus or mitochondrial DNA, yet was inhibited when two mitochondrion-stabilizing proteins, Bcl-2 or vMIA, were overexpressed. Contagious apoptosis could be induced in primary human T cells, as well as in vivo, in T cells exposed to dying Env-expressing cells. Altogether, these data point to a novel mechanism through which HIV-1 can induce bystander killing.

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.