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.

Synthetic induction of immunogenic cell death by genetic stimulation of endoplasmic reticulum stress

Abstract: Cis-diamminedichloridoplatinum(II) (CDDP), commonly referred to as cisplatin, is a chemotherapeutic drug used for the treatment of a wide range of solid cancers. CDDP is a relatively poor inducer of immunogenic cell death (ICD), a cell death modality that converts dying cells into a tumor vaccine, stimulating an immune response against residual cancer cells that permits long-lasting immunity and a corresponding reduction in tumor growth. The incapacity of CDDP to trigger ICD is at least partially due to its failure to stimulate the premortem endoplasmic reticulum (ER)-stress response required for the externalization of the "eat-me" signal calreticulin (CRT) on the surface of dying cancer cells. Here, we developed a murine cancer cell line genetically modified to express the ER resident protein reticulon-1c (Rtn-1c) by virtue of tetracycline induction and showed that enforced Rtn-1c expression combined with CDDP treatment promoted CRT externalization to the surface of cancer cells. In contrast to single agent treatments, the tetracycline-mediated Rtn-1c induction combined with CDDP chemotherapy stimulated ICD as measured by the capacity of dying tumor cells, inoculated into syngenic immunocompetent mice, to mount an immune response to tumor re-challenge 1 week later. More importantly, established tumors, forced to constitutively express Rtn-1c in vivo by continuous treatment with tetracycline, became responsive to CDDP and exhibited a corresponding reduction in the rate of tumor growth. The combined therapeutic effects of Rtn-1c induction with CDDP treatment was only detected in the context of an intact immune system and not in nu/nu mice lacking thymus-dependent T lymphocytes. Altogether, these results indicate that the artificial or "synthetic" induction of immunogenic cell death by genetic manipulation of the ER-stress response can improve the efficacy of chemotherapy with CDDP by stimulating anticancer immunity.

Glucocorticoid-regulated gene expression in the immune system. Analysis of glucocorticoid-regulated transcripts from the mouse macrophage-like cell line P388D1.

Abstract: To further elucidate the molecular mechanisms underlying glucocorticoid-mediated immune suppression, we have exploited cDNA cloning and subtractive screening methods to identify glucocorticoid-regulated transcripts in the mouse macrophage-like cell line, P388D1. Two of the three isolated glucocorticoid-regulated mRNA species corresponded to genes potentially important to immunoregulation: one glucocorticoid-suppressed mRNA species probably encoded the previously uncloned 3-hydroxy-3-methylglutaryl coenzyme A reductase, an enzyme that appears important for in vitro immune responses. The other mRNA species showed glucocorticoid-increased mRNA steady-state levels and was transcribed from an endogenous ecotropic type C retroviral locus. This transcript gives rise to a protein (transmembrane retroviral protein, formerly p15E), which, along with its feline and human homologs, has been implicated in immunosuppression caused by mouse, cat, and human retroviruses. Our results raise the possibility that the immunosuppressive activity of glucocorticoids might be mediated, in part, by regulating the expression of the above immunoregulatory proteins.

The mitochondriotoxic domain of Vpr determines HIV-1 virulence.

Abstract: Most patients infected with HIV-1 develop AIDS unless they receive antiretroviral medication. However, a small number of HIV-infected individuals with high viral titers remain disease free and do not experience progressive immunosuppression, even in the absence of therapy. Such individuals are labeled long-term nonprogressors (LTNPs) and are characterized by a series of laboratory parameters that are usually compromised in HIV-1 carriers who ultimately develop AIDS. In particular, LTNPs possess a high frequency of peripheral CD4plus; T cells, as well as a low level of spontaneous apoptosis, correlating with a normal mitochondrial transmembrane potential (Δψm) among circulating T cells. It has long been assumed that, as an experimentum naturae, LTNPs might furnish valuable clues for the identification of molecular determinants of HIV-1 pathogenesis. A study by Badley and colleagues involving LTNPs, reported in this issue of the JCI (1), strongly suggests that viral protein R (Vpr) is a major HIV-1 virulence factor.

Autophagy and innate immunity ally against bacterial invasion

Abstract: In this feature of a paper recently published in Science from the Dikic laboratory, phosphorylation of the autophagy receptor optineuron by TBK1 leads to selective clearance of ubiquitin-coated cytosolic Salmonella enterica. The work thus implicates phosphorylation of autophagy receptors as a general mechanism for regulation of cargo-selective autophagy.

Karyotypic Aberrations in Oncogenesis and Cancer Therapy

Abstract: The propagation of whole-chromosome (aneuploid) or whole-genome (polyploid) defects is normally prevented by robust cell-intrinsic mechanisms. Moreover, non-diploid cells are under strict immunological surveillance. Nonetheless, tumors contain a high percentage of non-diploid genomes, indicating that malignant cells acquire the ability to bypass these control mechanisms and obtain a survival/proliferation benefit from bulky karyotypic defects. The non-diploid state imposes a significant metabolic burden on cancer cells and hence can be selectively targeted for therapeutic purposes. Here we discuss the impact of abnormal karyotypes on oncogenesis, tumor progression, and response to treatment, focusing on the biochemical and metabolic liabilities of non-diploid cells that can be harnessed for the development of novel chemo(immuno)therapeutic regimens against cancer.

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.