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.

Methods to Measure Membrane Potential and Permeability Transition in the Mitochondria During Apoptosis

Abstract: Mitochondrial membrane permeabilization (MMP) constitutes an early event of the apoptotic process. MMP affects both mitochondrial membranes. Inner MMP leads to the dissipation of the inner transmembrane potential and outer MMP culminates in the efflux of apoptogenic factors. The exact molecular mechanisms of MMP are still controversial. A growing body of data suggests that the cell death regulatory activity of Bcl-2 family members depends, at least in some instances, on their ability to modulate the opening of the mitochondrial permeability transition pore complex. Here, we will detail some experimental protocols designed to measure mitochondrial membrane potential and permeability transition, either in intact cells or in isolated mitochondria.

IKK connects autophagy to major stress pathways.

Abstract: Cells respond to stress by activating cytoplasmic mechanisms as well as transcriptional programs that can lead to adaptation or death. Autophagy represents an important cytoprotective response that is regulated by both transcriptional and transcription-independent pathways. NFκB is perhaps the transcription factor most frequently activated by stress, and has been ascribed with either pro- or anti-autophagic functions, depending on the cellular context. Our results demonstrate that activation of the IKK (IκB kinase) complex, which is critical for the stress-elicited activation of NF-κB, is sufficient to promote autophagy independent of NFκB, and that IKK is required for the optimal induction of autophagy by both physiological and pharmacological autophagic triggers.

Entosis, a key player in cancer cell competition

Abstract: Cell-in-cell structures, also referred to as 'entosis', are frequently found in human malignancies, although their prognostic impact remains to be defined. Two articles recently published in Cell Research report the stimulation of entosis by one prominent oncogene, Kras, as well as by one class of tumor suppressors, namely epithelial cadherins E and P, illustrating the complex regulation of this biological process.

Victories and deceptions in tumor immunology: Stimuvax ®

Abstract: The last year closed with negative news for tumor immunology. Stimuvax®, an investigational therapeutic anticancer vaccine that Merck licensed from the US biotech firm Oncothyreon, failed to increase overall survival in a Phase III clinical trial designed to evaluate its efficacy in a cohort of non-small cell lung carcinoma (NSCLC) patients.1 Stimuvax®, also known as L-BLP25 or BLP25, is a liposomal vaccine conceived to generate an immune response against mucin 1 (MUC1), a cell-surface glycosylated phosphoprotein that is frequently overexpressed by epithelial tumors, including NSCLC as well as breast, colorectal and pancreatic carcinomas.2 The failure of this Phase III clinical trial may be attributed to multiple distinct causes. First, it may be an illusion to achieve therapeutic effects with anticancer vaccines in patients affected by advanced tumors without simultaneously employing checkpoint inhibitors (such as anti-CTLA4 or anti-PD1 antibodies)3,4 or without attempting to re-establish immunosurveillance by other manipulations.5,6 Indeed, the progression of neoplastic lesions until an advanced (metastatic) stage is believed to require the subversion of natural anticancer immune responses, either as malignant cells actively inhibit immune effectors or upon the generation of escape variants that are not recognized by the immune system or are resistant to its attack.7 Second, NSCLC may represent a class of tumors that is particularly resistant to all sorts of immunotherapy. Indeed, there are relatively few studies postulating that the intra- or peritumoral infiltration of NSCLC by effector memory T cells would influence patient prognosis.8 In this sense, NSCLC differs from many other tumor types in which the density, composition and architecture of the immune infiltrate does affect the course of disease at both the prognostic and predictive level.8-10 Unfortunately, individuals affected by NSCLC are usually treated with chemotherapeutic regimens based on cisplatin, a platinum derivative that is rather inefficient, as (1) it is often associated with the development of chemoresistance,11 and (2) it induces a non-immunogenic form of cell death.12 Thus, chemotherapeutic regimens against NSCLC cannot be expected to stimulate major anticancer immune responses. Third, Stimuvax® may have been designed in a suboptimal fashion. Indeed, given the propensity of malignant cells to undergo immunoediting and generate escape variants,7 it may be a mistake to conceive vaccines that target one single tumor-associated antigen (TAA) instead of attempting to generate a broader immune response. Along similar lines, the adjuvant employed for Stimuvax® (a monophosphoryl lipid A-based formulation) might have negatively influenced its clinical performance, as adjuvants dictate both the intensity and the type of immune responses to considerable extents.13,14 Fourth, the design of the clinical trial may have been overoptimistic, as NSCLC patients have not been filtered at enrollment based on biomarker-based exclusion criteria. For instance, it might have been worthwhile to monitor MUC1 expression levels on surgical/bioptic material (and to exclude patients bearing MUC1-negative tumors); to determine the general immune status of patients (and to exclude individuals exhibiting low peripheral T lymphocyte counts or high levels of circulating or intratumoral immunosuppressive cells); and/or to evaluate immune responses against MUC1 or other TAAs at baseline (and to exclude patients with poor TAA-specific responses).15 In a press release, the coordinating investigator of the study, Frances Shepherd (University of Toronto, Canada) stated that “notable treatment effects were observed in certain subgroups of patients.” Obviously, such subgroup analyses will not reverse the deception of this trial in its legal aspects (FDA approval is precluded at this stage). However, they may convert this defeat into a long-term victory, provided that additional prospective, carefully designed Phase III trials yield positive results. Hopefully, Merck’s competitor GlaxoSmithKline, which has also launched a clinical study to investigate the efficacy of a therapeutic vaccine against NSCLC, will be more fortunate and learn the lessons exemplified by the Stimuvax® case.

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.