Head and Neck: Paraganglioma: an overview

Review on Head and Neck paragangliomas, with data on clinics, and the genes involved

Early T Cell Signalling Is Reversibly Altered in PD-1+ T Lymphocytes Infiltrating Human Tumors

To improve cancer immunotherapy, a better understanding of the weak efficiency of tumor-infiltrating T lymphocytes (TIL) is necessary. We have analyzed the functional state of human TIL immediately after resection of three types of tumors (NSCLC, melanoma and RCC). Several signalling pathways (calcium, phosphorylation of ERK and Akt) and cytokine secretion are affected to different extents in TIL, and show a partial spontaneous recovery within a few hours in culture. The global result is an anergy that is quite distinct from clonal anergy induced in vitro, and closer to adaptive tolerance in mice. PD-1 (programmed death -1) is systematically expressed by TIL and may contribute to their anergy by its mere expression, and not only when it interacts with its ligands PD-L1 or PD-L2, which are not expressed by every tumor. Indeed, the TCR-induced calcium and ERK responses were reduced in peripheral blood T cells transfected with PD-1. Inhibition by sodium stibogluconate of the SHP-1 and SHP-2 phosphatases that associate with several inhibitory receptors including PD-1, relieves part of the anergy apparent in TIL or in PD-1-transfected T cells. This work highlights some of the molecular modifications contributing to functional defects of human TIL

Vaccination-based immunotherapy to target profibrotic cells in liver and lung

Fibrosis is the final path of nearly every form of chronic disease, regardless of the pathogenesis. Upon chronic injury, activated, fibrogenic fibroblasts deposit excess extracellular matrix, and severe tissue fibrosis can occur in virtually any organ. However, antifibrotic therapies that target fibrogenic cells, while sparing homeostatic fibroblasts in healthy tissues, are limited. We tested whether specific immunization against endogenous proteins, strongly expressed in fibrogenic cells but highly restricted in quiescent fibroblasts, can elicit an antigen-specific cytotoxic T cell response to ameliorate organ fibrosis. In silico epitope prediction revealed that activation of the genes Adam12 and Gli1 in profibrotic cells and the resulting “self-peptides” can be exploited for T cell vaccines to ablate fibrogenic cells. We demonstrate the efficacy of a vaccination approach to mount CD8+ T cell responses that reduce fibroblasts and fibrosis in the liver and lungs in mice. These results provide proof of principle for vaccination-based immunotherapies to treat fibrosis

The Warburg Effect Is Genetically Determined in Inherited Pheochromocytomas

The Warburg effect describes how cancer cells down-regulate their aerobic respiration and preferentially use glycolysis to generate energy. To evaluate the link between hypoxia and Warburg effect, we studied mitochondrial electron transport, angiogenesis and glycolysis in pheochromocytomas induced by germ-line mutations in VHL, RET, NF1 and SDH genes. SDH and VHL gene mutations have been shown to lead to the activation of hypoxic response, even in normoxic conditions, a process now referred to as pseudohypoxia. We observed a decrease in electron transport protein expression and activity, associated with increased angiogenesis in SDH- and VHL-related, pseudohypoxic tumors, while stimulation of glycolysis was solely observed in VHL tumors. Moreover, microarray analyses revealed that expression of genes involved in these metabolic pathways is an efficient tool for classification of pheochromocytomas in accordance with the predisposition gene mutated. Our data suggest an unexpected association between pseudohypoxia and loss of p53, which leads to a distinct Warburg effect in VHL-related pheochromocytomas

Un numéro thématique sur l’immuno-oncologie

International audienceLe but de ce numéro thématique des Annales de Pathologie est de sensibiliser notre communauté à cette nouvelle discipline, séduisante dans son concept et dans les résultats qu’elle obtient. Pour ce faire, nous vous proposons quelques articles de synthèse sur l’immuno-oncologie, ses principes et une approche par organe, illustrant les stratégies d’aujourd’hui et de demain ainsi que les challenges que nous devrons relever. Cela va entraîner inévitablement quelques superpositions entre les domaines couverts, mais qui sont le reflet de la transversalité de cette discipline, et qui permettront au lecteur d’aborder ce numéro thématique en toute liberté, en retrouvant les prérequis de l’immuno-oncologie à chaque article. La morphologie sera-t-elle oubliée dans ce grand débat? Certainement pas ! L’histoire rebondit et gageons que les nouvelles approches en oncologie permettront d’isoler de nouvelles entités en pathologie… ou inversement. N’oublions pas que Jeremy Jass, pathologiste anglais, avait il y a déjà 30 ans, souligné l’importance de l’infiltrat immun dans les cancers colorectaux [1]. L’histoire n’est qu’un éternel recommencement

La pathologie augmentée, futur ou présent ?

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Juvenile onset recurrent respiratory papillomatosis: What do we know in 2024 ?

International audienceJuvenile onset recurrent respiratory papillomatosis is a lifelong benign squamous lesion associated with HPV infection, particularly HPV6 and HPV11 genotypes. These lesions are rare, but can lead to laryngeal obturations, which can cause disabling dyspnea, or transform into squamous cell carcinoma. The aim here is to provide an epidemiological, biological and clinical overview of this pathology, particularly in children, in order to understand the issues at stake in terms of research and the development of medical and therapeutic management tools

Analyse de l'infiltration des carcinomes épidermoïdes des VADS associés ou non à HPV par des sous populations de lymphocytes T régulateurs et anergiques

PARIS-BIUP (751062107) / SudocSudocFranceF

Hypothesis of a CD137/Eomes activating axis for effector T cells in HPV oropharyngeal cancers

International audienceChronic Human Papilloma Virus (HPV) infection is supplanting alcohol and tobacco intoxications as the leading cause of oropharyngeal cancer in developed countries. HPV-related squamous cell carcinomas of the oropharynx (HPV + OSC) present better survival and respond better to radiotherapy and chemotherapy. Regulatory T cells (T REG ) are mainly described as immunosuppressive and protumoral in most solid cancers. However, T REG are paradoxically associated with a better prognosis in HPV + OSCs. The transcription factor FoxP3 is the basis for the identification of T REG . Among CD4 + FoxP3 + T cells, some have effector functions. A medical hypothesis is formulated here: the existence of a CD137 (4.1BB)-Eomesodermin (Eomes) activated pathway downstream of TCR-specific activation in a subpopulation of CD4 + FoxP3 + T cells may explain this effector function. Evidence suggest that this axis may exist either in CD4 + FoxP3 + T cells or CD8 + T cells. This pathway could lead T cells to strong antitumor cytotoxic activity in a tumor-specific manner. Furthermore, CD137 is one of the most expected targets for the development of agonist immunotherapies. The identification of CD137 + Eomes + FoxP3+/- T cells could be a key element in the selective activation of the most anti-tumor cells in the HPV + OSC microenvironment