Dual Relief of T-lymphocyte Proliferation and Effector Function Underlies Response to PD-1 Blockade in Epithelial Malignancies

Although understanding of T-cell exhaustion is widely based on mouse models, its analysis in patients with cancer could provide clues indicating tumor sensitivity to immune checkpoint blockade (ICB). Data suggest a role for costimulatory pathways, particularly CD28, in exhausted T-cell responsiveness to PD-1/PD-L1 blockade. Here, we used single-cell transcriptomic, phenotypic, and functional approaches to dissect the relation between CD8+ T-cell exhaustion, CD28 costimulation, and tumor specificity in head and neck, cervical, and ovarian cancers. We found that memory tumor–specific CD8+ T cells, but not bystander cells, sequentially express immune checkpoints once they infiltrate tumors, leading, in situ, to a functionally exhausted population. Exhausted T cells were nonetheless endowed with effector and tumor residency potential but exhibited loss of the costimulatory receptor CD28 in comparison with their circulating memory counterparts. Accordingly, PD-1 inhibition improved proliferation of circulating tumor–specific CD8+ T cells and reversed functional exhaustion of specific T cells at tumor sites. In agreement with their tumor specificity, high infiltration of tumors by exhausted cells was predictive of response to therapy and survival in ICB-treated patients with head and neck cancer. Our results showed that PD-1 blockade–mediated proliferation/reinvigoration of circulating memory T cells and local reversion of exhaustion occur concurrently to control tumors

Cure de cystocèle avec implant de renforcement prothétique par voie vaginale enquête de qualité de vie et de sexualité

Il s'agit d'une étude rétrospective sur 112 patientes évaluant la mise en place de prothèse non résorbable dans la cure de cystocèle par voie vaginale. L'impact sur la qualité de vie et la sexualité des femmes a été l'objet d'une enquête grâce aux questionnaires spécifiques et validés en français : le Pelvic Floor Distress Inventory (PFDI-20)'le Pelvic Floor Impact Questionnaire (PFIQ-7)'et le Prolapse and Incontinence Sexual Function Questionnaire (PISQ-12). Les résultats de l'étude ont montré un faible taux de récidive et de complications'une amélioration globale de la qualité de vie des femmes et'dans une moindre mesure'de leur sexualité. Ces résultats sont encourageants'en accord avec les données récentes de la littérature'mais nécessitent la mise en place d'une étude prospective pour poursuivre l'évaluation de cette technique chirurgicale'tant d'un point de vue anatomique que fonctionnel.TOULOUSE3-BU Santé-Centrale (315552105) / SudocSudocFranceF

Hystérectomies pour pathologies utérines bénignes (comparaison entre les voies d'abord abdominale et vaginale)

TOULOUSE3-BU Santé-Centrale (315552105) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Vaginal Evisceration: An Unexpected Complication of Conization

Background. Large loop excision of the transformation zone (LLETZ) is routinely performed for the management of high grade intracervical neoplasia (CIN). Several uncommon complications have been described, including postoperative peritonitis, pseudoaneurysm of uterine artery, and bowel fistula. We report a unique case of postoperative vaginal evisceration and the subsequent management. Case. A 73-years-old woman underwent LLETZ for high grade CIN. On postoperative day 3, she was admitted for small bowel evisceration through the vagina. Surgical management was based on combined laparoscopic and transvaginal approach and consisted in bowel inspection and reinstatement, peritoneal washing, and dehiscence repair. Conclusions. Vaginal evisceration is a rare but potentially serious complication of pelvic surgery. This case report is to make clinicians aware of such complication following LLETZ and its management

Usutu Virus Infects Human Placental Explants and Induces Congenital Defects in Mice

International audienceUsutu virus (USUV) is a neurotropic mosquito-borne flavivirus that has dispersed quickly in Europe these past years. This arbovirus mainly follows an enzootic cycle involving mosquitoes and birds, but can also infect other mammals, causing notably sporadic cases in humans. Although it is mainly asymptomatic or responsible for mild clinical symptoms, USUV has been associated with neurological disorders, such as encephalitis and meningoencephalitis, highlighting the potential health threat of this virus. Among the different transmission routes described for other flaviviruses, the capacity for some of them to be transmitted vertically has been demonstrated, notably for Zika virus or West Nile virus, which are closely related to USUV. To evaluate the ability of USUV to replicate in the placenta and gain access to the fetus, we combined the use of several trophoblast model cell lines, ex vivo human placental explant cultures from first and third trimester of pregnancy, and in vivo USUV-infected pregnant mice. Our data demonstrate that human placental cells and tissues are permissive to USUV replication, and suggest that viral transmission can occur in mice during gestation. Hence, our observations suggest that USUV could be efficiently transmitted by the vertical route

Human Cytomegalovirus Modifies Placental Small Extracellular Vesicle Composition to Enhance Infection of Fetal Neural Cells In Vitro

International audienceAlthough placental small extracellular vesicles (sEVs) are extensively studied in the context of pregnancy, little is known about their role during viral congenital infection, especially at the beginning of pregnancy. In this study, we examined the consequences of human cytomegalovirus (hCMV) infection on sEVs production, composition, and function using an immortalized human cytotrophoblast cell line derived from first trimester placenta. By combining complementary approaches of biochemistry, electron microscopy, and quantitative proteomic analysis, we showed that hCMV infection increases the yield of sEVs produced by cytotrophoblasts and modifies their protein content towards a potential proviral phenotype. We further demonstrate that sEVs secreted by hCMV-infected cytotrophoblasts potentiate infection in naive recipient cells of fetal origin, including human neural stem cells. Importantly, these functional consequences are also observed with sEVs prepared from an ex vivo model of infected histocultures from early placenta. Based on these findings, we propose that placental sEVs could be important actors favoring viral dissemination to the fetal brain during hCMV congenital infection

Human Cytomegalovirus Infection Changes the Pattern of Surface Markers of Small Extracellular Vesicles Isolated From First Trimester Placental Long-Term Histocultures

International audienceExtracellular vesicles (EVs) have increasingly been recognized as key players in a wide variety of physiological and pathological contexts, including during pregnancy. Notably, EVs appear both as possible biomarkers and as mediators involved in the communication of the placenta with the maternal and fetal sides. A better understanding of the physiological and pathological roles of EVs strongly depends on the development of adequate and reliable study models, specifically at the beginning of pregnancy where many adverse pregnancy outcomes have their origin. In this study, we describe the isolation of small EVs from a histoculture model of first trimester placental explants in normal conditions as well as upon infection by human cytomegalovirus. Using bead-based multiplex cytometry and electron microscopy combined with biochemical approaches, we characterized these small EVs and defined their associated markers and ultrastructure. We observed that infection led to changes in the expression level of several surface markers, without affecting the secretion and integrity of small EVs. Our findings lay the foundation for studying the functional role of EVs during early pregnancy, along with the identification of new predictive biomarkers for the severity and outcome of this congenital infection, which are still sorely lacking