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Leukemia, radiation induced --- Leukemia, radiation induced

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Résumé

STROMAL CELLS --- IMMUNOLOGY --- STROMAL CELLS --- IMMUNOLOGY

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Malignant Pleural Mesothelioma is an aggressive tumor arising from the pleura. The World Health Organization reported 30,870 new cases and 26,278 deaths in 2020, highlighting the extremely high mortality rate of this malignancy. The overall survival varies from 9 to 15 months depending on the histological subtype, the stage, and the treatment. For more than a decade, a combination of two chemotherapeutic agents (pemetrexed plus cisplatin) was the standard-of-care for malignant pleural mesothelioma. However, the survival remained poor (~12 months). Interestingly, in 2021, the Food and Drug Administration approved a combination of ipilimumab plus nivolumab for the treatment of this cancer, showing the benefit of immunotherapy in this context. The purpose of this present master thesis was the characterization of the immune checkpoint profile of pleural mesothelioma as well as of their immune microenvironment. Bioinformatic analyses, immunohistochemistry, western blot, and syngeneic models were performed/used to correctly characterize and select promising targets for further investigations. Collectively, in this project, we highlighted VISTA, CD200 and CD47 as potential promising targets which could be blocked by inhibitors (e.g. monoclonal antibodies). These data provide strong evidence for further exploring these “second-generation” immune checkpoints as potential novel immunotherapeutic targets in the context of malignant pleural mesothelioma.

Immunotherapy --- Pleural Mesothelioma --- immune checkpoint inhibitors --- Immune microenvironment --- VISTA --- CD47 --- CD200 --- Sciences de la santé humaine > Oncologie

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L’arthrose est la pathologie dégénérative articulaire la plus fréquente. Elle touche à ce jour dix à quinze pour cent de la population adulte mondiale. Cette maladie, par sa prévalence en constante augmentation et l’absence de biomarqueur validé en routine, est classée par l’OMS parmi les pathologies prioritaires.
Précédemment, il a été mis en évidence une expression différentielle de l’ostéomoduline (OMD), une petite protéoglycane riche en leucines (SLRP), entre les ostéoblastes sains et les ostéoblastes dérivés d’os sclérotique en faisant ainsi un candidat biomarqueur pour le diagnostic et le suivi de la maladie.
Le but de ce mémoire était, d’une part, d’étudier, in vitro, les effets de l’OMD sur la capacité de minéralisation d’ostéoblastes dérivés d’os sous-chondral sclérotique et, d’autre part, d’évaluer les effets de la molécule sur le développement de l’arthrose chez la souris.
Il n’a pas été possible de mettre en évidence un effet de l’OMD sur la capacité de minéralisation des ostéoblastes. Cependant, les paramètres de démarche des souris transgéniques n’exprimant pas l’OMD étaient altérés, suggérant la présence de douleur lors de la marche.
Des investigations complémentaires, histologiques, permettront de déterminer si ces altérations sont la conséquence de la dégradation articulaire. Osteoarthritis is the most common degenerative joint disease. It currently affects ten to fifteen per cent of the adult population worldwide. Due to its constantly increasing prevalence and the absence of a validated routine biomarker, this condition is classified by the WHO as a priority disease.
Previously, differential expression of osteomodulin (OMD), a small leucine-rich proteoglycan (SLRP), between healthy and sclerotic bone-derived osteoblasts has been demonstrated, making it a candidate biomarker for the diagnosis and monitoring of the disease.
The aim of this master thesis was to study the effects of OMD on the mineralisation capacity of sclerotic subchondral bone-derived osteoblasts in vitro and to assess the effects of the molecule on the development of osteoarthritis in mice.
It was not possible to demonstrate an effect of OMD on the mineralisation capacity of osteoblasts. However, the gait parameters of transgenic mice not expressing OMD were impaired, suggesting the existence of pain during locomotion.
Further histological examinations will determine whether these alterations are the consequence of joint degradation.

ostéomoduline --- ostéoadhérine --- arthrose --- biomarqueur --- catwalk --- osteoblaste --- protéoglycane --- histologie --- os sous-chondral --- os --- cartilage --- osteomodulin --- osteoadherin --- osteoarthritis --- biomarker --- catwalk --- osteoblast --- proteoglycan --- slrp --- histology --- subchondral bone --- bone --- cartilage --- Sciences de la santé humaine > Rhumatologie