Mechanisms and therapeutic implications of hypermutation in gliomas

Abstract

Je tiens à exprimer mes sincères remerciements à :Monsieur le Professeur Éric Deutsch, de m'avoir fait l'honneur de présider cette thèse. Monsieur le Professeur Ahmed Idbaih et Monsieur le Professeur Keith Ligon, d'avoir pris le temps de diriger et encadrer cette thèse. Monsieur le Docteur Franck Bourdeaut, Madame la Professeure Magali Svrcek, et Monsieur le Professeur Alex Duval, d'avoir pris le temps de juger ce travail. Monsieur le Docteur Franck Bielle, et Monsieur le Professeur Marc Sanson, pour leur participation à ces travaux. Une partie importante de ces travaux a été réalisée au Dana-Farber Cancer Institute et je tiens à remercier ici très sincèrement mes collègues de Boston pour leur amitié et leurs efforts déterminants dans l'obtention de ces résultats, en particulier Keith Ligon pour son accueil au sein de son laboratoire, ses conseils et ses encouragements.

New hints towards a precision medicine strategy for IDH wild-type glioblastoma

“…97 Notwithstanding these assumptions, it has yet remained unclear whether high mutational burden may support a superior immune response to immune checkpoint blockade. In an attempt to more accurately characterise the phenotypic and molecular features of hypermutated gliomas, Touat et al 98 recently showed that a low PD-1 blockade response rate was observed within a population of hypermutant gliomas that emerged following TMZ treatment. As such, it would seem that a TMZ-driven hypermutator phenotype does not guarantee an immune response to PD-1 blockade, likely due to the concurrent presence of mismatch repair deficits and the subclonal nature of emergent neo-antigens.…”

Glioblastoma Immune Landscape and the Potential of New Immunotherapies

“…dMMR gliomas are rare ( 65 ), but earlier results from two case reports showed a response to pembrolizumab in one pediatric ( 66 ) and one adult ( 67 ) patients. Despite these promising results, a recent study reported that PD-1 blockade did not impact mOS in hypermutated gliomas, consistent with an observed lack of TILs in these cancers ( 68 ). However, another study reported significant clinical and radiological responses of nivolumab in two young siblings with biallelic mismatch repair deficiency ( 66 ), suggesting that ICI therapy might benefit pediatric GBM with high mutational burden [e.g., with MSH6 mutations ( 69 )].…”

Cell plasticity and genomic instability in cancer evolution

“…Functional analyses that follow could help experimentally link the mutagens and mutations, as well as discover the role of novel resistant mutations in cancer relapse and evolution are sparse. Recently, it was revealed that the TMZ mutational signature can only be generated in MMR-deficient gliomas (Touat et al 2020). Studying the interaction between therapeutic agents and the genetic background here might yield insights into the clonal evolution mechanism, the optimal usage of therapeutic drugs and new therapeutic strategy.…”