Biology subjects

Gros, A.

Publications and source records attributed to Gros, A..

3 recordsLinked to original sources

bioRxiv2022

Driver mutations in GNAQ and GNA11 genes as potential targets for precision immunotherapy in uveal melanoma patients

Uveal melanoma (UM) is the most common ocular malignancy in adults. Nearly 95% of UM patients carry the mutually exclusive mutations in the homologous genes GNAQ (aminoacid change Q209L/Q209P) and GNA11 (aminoacid change Q209L). UM is located in an immunosuppressed organ and do not suffer immunoediting. Therefore, we hypothesize that driver mutations in GNAQ/11 genes could be recognized by the immune system. Genomic and transcriptomic data for primary uveal tumors was collected from TCGA-UM dataset (n=80). The immunogenic potential for GNAQ/GNA11 Q209L/Q209P mutations was assessed using a variety of tools and HLA types information. The immune microenvironment was characterized using gene expression data. All prediction tools showed stronger GNAQ/11 Q209L binding to HLA. The immunogenicity analysis revealed that Q209L is likely to be presented by more than 73% of individuals in 1000G database whereas Q209P is only predicted to be presented in 24% of individuals. GNAQ/11 Q209L showed higher likelihood to be presented by HLA-I molecules than almost all driver mutations analyzed. Samples carrying Q209L had a higher immune-reactive phenotype: (i) expression of antigen presenting genes HLA-A (p=0.009) and B2M (p=0.043); (ii) immunophenoscore (p=0.008); (iii) infiltration of immune system cells NK (p=0.002) and CD8+ T lymphocytes (p=0.02). Results suggest a high potential immunogenicity of the GNAQ/11 Q209L variant that could allow the generation of novel therapeutic tools to treat UM like neoantigen vaccinations.

genomics↗

bioRxiv2022

Distinct brain networks for remote episodic memory depending on content and emotional value

The mechanisms that underlie the storage of old nontraumatic episodic memories remain enigmatic because of the difficulty in modelling this particular type of memory in humans and animals. Episodic memories combine incidental and occasional "What-Where-When/In which context" multisensory information and can be stored for long periods of time. Here, using a task in rodents that models human episodic memory, including odour/place/context components, we applied advanced behavioural and computational analyses and brain imaging of c-Fos and Zif268 to characterize remote episodic memories and their engrams for the first time. We show that the content and accuracy of memories vary across individuals and depend on the emotional relationship with odours experienced during episodes. Activated brain networks reflect the nature and content of remote episodic memories and their transformation over time, and emotional cortico-hippocampal networks play critical roles in maintaining vivid memories.

neuroscience↗

bioRxiv2022

Induction of senescence renders cancer cells highly immunogenic

Cellular senescence is a stress response that activates innate immunity. However, the interplay between senescent cells and the adaptive immune system remains largely unexplored. Here, we show that senescent cells display enhanced MHC class I (MHC-I) antigen processing and presentation. Immunization of mice with senescent syngeneic fibroblasts generates CD8 T cells reactive against both normal and senescent fibroblasts, some of them targeting senescence-associated MHC-I-peptides. In the context of cancer, we demonstrate that senescent cancer cells trigger strong anti-tumor protection mediated by antigen-presenting cells and CD8 T cells. This response is superior to the protection elicited by cells undergoing immunogenic cell death. Finally, induction of senescence in patient-derived cancer cells exacerbates the activation of autologous tumor-reactive CD8 tumor-infiltrating lymphocytes (TILs) with no effect on non-reactive TILs. Our study indicates that immunization with senescent cancer cells strongly activates anti-tumor immunity, and this can be exploited for cancer therapy. STATEMENT OF SIGNIFICANCEOur study shows that senescent cells are endowed with a high immunogenic potential, superior to the gold standard of immunogenic cell death. The induction of senescence in cancer cells can be exploited to develop efficient and protective CD8-dependent anti-tumor immune responses.

cancer biology↗