WP4 - Biomarkers of PNS tumors
B. Dubois (PhD, CLB, UMR Inserm1052/CNRS 5286)
V. Desestret (MD, PhD, UMR MeLis/Inserm U1314/CNRS 5284)
Autoantibodies (Abs) are highly specific biomarkers of PNS and AE. However, the role of these Abs in the mechanisms of the disease may vary according to the localization of the identified antigen. In these paraneoplastic diseases, T cells are supposed to be the main immune effectors of the brain immune attack. However, the antigens recognized by these T cells are unknown as well as the mechanisms leading to their activation in the tumors. Moreover, we cannot exclude the involvement of others Abs not yet identified and maybe directly reflecting the anti-tumor immune response triggering the PNS.
Our preliminary data showed that tumor cells from patients with PNS may drive the auto-immune reaction by specific tumor cell genetic alterations leading to the creation of neoepitopes in onconeural antigens.
The purpose of this WP is to characterize these tumor genetic alterations and microenvironment to identify mechanisms of tolerance breakdown, characteristics of the pathogenic immune response and new onconeural antigens.
Task 4.1: Characterization of PNS tumor molecular alterations
Objective: Use several approaches (CGH, RNAseq, whole-exome analysis, transcriptomic NGS) to identify in other PNS associated tumors the molecular tumor cell abnormalities leading to immune reaction.
Task 4.2: Characterization of the immune response in PNS tumors
Objective: Characterize the cellular and humoral arms of adaptive immunity, which, alone or together, can contribute to the autoimmune brain disorders, and to compare this immune reaction in different kinds of PNS-tumors.
Task 4.3: Characterization of new neoantigens in PNS tumors
Objective: Identify putative Neo-Ag that will be used to identify new Abs associated to PNS and specific T/B cells responses in order to determine the immune triggers for the different autoantibody targets that could explain PNS.
Task 4.4: Profiling of Abs reactivity in fresh PNS-tumors to identify new onconeural Ag
Objectif: Screen the Ag specificities of Abs produced within the tumor microenvironment in order to identify potential new onconeural Ag in PNS.
Task 4.5: Characterization of the clonal diversity of immune cells in PNS tumors
Objectif: Better understand the immune response in PNS and characterize some specificities that could be used to develop animal models.