Aurelie Dutour, PhD, CRI-Chordoma Foundation CLIP Investigator Centre Léon BERARD Chordoma is a very rare bone tumor for which the five-year relapse-free survival rate plateaus at 50%, making chordoma a therapeutic challenge despite aggressive treatment. Given its rarity, the constitution of large chordoma cohorts enabling large scale biological and molecular studies is problematic. Thus, chordoma’s biology, genetic drivers, and molecular alterations are only partially described as well as chordoma’s interactions with the immune tumor microenvironment (IME). Outstanding questions that remain to be addressed regarding chordoma IME are: (1) Where are the immune infiltrate localized in chordoma, what is their composition depending on their location, and what is the activation status of immune pathways of the IME; (2) How does the IME interact with main chordoma signaling pathways; (3) How do targeted and immune-therapies impact the chordoma IME and what are the consequences of these changes on chordoma’s signalling pathways. In the growing era of tailored treatments, it is now urgent to answer these questions by deciphering the chordoma immunome to further adapt therapies to this tumor’s specificities. To answer these questions, the presented project regroup a unique chordoma cohort, gathering untreated chordoma, chordoma from pembrolizumab-treated chordoma (from the Acsé Pembro clinical trial, erlotinib treated chordoma from clinical practice, and regorafenib-treated chordoma from the Regobone trial. This cohort will enable Dr. Dutour to address for the first time the changes in chordoma’s IME in response to therapy. The most complete immune signature of chordomas will be established by using complementary techniques enabling a molecular, proteic, spatial profile of the IME, how it interacts with tumor cells, and the effects of the IME on tumor cells at the molecular level. Integrative analyses of molecular, biological, and clinical data will allow for a whole picture of the chordoma immunone, its interconnections with tumor cells at the molecular level, and will lead to the identification of predictive factors of therapeutic response to targeted and immune-therapies. Dr. Dutour’s comparative approach is necessary to help understand the implications of immune effectors in tumor progression and response and permits the identification of predictive markers and/or targets of interest. Her project will enable the design of future clinical trials in which tailored treatments will be adapted to chordoma specificities. Projects and Grants Deciphering the immune signature of chordoma extreme responders to targeted therapies to move toward tailored therapy of chordoma Centre Léon BERARD | All Cancers | 2022
