The role of IMMune OSteoclasts in CANcer – Implications for therapy
Primary and secondary bone tumors affect patients from children to elderly. Despite advances in diagnosis and treatment, bone tumors are incurable and thus, new therapies are needed. In the bone microenvironment (ME), cancer cells disrupt the physiological balance between bone forming osteoblasts, bone resorbing osteoclasts (OCs) and immune cells, leading to excessive OC-mediated bone destruction. Beyond resorbing bone, OCs have recently been identified as innate immune cells with subsets prone to immune suppression, which might create a permissive ME for cancer and resistance to immunotherapies. Consistently, our results from single cell RNA deep sequencing (scRNAdSeq) revealed an OC population with low expression of bone resorption genes and high abundance of immune checkpoint molecules. Furthermore, analysis of patient biopsies from bone tumors uncovered abundant OCs distant from bone surface. These cells are unlikely to resorb bone but might have an immunomodulatory role. Based on these findings the hypothesis of IMMOSCAN is that immunosuppressive OCs (IsOCs) create a cancer permissive ME in bone and thus, targeting IsOCs might be a novel therapeutic strategy to limit tumor growth in bone. To address this hypothesis, we aim to i) identify and characterize IsOCs in the bone-cancer ME, ii) determine the origin, function and molecular mechanism of IsOCs and iii) target the IsOCs to improve the efficacy of immunotherapy and control tumor progression. Patient samples will be a base of all aims ensuring clinical relevance. Experimentally, we will use scRNAdSeq and latest bone imaging techniques to characterize OC subpopulations in the bone-cancer ME. Mechanistic insights will be elucidated by cell- and molecular biology and novel therapeutic strategies to target IsOCs will be explored in pre-clinical models. In-depth phenotyping of IsOCs and identification of targetable pathways may allow the suppression of their expansion by innovative immune therapy in bone cancers.
Funded by the European Union under the Horizon Europe Framework Programme - Grant Agreement Nº: 101095654. Views and opinions expressed are however those of the author(s) only and do not necessarily reflect those of the European Union or European Health and Digital Executive Agency (HADEA). Neither the European Union nor the granting authority can be held responsible for them.