New therapeutic approaches in sarcoma: Immunomodulation and tumor microenvironment

High‐grade sarcomas are a heterogeneous group of aggressive tumors arising in bone and soft tissues. They are usually treated with surgery combined in some cases with chemotherapy. Drugs active in osteosarcoma include adriamycin (ADM), cisplatin (CDDP), ifosfamide (IFO) and methotrexate (MTX), while ADM and IFO represent standard chemotherapy for synovial sarcomas. The survival of sarcomas has minimally improved in the past decades, and after relapse treatment options are limited. Tumors grow within an intricate network of epithelial cells, vascular and lymphatic vessels, cytokines, chemokines and infiltrating immune cells. T‐ lymphocyte and antigen‐presenting cells (APCs) interactions are bi‐directional and mediated by ligands such as programmed cell death ligand 1 (PD‐L1) on APCs and PD1 on lymphocytes. PD‐L1 is expressed also by several tumors. PD‐1 inhibitors such as pembrolizumab or nivolumab have been approved for many tumors and PD‐L1 expression on tumoral cells has been associated with response in some of the studies. However, few data on the prognostic and predictive role of infiltrating immune cells and PD‐1/PD‐L1 system in sarcoma are available. Stromal cells present in the tumor microenvironment express high levels of CXCL12 protein, directly stimulating proliferation and migration of CXCR4‐expressing cancer cells. CXCR4/CXCL12 signalling therefore is an attractive therapeutic target in cancer, since CXCR4 inhibition might sensitize cancer cells to conventional chemotherapy. Finally, another key element of the tumor microenvironment involves its vasculature. Tumor angiogenesis is related to suppression of T cell‐mediated tumor rejection. There are numerous examples that demonstrate a simultaneous activation of angiogenesis and immunosuppression. The overall goal of this project is to characterize the osteosarcoma and synovial sarcoma tumor microenvironment, to assess how the infiltrating immune cells can affect the prognosis of patients and to assess the activity of immune modulating (anti‐PD‐1), migration inhibitors (anti‐CXCR4) and antiangiogenetic (anti‐VEGFRs, anti‐PDGFRs) compounds in an in vitro sarcoma model.