Tumor - host immune interactions in Ewing sarcoma : implications for therapy

Abstract

In this thesis, we report on various aspects of tumor - host (immune) interactions in Ewing sarcoma patients with the aim to obtain leads for immunotherapeutic or targeted treatment strategies. We demonstrate a key role for interferon gamma (IFNg) in enhancing both Ewing sarcoma immunogenicity and susceptibility to cytotoxicity. An (endogenous) pro-inflammatory tumor microenvironment consisting of cytotoxic T-lymphocytes and IFNg-inducible chemokines provides prognostic benefit. Moreover, despite evidence for immunologic pressure in selection of HLA class I loss variants, intact IFNg-inducibility of the HLA class I antigen processing machinery emphasizes the significance of a pro-inflammatory microenvironment for initiation/ execution of adaptive anti-tumor immunity. Pre-clinical support for the potential of adoptive cell transfer therapies, in particular combinatorial natural killer cell-based therapy, is provide d. Sensitization of Ewing sarcoma by conventional or targeted therapies, including histone deacetylase inhibitors, combined with cytokine activation of natural killer cells enhances anti-tumor responses and overcomes both intrinsic functional natural killer cell defects as well as cross-resistance of chemotherapy-resistant Ewing sarcoma to natural killer cells. Finally, due to a crucial role of the CXCR4-CXCL12 axis in Ewing sarcoma progression, disruption of this axis by a CXCR4-specific antagonist may represent a promising treatment option for patients with Ewing sarcoma.