Abstract
Interleukin-2 (IL-2) transgenic Ewing sarcoma cells can induce tumor specific T and NK cell responses and reduce tumor growth in vivo and in vitro. Nevertheless, the efficiency of this stimulation is not high enough to inhibit tumor growth completely. In addition to recognition of the cognate antigen, optimal T-cell stimulation requires signals from so-called co-stimulatory molecules. Several members of the tumor necrosis factor superfamily have been identified as co-stimulatory molecules that can augment antitumor immune responses. OX40 (CD134) and OX40 ligand (OX40L = CD252; also known as tumor necrosis factor ligand family member 4) is one example of such receptor/ligand pair with co-stimulatory function. In the present investigation, we generated OX40L transgenic Ewing sarcoma cells and tested their immunostimulatory activity in vitro. OX40L transgenic Ewing sarcoma cells showed preserved expression of Ewing sarcoma-associated (anti)gens including lipase member I, cyclin D1 (CCND1), cytochrome P450 family member 26B1 (CYP26B1), and the Ewing sarcoma breakpoint region 1-friend leukemia virus integration 1 (EWSR1-FLI1) oncogene. OX40L-expressing tumor cells showed a trend for enhanced immune stimulation against Ewing sarcoma cells in combination with IL-2 and stimulation of CD137. Our data suggest that inclusion of the OX40/OX40L pathway of co-stimulation might improve immunotherapy strategies for the treatment of Ewing sarcoma.
Highlights
Ewing sarcomas represent bone and/or soft-tissue tumors of uncertain histogenetic origin
The role of cancer immunotherapy that boosts the extraordinary power of our immune system to detect and destroy cancer cells still remains unclear
The tumor microenvironment can reduce activation of T cells, tumor cells can escape immune recognition by downregulation of tumor-associated antigens or antigen-presenting human leukocyte antigen (HLA) molecules, tumor cells can produce antigen-loss variants, tumor cells can secrete immunosuppressive factors, and co-stimulatory signals can be absent from antigen-presenting cells [53,54,55,56,57]
Summary
Ewing sarcomas (or “Ewing family tumors,” EFT) represent bone and/or soft-tissue tumors of uncertain histogenetic origin. More than half of the patients with localized EFT can be cured. EFTs are characterized by the expression of tumor-specific oncofusion proteins [2]. These fusion proteins are highly tumor specific and might be interesting targets for immunological treatment strategies. Using high-density DNA microarrays, we identified additional potential tumor antigens expressed in EFT [4,5,6,7]. The presence of such tumorspecific antigens alone is not sufficient for the induction of efficient immune responses.
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