Abstract
BackgroundThe lack of effective treatments for gliomas makes them a significant health problem and highlights the need for the development of novel and innovative treatment approaches. Immunotherapy is an appealing strategy because of the potential ability for immune cells to traffic to and destroy infiltrating tumor cells. However, the absence of well-characterized, highly immunogenic tumor-rejection antigens (TRA) in gliomas has limited the implementation of targeted immune-based therapies.MethodsWe hypothesized that treatment with the demethylating agent, decitabine, would upregulate the expression of TRA on tumor cells, thereby facilitating enhanced surveillance by TRA-specific T cells.Results and DiscussionTreatment of human glioma cells with decitabine increased the expression of NY-ESO-1 and other well characterized cancer testes antigens. The upregulation of NY-ESO-1 made these tumors susceptible to NY-ESO-1-specific T-cell recognition and lysis. Interestingly, decitabine treatment of T98 glioma cells also sensitized them to Fas-dependent apoptosis with an agonistic antibody, while a Fas blocking antibody could largely prevent the enhanced functional recognition by NY-ESO-1 specific T cells. Thus, decitabine treatment transformed a non-immunogenic glioma cell into an immunogenic target that was efficiently recognized by NY-ESO-1--specific T cells.ConclusionsSuch data supports the hypothesis that agents which alter epigenetic cellular processes may "immunosensitize" tumor cells to tumor-specific T cell-mediated lysis.
Highlights
The lack of effective treatments for gliomas makes them a significant health problem and highlights the need for the development of novel and innovative treatment approaches
We analyzed the expression of NY-ESO-1 in 5 established human glioma cell lines and 4 primary glioma cell lines. We demonstrated that their treatment with decitabine up-regulated the expression of NY-ESO1 and MHC I class, and as a result, induced simultaneous release of T cell effector pro-inflammatory cytokines and tumor cell killing. These results suggest that treatment with decitabine increases the expression of an immunogenic Cancer testis antigens (CTAs), but can re-establish functionality of the apoptotic signaling system within tumor cells and sensitize these cells to immunemediated cell death via the Fas/Fas Ligand pathway
Decitabine increases MHC I and CTA expression We previously demonstrated that many melanoma associated antigens (MAA) are expressed by glioma cells, but at distinctly lower levels compared with melanoma cells [32]
Summary
The lack of effective treatments for gliomas makes them a significant health problem and highlights the need for the development of novel and innovative treatment approaches. The absence of well-characterized, highly immunogenic tumor-rejection antigens (TRA) in gliomas has limited the implementation of targeted immune-based therapies. Gliomas lack well defined TRA for immune targeting by CD8+ T-cell effectors. Cancer testis antigens (CTAs) are expressed in a variety of tumors, but not in non-neoplastic normal human cells, with the exception of germ cells [6,7]. NY-ESO-1, a member of the cancer/testis antigen family, is considered to be one of the most immunogenic TRAs and a promising target for cell mediated immunity [8,9,10,11,12,13]. NY-ESO-1 expression has been identified at the protein level in a variety of malignant neoplasms such as lung cancers, melanomas, synovial sarcomas, and bladder cancers [11,13,14,15].
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