Abstract
BackgroundA current focus in cancer treatment is to broaden responses to immunotherapy. One reason these therapies may prove inadequate is that T lymphocytes fail to recognize the tumor due to differences in immunogenic epitopes presented by the cancer cells under inflammatory or non-inflammatory conditions.The antigen processing machinery of the cell, the proteasome, cleaves proteins into peptide epitopes for presentation on MHC complexes. Immunoproteasomes in inflammatory melanomas, and in antigen presenting cells of the immune system, are enzymatically different to standard proteasomes expressed by tumors with no inflammation. This corresponds to alterations in protein cleavage between proteasome subtypes, and a disparate repertoire of MHC-presented epitopes.MethodsWe assessed steady state and IFNγ-induced immunoproteasome expression in melanoma cells. Using epitope specific T-lymphocyte clones, we studied processing and presentation of three NY-ESO-1 HLA-Cw3 restricted epitopes by melanoma cell lines. Our experimental model allowed comparison of the processing of three distinct epitopes from a single antigen presented on the same HLA complex. We further investigated processing of these epitopes by direct inhibition, or siRNA mediated knockdown, of the immunoproteasome catalytic subunit LMP7.ResultsOur data demonstrated a profound difference in the way in which immunogenic T-lymphocyte epitopes are presented by melanoma cells under IFNγ inflammatory versus non-inflammatory conditions. These alterations led to significant changes in the ability of T-lymphocytes to recognize and target melanoma cells.ConclusionsOur results illustrate a little-studied mechanism of immune escape by tumor cells which, with appropriate understanding and treatment, may be reversible. These data have implications for the design of cancer vaccines and adoptive T cell therapies.Electronic supplementary materialThe online version of this article (doi:10.1186/s40425-016-0111-7) contains supplementary material, which is available to authorized users.
Highlights
A current focus in cancer treatment is to broaden responses to immunotherapy
In melanoma, the presence of tumor infiltrating lymphocytes (TILs); the frequency of neoepitopes arising from tumor specific mutations; and the presence of an interferon–gamma related immune signature have all been correlated with positive outcomes for immune checkpoint inhibition [6,7,8]
We demonstrate that optimal processing of each of the NY-ESO-1 epitopes is dependent on different proteasome subtypes, with significant corresponding impact on T-lymphocyte recognition and killing of melanoma cells
Summary
A current focus in cancer treatment is to broaden responses to immunotherapy. One reason these therapies may prove inadequate is that T lymphocytes fail to recognize the tumor due to differences in immunogenic epitopes presented by the cancer cells under inflammatory or non-inflammatory conditions. Immune recognition of cancer occurs frequently, spontaneous immune responses leading to clinical benefit in cancer patients are rare [1, 2] This failure of effective immunity may result from tumor-mediated immune suppression and evasion. Immunotherapies that counter these mechanisms, such as immune checkpoint inhibition [3, 4] and adoptive transfer of T-lymphocytes [5], have been successfully developed for melanoma and other cancers. These approaches have established that functional T-lymphocytes capable of recognizing specific HLA-peptide complexes on cancer cells can mediate powerful anti-tumor effects. The concept has emerged that a T-lymphocyte/IFNγ inflamed tumor microenvironment carries positive predictive value for responses to immunotherapy
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