TY - JOUR
T1 - Mismatch in epitope specificities between IFNγ inflamed and uninflamed conditions leads to escape from T lymphocyte killing in melanoma
AU - Woods, Katherine
AU - Knights, Ashley J.
AU - Anaka, Matthew
AU - Schittenhelm, Ralf B.
AU - Purcell, Anthony W.
AU - Behren, Andreas
AU - Cebon, Jonathan
PY - 2016/2/16
Y1 - 2016/2/16
N2 - Background: 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.
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. Methods: We 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. Results: Our 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. Conclusions: Our 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.
AB - Background: 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.
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. Methods: We 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. Results: Our 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. Conclusions: Our 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.
KW - T-cell killing
KW - antigen processing
KW - immunoproteasome
KW - melanoma
KW - tumor antigens
UR - http://www.ncbi.nlm.nih.gov/pubmed/26885372
U2 - 10.1186/s40425-016-0111-7
DO - 10.1186/s40425-016-0111-7
M3 - Article
SN - 2051-1426
VL - 4
JO - Journal for ImmunoTherapy of Cancer
JF - Journal for ImmunoTherapy of Cancer
M1 - 10
ER -