Absence of gamma-interferon-inducible lysosomal thiol reductase in melanomas disrupts T cell recognition of select immunodominant epitopes.
Long-lasting tumor immunity requires functional mobilization of CD8+ and CD4+ T lymphocytes. CD4+ T cell activation is enhanced by presentation of shed tumor antigens by professional antigen-presenting cells (APCs), coupled with display of similar antigenic epitopes by major histocompatibility complex class II on malignant cells. APCs readily processed and presented several self-antigens, yet T cell responses to these proteins were absent or reduced in the context of class II+ melanomas. T cell recognition of select exogenous and endogenous epitopes was dependent on tumor cell expression of gamma-interferon-inducible lysosomal thiol reductase (GILT). The absence of GILT in melanomas altered antigen processing and the hierarchy of immunodominant epitope presentation. Mass spectral analysis also revealed GILT's ability to reduce cysteinylated epitopes. Such disparities in the profile of antigenic epitopes displayed by tumors and bystander APCs may contribute to tumor cell survival in the face of immunological defenses.
Haque
M Azizul
MA
Department of Microbiology and Immunology, and the Walther Oncology Center, Indiana University School of Medicine, and the Walther Cancer Institute, Indianapolis, IN 46202, USA.
Li
Ping
P
Jackson
Sheila K
SK
Zarour
Hassane M
HM
Hawes
John W
JW
Phan
Uyen T
UT
Maric
Maja
M
Cresswell
Peter
P
Blum
Janice S
JS
D000938:Antigen-Presenting Cells / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002455:Cell Division; D003545:Cysteine / Q000378:metabolism; D018984:Epitopes, T-Lymphocyte / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D016056:Immunodominant Epitopes / Q000276:immunology* / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism*; D013058:Mass Spectrometry; D008545:Melanoma / Q000201:enzymology* / Q000276:immunology*; D010084:Oxidation-Reduction; D010088:Oxidoreductases / Q000378:metabolism*; D050862:Oxidoreductases Acting on Sulfur Group Donors; D010446:Peptide Fragments / Q000276:immunology / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D014162:Transfection; D014407:Tumor Cells, Cultured
D018984:Epitopes, T-Lymphocyte; D016056:Immunodominant Epitopes; D010446:Peptide Fragments; D007371:Interferon-gamma; D010088:Oxidoreductases; C056859:IFI30 protein, human; D050862:Oxidoreductases Acting on Sulfur Group Donors; D003545:Cysteine