Identification of novel human CTL epitopes and their agonist epitopes of mesothelin.
OBJECTIVE
Mesothelin is overexpressed in many pancreatic and ovarian cancers, mesotheliomas, and other tumor types. Clinical trials are ongoing using immunotoxins to target mesothelin, and patients immunized with allogeneic pancreatic tumor cell lines have shown immune responses to previously defined mesothelin epitopes. The purpose of this study was to define novel mesothelin CTL epitopes and, more importantly, agonist epitopes that would more efficiently activate human T cells to more efficiently lyse human tumors.


RESULTS
Two novel mesothelin HLA-A2 epitopes were defined. T-cell lines generated from one of these epitopes were shown to lyse pancreatic and ovarian tumor cells. Several agonist epitopes were defined and were shown to (a) have higher affinity and avidity for HLA-A2, (b) activate mesothelin-specific T cells from normal individuals or cancer patients to a greater degree than the native epitope in terms of induction of higher levels of IFN-gamma and the chemokine lymphotactin, and (c) lyse several mesothelin-expressing tumor types in a MHC-restricted manner more effectively than T cells generated using the native peptide. External beam radiation of tumor cells at nontoxic levels was shown to enhance the expression of mesothelin and other accessory molecules, resulting in a modest but statistically significant increase in tumor cell lysis by mesothelin-specific T cells.


CONCLUSIONS
The identification of novel CTL agonist epitopes supports and extends observations that mesothelin is a potential target for immunotherapy of pancreatic and ovarian cancers, as well as mesotheliomas.
Yokokawa
Junko
J
Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland 20892, USA.
Palena
Claudia
C
Arlen
Philip
P
Hassan
Raffit
R
Ho
Mitchell
M
Pastan
Ira
I
Schlom
Jeffrey
J
Tsang
Kwong Y
KY
D002294:Carcinoma, Squamous Cell / Q000276:immunology / Q000821:virology; D019744:Chemokines, C; D016207:Cytokines / Q000378:metabolism; D003602:Cytotoxicity, Immunologic; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000276:immunology*; D005260:Female; D058851:GPI-Linked Proteins; D015789:HLA-A2 Antigen / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D008222:Lymphokines / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000235:genetics / Q000276:immunology*; D000090204:Mesothelin; D010051:Ovarian Neoplasms / Q000276:immunology; D010190:Pancreatic Neoplasms / Q000276:immunology; D012795:Sialoglycoproteins / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014407:Tumor Cells, Cultured / Q000528:radiation effects; D014616:Vaccinia virus / Q000276:immunology
D019744:Chemokines, C; D016207:Cytokines; D018984:Epitopes, T-Lymphocyte; D058851:GPI-Linked Proteins; D015789:HLA-A2 Antigen; D008222:Lymphokines; D008562:Membrane Glycoproteins; D012795:Sialoglycoproteins; C092390:XCL1 protein, human; C018997:lymphotactin; D000090204:Mesothelin