Tumor endothelial marker 8 enhances tumor immunity in conjunction with immnization against differentiation Ag.
BACKGROUND
We have previously shown that xenogenic DNA vaccines encoding rat neu and melanosomal differentiation Ag induce tumor immunity. Others have developed vaccines targeting tumor neovasculature. Tumor endothelial marker 8 (TEM8) is expressed in the neovasculature of human tumors, and in the mouse melanoma B16, but its expression is limited in normal adult tissues. We describe a DNA vaccine combining xenogeneic tumor Ag and TEM8.


METHODS
In-situ hybridization was used to detect TEM8 RNA in mouse tumors. Mice transgenic for the rat neu proto-oncogene were immunized with DNA vaccines encoding TEM8 and the extracellular domain of rat neu and challenged with the 233-VSGA1 breast cancer cell line. In parallel experiments, C57BL/6 mice were immunized with TEM8 and human tyrosinase-related protein 1 (hTYRP1/hgp75) and challenged with B16F10 melanoma.


RESULTS
TEM8 was expressed in the stroma of transplantable mouse breast and melanoma tumors. In both model systems, TEM8 DNA had no activity as a single agent but significantly enhanced the anit-tumor immunity of neu and hTYRP1/hgp75 DNA vaccines when given in concert. The observed synergy was dependent upon CD8+ T cells, as depletion of this cell population just prior to tumor challenge obviated the effect of the TEM8 vaccine in both tumor models.


CONCLUSIONS
A local immune responses to TEM8 may increase inflammation or tumor necrosis within the tumor, resulting in improved Ag presentation of HER2/neu and hTYRP1/hgp75. Alternatively, TEM8 expression in host APC may act more as an adjuvant than an immunologic target.
Felicetti
P
P
Swim Across America Laboratory of Tumor Immunology, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
Mennecozzi
M
M
Barucca
A
A
Montgomery
S
S
Orlandi
F
F
Manova
K
K
Houghton
A N
AN
Gregor
P D
PD
Concetti
A
A
Venanzi
F M
FM
D000818:Animals; D000943:Antigens, Differentiation / Q000276:immunology*; D015153:Blotting, Western; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D019496:Cancer Vaccines / Q000235:genetics / Q000276:immunology*; D002454:Cell Differentiation / Q000276:immunology; D045744:Cell Line, Tumor; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007108:Immune Tolerance / Q000235:genetics / Q000276:immunology*; D007114:Immunization; D017403:In Situ Hybridization; D015674:Mammary Neoplasms, Animal / Q000235:genetics / Q000276:immunology / Q000473:pathology; D008546:Melanoma, Experimental / Q000235:genetics / Q000276:immunology / Q000473:pathology; D008562:Membrane Glycoproteins / Q000276:immunology; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008840:Microfilament Proteins; D009363:Neoplasm Proteins / Q000235:genetics / Q000276:immunology*; D010088:Oxidoreductases / Q000276:immunology; D000090063:Proto-Oncogene Mas; D051381:Rats; D011956:Receptors, Cell Surface / Q000235:genetics / Q000276:immunology*; D011994:Recombinant Proteins / Q000276:immunology; D016019:Survival Analysis
C473287:ANTXR1 protein, human; D000943:Antigens, Differentiation; D019496:Cancer Vaccines; C000715470:MAS1 protein, human; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D008840:Microfilament Proteins; D009363:Neoplasm Proteins; D000090063:Proto-Oncogene Mas; D011956:Receptors, Cell Surface; D011994:Recombinant Proteins; D010088:Oxidoreductases; C489799:TYRP1 protein, human