Lack of ignorance to tumor antigens: evaluation using nominal antigen transfection and T-cell receptor transgenic lymphocytes in Lyons-Parish analysis--implications for tumor tolerance.
A substantial body of literature has described weak antitumor CTL responses in tumor-bearing hosts, and a number of authors have suggested that tumor tissue in some way sequesters antigen from the immune system, a failure of the tumor-specific immune response largely attributable to "ignorance." To evaluate this in a tumor model, we stably transfected murine tumor cell lines with genes coding for the nominal antigens influenza hemagglutinin (HA) or ovalbumin (OVA) and adoptively transferred HA- or OVA-specific T-cell receptor-transgenic, CD8-positive T cells into mice-bearing these tumors. Tumor antigen cross-presentation within draining lymph nodes (LNs) was then examined using Lyons-Parish analysis, detection of a proliferative response of 5,6-carboxyfluorescein diacetate succinimidyl ester-labeled CD8 T cells from T-cell receptor mice using flow cytometric analysis. Our studies demonstrate clearly that tumor antigens are constitutively presented in LNs draining tumors and can stimulate a T-cell proliferative response. This lack of ignorance was not simply attributable to the model chosen, because it was seen with three different cell lines, two different antigens, and two different mouse strains. Furthermore, it occurred regardless of whether these tumor antigens were expressed as cytoplasmic, transmembrane, or secreted proteins. When tumor antigens were present in low concentrations, antigen cross-presentation was not absent but simply delayed. Interestingly, tumor antigen cross-presentation remained localized to the LNs draining the tumor throughout the period of tumor growth. Curiously, in animals where tumors failed to grow, evidence of continued cross-presentation of the tumor antigen was seen up to 6 months after tumor inoculation. These data suggest that ignorance is not an explanation for the failure of the host immune system to respond to tumor antigens.
Robinson
B W
BW
University Department of Medicine, University of Western Australia, Nedlands, Australia. bwsrobin@cyllene.uwa.edu.au
Scott
B M
BM
Lake
R A
RA
Stumbles
P A
PA
Nelson
D J
DJ
Fisher
S
S
Marzo
A L
AL
D000818:Animals; D017951:Antigen Presentation; D000951:Antigens, Neoplasm / Q000378:metabolism*; D002455:Cell Division; D003593:Cytoplasm / Q000378:metabolism; D005260:Female; D006388:Hemagglutinins / Q000378:metabolism; D006801:Humans; D008214:Lymphocytes / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010047:Ovalbumin / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000235:genetics*; D013602:T-Lymphocytes, Cytotoxic / Q000378:metabolism; D013997:Time Factors; D014162:Transfection / Q000379:methods*; D014407:Tumor Cells, Cultured
D000951:Antigens, Neoplasm; D006388:Hemagglutinins; D011948:Receptors, Antigen, T-Cell; D010047:Ovalbumin