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 lin es with genes coding for the nominal antigens influenza hemagglutinin (HA) or ovalbumin (OVA) and adoptively transferred HA- or OVA-specific T-cell re ceptor-transgenic, CD8-positive T cells into mice-bearing these tumors. Tum or antigen cross-presentation within draining lymph nodes (LNs) was then ex amined using Lyons-Parish analysis, detection of a proliferative response o f 5,6-carboxyfluorescein diacetate succinimidyl ester-labeled CD8 T cells f rom T-cell receptor mice using flow cytometric analysis. Our studies demons trate clearly that tumor antigens are constitutively presented in LNs drain ing tumors and can stimulate a T-cell proliferative response. This lack of ignorance was not simply attributable to the model chosen, because it was s een with three different cell lines, two different antigens, and two differ ent mouse strains. Furthermore, it occurred regardless of whether these tum or antigens were expressed as cytoplasmic, transmembrane, or secreted prote ins, When tumor antigens were present in low concentrations, antigen cross- presentation was not absent but simply delayed. Interestingly, tumor antige n cross-presentation remained localized to the LNs draining the tumor throu ghout 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 ignor ance is not an explanation for the failure of the host immune system to res pond to tumor antigens.