T cell-mediated delay of spontaneous mammary tumor onset: increased efficacy with in vivo versus in vitro activation.
Peripheral tolerance to shared Ags expressed on both tumors and normal self-tissues presents a major barrier to T cell-based immunotherapy as a treatment for cancer. To assess the activity of tumor-specific T cells against spontaneously arising carcinomas in the context of shared Ag expression, we developed a model system whereby an identified tumor Ag, tumor ERK (tERK), is expressed transgenically on both normal mammary tissue and spontaneous mammary carcinomas. Transfer of in vitro-activated, tERK-specific DUC18 T cells delayed spontaneous tumor development in tERK-expressing mice when T cells were given before the development of palpable carcinomas. However, antitumor activity mediated by in vitro-activated DUC18 T cells, as measured by responsiveness against a transplanted tERK-expressing fibrosarcoma challenge, was lost within days of transfer. This loss was due to expression of tERK as a self-Ag on normal tissues and was independent of the presence of mammary tumors. In contrast, transferred naive DUC18 T cells maintained a long-term protective function in tERK-expressing mice. Ten-fold fewer naive T cells activated in vivo were able to replicate the delay in spontaneous tumor development achieved by in vitro-activated T cells. These results are in contrast to our earlier studies using transplanted tumors alone, in which in vitro-activated DUC18 T cells were more efficacious than naive DUC18 T cells and highlight the need to perform tumor studies in the presence of tumor Ag expression on normal self-tissue.
O'Mara
Leigh A
LA
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
Norian
Lyse A
LA
Kreamalmeyer
Darren
D
White
J Michael
JM
Allen
Paul M
PM
D000818:Animals; D000951:Antigens, Neoplasm; D001324:Autoantigens; D001483:Base Sequence; D004274:DNA, Recombinant / Q000235:genetics; D005260:Female; D007108:Immune Tolerance; D016219:Immunotherapy, Adoptive; D066298:In Vitro Techniques; D008213:Lymphocyte Activation; D008325:Mammary Neoplasms, Experimental / Q000209:etiology* / Q000276:immunology* / Q000628:therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D013601:T-Lymphocytes / Q000276:immunology*
D000951:Antigens, Neoplasm; D001324:Autoantigens; D004274:DNA, Recombinant