T cell recognition of a tumor-associated glycoprotein and its synthetic carbohydrate epitopes: stimulation of anticancer T cell immunity in vivo

Abstract

The Thomsen, Friedenreich (TF) and Tn carbohydrate antigens are expressed on the vast majority of human adenocarcinomas and are associated with aggressive behavior of certain tumors. TF and Tn antigens are also expressed on certain murine cancer cell lines including TA3-Ha, a highly lethal, transplantable mammary adenocarcinoma. TF and Tn cancer-associated carbohydrate haptens were synthesized, conjugated to protein carriers and used to demonstrate that delayed-type hypersensitivity (DTH) effector T cells can specifically recognize and respond to carbohydrate determinants on the TA3-Ha tumor-associated glycoprotein, epiglycanin. The effector cells were shown to have the helper DTH phenotype (Lyt1+, Lyt2-, Thy1+) and it was demonstrated that they respond to specific carbohydrate determinants in an MHC-restricted fashion. These experiments provide the rationale for the use of synthetic tumor-associated glycoconjugates (S-TAGs) to stimulate anticancer T cell immunity. In support of this hypothesis, it was shown that preimmunization with the appropriate S-TAGs could provide a degree of protection against a subsequent tumor transplant and that antitumor effector Lyt1+, Lyt2- T cells could be generated in vitro using the appropriate S-TAGs as antigens.

Major histocompatibility complex class II association and induction of T cell responses by carbohydrates and glycopeptides

“…In several instances, T lymphocyte responses against peptidoglycans, lipophosphoglycans, gangliosides, and glycopeptides have been reported [5,12,15,16,18]. Interpretation of priming studies using carbohydrates as the immunogen have often been difficult due to the possibility that other antigens may have been responsible for T cell induction.…”

Immunogenicity of synthetic peptides related to the core peptide sequence encoded by the human MUC1 mucin gene: Effect of immunization on the growth of murine mammary adenocarcinoma cells transfected with the human MUC1 gene

“…Cancer-associated mucins are also known to be underglycosylated [14] and hence antigenically different from their normal cell counterparts exposing normally cryptic carbohydrate [10,28,33], peptide [2] and perhaps even glycopeptide epitopes. Therefore, because cell-surface mucins protrude such relatively great distances into the external environment, they themselves may serve as targets for immune attack [6,12,29]. 10 We have used an animal model, the TA3-Ha murine mammary adenocarcinoma, to study how cancer-associated mucins modulate the immune system [5] and have developed novel synthetic "vaccines" for active specific immunotherapy, targeting specific carbohydrate epitopes on cell-surface mucins of TA3-Ha cancer cells [6,12].…”

“…Therefore, because cell-surface mucins protrude such relatively great distances into the external environment, they themselves may serve as targets for immune attack [6,12,29]. 10 We have used an animal model, the TA3-Ha murine mammary adenocarcinoma, to study how cancer-associated mucins modulate the immune system [5] and have developed novel synthetic "vaccines" for active specific immunotherapy, targeting specific carbohydrate epitopes on cell-surface mucins of TA3-Ha cancer cells [6,12]. Our results show that (a) epiglycanin, a mucin produced and secreted by TA3-Ha cells, can induce a state of specific suppressor-T-cell-mediated immunosuppression against carbohydrate epitopes expressed on epiglycanin and on the surface of TA3-Ha cells [5], (b) epiglycanin-induced specific immunosuppression can be completely reversed by treatment of the suppressed mice with low-dose cyclophosphamide [5] and (c) cyclophosphamide-treated mice can be successfully immunized with a "vaccine" consisting of a synthetic hapten (mimicking a specific carbohydrate epitope on epiglycanin) conjugated to keyhole limpet hemocyanin (KLH) and emulsified in RIBI adjuvant.…”

Receptor for the globular heads of C1q (gC1q‐R, p33, hyaluronan‐binding protein) is preferentially expressed by adenocarcinoma cells

“…A number of approaches have been used to identify antitumor antibodies and/or their corresponding antigens, including isolation of antigen-specific T cells, generation of murine-murine or murine-human antitumor hybridomas and screening of unamplified human serum. [1][2][3] To date, a variety of molecules have been seen to be overexpressed by tumor; a partial list of these includes the multimeric mucins such as MUC-1, 4 mammaglobin, 5 CD20, 6 Tn and sialyl Tn 7,8 CEA, ING1 tumor-suppressor gene product, 9 putative transcription factor NY-BR-1-7, 10 Her-2/neu (c-erB2), 11 MAGE 12 and PSA. 13 Of the tumor-associated antigens described to date, antibodies against only 2, Her-2/neu (c-erb-B2), a protooncogene overexpressed in a subset of breast cancer patients, and CD20, an antigen expressed in hematologic malignancies, have proven to be clinically effective.…”