Multiple cancer-specific antigens are targeted by a chimeric antigen receptor on a single cancer cell
| Autor: | Madeline Steiner, Karin Schreiber, Jonathan Zerweck, Ulla Mandel, Carl H. June, Preeti Sharma, H. Michael Shepard, Steven P. Wolf, Frank Wen, Catharina Steentoft, Hans Schreiber, Henrik Clausen, Stephen C. Meredith, Avery D. Posey, Matthias Leisegang, Yanran He, David M. Kranz |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Adoptive cell transfer Glycosylation Cell Cell Line 03 medical and health sciences Mice 0302 clinical medicine Antigen Antigens Neoplasm Neoplasms medicine Animals Humans Antigens Tumor-Associated Carbohydrate Membrane Glycoproteins Receptors Chimeric Antigen biology Chemistry General Medicine Adoptive Transfer Chimeric antigen receptor 030104 developmental biology medicine.anatomical_structure Cell culture 030220 oncology & carcinogenesis Cancer cell biology.protein Cancer research Antibody Cell activation Corrigendum Research Article |
| Zdroj: | JCI insight. 4(21) |
| ISSN: | 2379-3708 |
| Popis: | Human cancer cells were eradicated by adoptive transfer of T cells transduced with a chimeric antigen receptor (CAR) made from an antibody (237Ab) that is highly specific for the murine Tn-glycosylated podoplanin (Tn-PDPN). The objectives were to determine the specificity of these CAR-transduced T (CART) cells and the mechanism for the absence of relapse. We show that although the 237Ab bound only to cell lines expressing murine Tn-PDPN, the 237Ab-derived 237CART cells lysed multiple different human and murine cancers not predicted by the 237Ab binding. Nevertheless, the 237CART cell reactivities remained cancer specific because all recognitions were dependent on the Tn glycosylation that resulted from COSMC mutations that were not present in normal tissues. While Tn was required for the recognition by 237CART, Tn alone was not sufficient for 237CART cell activation. Activation of 237CART cells required peptide backbone recognition but tolerated substitutions of up to 5 of the 7 amino acid residues in the motif recognized by 237Ab. Together, these findings demonstrate what we believe is a new principle whereby simultaneous recognition of multiple independent Tn-glycopeptide antigens on a cancer cell makes tumor escape due to antigen loss unlikely. |
| Databáze: | OpenAIRE |
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