Effective NY-ESO-1–specific MHC II–restricted T cell receptors from antigen-negative hosts enhance tumor regression
| Autor: | Thomas Blankenstein, Felix K.M. Lorenz, Lucia Poncette, Xiaojing Chen |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
CD4-Positive T-Lymphocytes
0301 basic medicine Adoptive cell transfer T cell medicine.medical_treatment Receptors Antigen T-Cell HLA-DR alpha-Chains Mice Transgenic chemical and pharmacologic phenomena CD8-Positive T-Lymphocytes Major histocompatibility complex Mice 03 medical and health sciences Antigen Cancer immunotherapy Antigens Neoplasm Cell Line Tumor Neoplasms MHC class I medicine Animals Humans biology T-cell receptor Membrane Proteins hemic and immune systems General Medicine Adoptive Transfer 030104 developmental biology medicine.anatomical_structure Commentary biology.protein Cancer research CD8 HLA-DRB1 Chains |
| Zdroj: | Journal of Clinical Investigation. 129:324-335 |
| ISSN: | 1558-8238 0021-9738 |
| DOI: | 10.1172/jci120391 |
| Popis: | Adoptive transfer of T cell receptor-engineered (TCR-engineered) T cells is a promising approach in cancer therapy but needs improvement for more effective treatment of solid tumors. While most clinical approaches have focused on CD8+ T cells, the importance of CD4+ T cells in mediating tumor regression has become apparent. Regarding shared (self) tumor antigens, it is unclear whether the human CD4+ T cell repertoire has been shaped by tolerance mechanisms and lacks highly functional TCRs suitable for therapy. Here, TCRs against the tumor-associated antigen NY-ESO-1 were isolated either from human CD4+ T cells or from mice that express a diverse human TCR repertoire with HLA-DRA/DRB1*0401 restriction and are NY-ESO-1 negative. NY-ESO-1-reactive TCRs from the mice showed superior recognition of tumor cells and higher functional activity compared with TCRs from humans. We identified a candidate TCR, TCR-3598_2, which was expressed in CD4+ T cells and caused tumor regression in combination with NY-ESO-1-redirected CD8+ T cells in a mouse model of adoptive T cell therapy. These data suggest that MHC II-restricted TCRs against NY-ESO-1 from a nontolerant nonhuman host are of optimal affinity and that the combined use of MHC I- and II-restricted TCRs against NY-ESO-1 can make adoptive T cell therapy more effective. |
| Databáze: | OpenAIRE |
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