Journal
CANCER IMMUNOLOGY IMMUNOTHERAPY
Volume 62, Issue 2, Pages 359-369Publisher
SPRINGER
DOI: 10.1007/s00262-012-1336-z
Keywords
TCR; Adoptive T-cell therapy; Tumor targeting; Cancer immunotherapy; Melanoma
Categories
Funding
- Melanoma Research Alliance
- NIH [CA097296]
- Research Fellowship of the Deutsche Forschungsgemeinschaft
- Samuel and Ruth Engelberg/Irvington Institute Fellowship of the Cancer Research Institute
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Clinical studies with immunotherapies for cancer, including adoptive cell transfers of T cells, have shown promising results. It is now widely believed that recruitment of CD4(+) helper T cells to the tumor would be favorable, as CD4(+) cells play a pivotal role in cytokine secretion as well as promoting the survival, proliferation, and effector functions of tumor-specific CD8(+) cytotoxic T lymphocytes. Genetically engineered high-affinity T-cell receptors (TCRs) can be introduced into CD4(+) helper T cells to redirect them to recognize MHC-class I-restricted antigens, but it is not clear what affinity of the TCR will be optimal in this approach. Here, we show that CD4(+) T cells expressing a high-affinity TCR (nanomolar K (d) value) against a class I tumor antigen mediated more effective tumor treatment than the wild-type affinity TCR (micromolar K (d) value). High-affinity TCRs in CD4(+) cells resulted in enhanced survival and long-term persistence of effector memory T cells in a melanoma tumor model. The results suggest that TCRs with nanomolar affinity could be advantageous for tumor targeting when expressed in CD4(+) T cells.
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