Identification of a tumor-specific allo-HLA-restricted gamma delta TCR

Kierkels, G.J.J.; Scheper, W.; Meringa, A.D.; Johanna, I.; Beringer, D.X.; Janssen, A.; Schiffler, M.; Aarts-Riemens, T.; Kramer, L.; Straetemans, T.; Heijhuurs, S.; Leusen, J.H.W.; San Jose, E.; Fuchs, K.; Griffioen, M.; Falkenburg, J.H.; Bongiovanni, L.; Bruin, A. de; Vargas-Diaz, D.; Altelaar, M.; Heck, A.J.R.; Shultz, L.D.; Ishikawa, F.; Nishimura, M.I.; Sebestyen, Z.; Kuball, J.

doi:doi:10.1182/bloodadvances.2019032409

gamma delta T cells are key players in cancer immune surveillance because of their ability to recognize malignant transformed cells, which makes them promising therapeutic tools in the treatment of cancer. However, the biological mechanisms of how gamma delta T-cell receptors (TCRs) interact with their ligands are poorly understood. Within this context, we describe the novel allo-HLA-restricted and CD8 alpha-dependent V gamma 5V delta 1TCR. In contrast to the previous assumption of the general allo-HLA reactivity of a minor fraction of gamma delta TCRs, we show that classic anti-HLA-directed, gamma delta TCR-mediated reactivity can selectively act on hematological and solid tumor cells, while not harming healthy tissues in vitro and in vivo. We identified the molecular interface with proximity to the peptide-binding groove of HLA-A*24:02 as the essential determinant for recognition and describe the critical role of CD8 as a coreceptor. We conclude that alloreactive gamma delta T...Show moregamma delta T cells are key players in cancer immune surveillance because of their ability to recognize malignant transformed cells, which makes them promising therapeutic tools in the treatment of cancer. However, the biological mechanisms of how gamma delta T-cell receptors (TCRs) interact with their ligands are poorly understood. Within this context, we describe the novel allo-HLA-restricted and CD8 alpha-dependent V gamma 5V delta 1TCR. In contrast to the previous assumption of the general allo-HLA reactivity of a minor fraction of gamma delta TCRs, we show that classic anti-HLA-directed, gamma delta TCR-mediated reactivity can selectively act on hematological and solid tumor cells, while not harming healthy tissues in vitro and in vivo. We identified the molecular interface with proximity to the peptide-binding groove of HLA-A*24:02 as the essential determinant for recognition and describe the critical role of CD8 as a coreceptor. We conclude that alloreactive gamma delta T-cell repertoires provide therapeutic opportunities, either within the context of haplotransplantation or as individual gamma delta TCRs for genetic engineering of tumor-reactive T cells.Show less

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Identification of a tumor-specific allo-HLA-restricted gamma delta TCR