Tumor resistance mechanisms continue to hinder responses in many cancer contexts. The non-classical human leukocyte antigen (HLA) class I molecule HLA-E has elevated expression in many human tumors including glioblastoma, and is emerging as a major checkpoint for NKG2A+ CD8+ T cells and natural killer (NK) cells. Michelle Sætersmoen, Ivan Kotchetskov, and Lamberto Torralba-Raga (PRIMA) (shared 1st authors) and collaborators have engineered a molecule called the activating/cytolytic (A/C) switch, which converts suppressive signaling from human leukocyte antigen (HLA)-E on cancer cells into activating signals for T and natural killer (NK) cells, enabling these immune cells to eliminate tumors. A/C switch-transduced T cells were able to efficiently control tumor growth in an orthotopic glioblastoma mouse model.
“HLA-E is emerging as a critical barrier for both T and NK cell based therapy. We hope this new NKG2A/ NKG2C (A/C switch) receptor developed in collaboration with the Michel Sadelain lab can be useful as a cell-intrinsic check-point converter for the design of more effective adoptive cell therapy strategies”, says team leader Prof Karl-Johan Malmberg.
Radiumhospitalets Legater supported this collaboration through a one-year research visit of Sætersmoen at MSKCC.
Torralba-Raga has a Synergy grant from PRIMA to develop a new immunoreceptor system for use in cancer immunotherapy.
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