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T cell circuits that sense antigen density with an ultrasensitive threshold

Hernandez-Lopez, Rogelio A ; Yu, Wei ; Cabral, Katelyn A ; Creasey, Olivia A ; Lopez Pazmino, Maria Del Pilar ; Tonai, Yurie ; De Guzman, Arsenia ; Mäkelä, Anna ; Saksela, Kalle ; Gartner, Zev J ; Lim, Wendell A

Science (American Association for the Advancement of Science), 2021-03, Vol.371 (6534), p.1166-1171 [Periódico revisado por pares]

United States: American Association for the Advancement of Science

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Título:
T cell circuits that sense antigen density with an ultrasensitive threshold
Autor: Hernandez-Lopez, Rogelio A ; Yu, Wei ; Cabral, Katelyn A ; Creasey, Olivia A ; Lopez Pazmino, Maria Del Pilar ; Tonai, Yurie ; De Guzman, Arsenia ; Mäkelä, Anna ; Saksela, Kalle ; Gartner, Zev J ; Lim, Wendell A
Assuntos: Animals ; Antigens ; Antigens, Neoplasm - immunology ; B cells ; Cancer ; Cell Engineering ; Cell Line, Tumor ; Density ; Epidermal growth factor ; Health aspects ; Humans ; Immunotherapy, Adoptive ; K562 Cells ; Lymphocytes ; Lymphocytes T ; Mice ; Receptor, ErbB-2 - genetics ; Receptor, ErbB-2 - immunology ; Receptor, ErbB-2 - metabolism ; Receptors, Artificial - metabolism ; Receptors, Chimeric Antigen - genetics ; Receptors, Chimeric Antigen - immunology ; Receptors, Chimeric Antigen - metabolism ; Receptors, Notch - genetics ; Receptors, Notch - metabolism ; Spheroids, Cellular ; T cells ; T-Lymphocytes, Cytotoxic - immunology ; T-Lymphocytes, Cytotoxic - metabolism ; Tumors ; Xenograft Model Antitumor Assays
É parte de: Science (American Association for the Advancement of Science), 2021-03, Vol.371 (6534), p.1166-1171
Notas: These authors contributed equally to this work
Author contributions: R.A.H.-L. and W.A.L. conceived the project. The experimental plan was implemented by R.A.H.-L., W.Y., K.A.C., O.A.C., M.d.P.L.P., Y.T., and A.D.G.; R.A.H.-L., K.A.C., and O.A.C. designed and carried out 3D culture experiments supervised by Z.J.G. and W.A.L.; R.A.H.-L., W.Y., Y.T., and A.D.G. designed and carried out in vivo experiments supervised by W.A.L.; and A.M. and K.S. designed protein expression vectors and provided scFv-GST purified protein constructs. R.A.H.-L. analyzed all data. R.A.H.-L. and W.A.L. prepared the figures and wrote the manuscript with suggestions from all authors. W.A.L. supervised all aspects of the work.
Descrição: Overexpressed tumor-associated antigens [for example, epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2)] are attractive targets for therapeutic T cells, but toxic "off-tumor" cross-reaction with normal tissues that express low levels of target antigen can occur with chimeric antigen receptor (CAR)-T cells. Inspired by natural ultrasensitive response circuits, we engineered a two-step positive-feedback circuit that allows human cytotoxic T cells to discriminate targets on the basis of a sigmoidal antigen-density threshold. In this circuit, a low-affinity synthetic Notch receptor for HER2 controls the expression of a high-affinity CAR for HER2. Increasing HER2 density thus has cooperative effects on T cells-it increases both CAR expression and activation-leading to a sigmoidal response. T cells with this circuit show sharp discrimination between target cells expressing normal amounts of HER2 and cancer cells expressing 100 times as much HER2, both in vitro and in vivo.
Editor: United States: American Association for the Advancement of Science
Idioma: Inglês

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T cell circuits that sense antigen density with an ultrasensitive threshold

Hernandez-Lopez, Rogelio A ; Yu, Wei ; Cabral, Katelyn A ; Creasey, Olivia A ; Lopez Pazmino, Maria Del Pilar ; Tonai, Yurie ; De Guzman, Arsenia ; Mäkelä, Anna ; Saksela, Kalle ; Gartner, Zev J ; Lim, Wendell A

United States: American Association for the Advancement of Science

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