RT Journal Article
SR Electronic
T1 Precise T cell recognition programs designed by transcriptionally linking multiple receptors
JF Science
JO Science
FD American Association for the Advancement of Science
SP 1099
OP 1104
DO 10.1126/science.abc6270
VO 370
IS 6520
A1 Williams, Jasper Z.
A1 Allen, Greg M.
A1 Shah, Devan
A1 Sterin, Igal S.
A1 Kim, Ki H.
A1 Garcia, Vivian P.
A1 Shavey, Gavin E.
A1 Yu, Wei
A1 Puig-Saus, Cristina
A1 Tsoi, Jennifer
A1 Ribas, Antoni
A1 Roybal, Kole T.
A1 Lim, Wendell A.
YR 2020
UL http://science.sciencemag.org/content/370/6520/1099.abstract
AB There has been exciting progress in the field of cancer immunotherapy, which harnesses a patient's own immune system to kill cancer cells. However, achieving precise recognition of cancer cells remains challenging. Cells engineered with synthetic Notch (synNotch) receptors bind to specific antigens, and binding induces the expression of defined genes. Williams et al. used synNotch modules as transcriptional connectors that daisy-chain together multiple receptors. They engineered T cells that can recognize up to three target antigens expressed on or inside cancer cells and integrated these inputs to achieve NOT, AND, and OR logic. The engineered cells achieved precise recognition of targeted cancer cells.Science, this issue p. 1099Living cells often identify their correct partner or target cells by integrating information from multiple receptors, achieving levels of recognition that are difficult to obtain with individual molecular interactions. In this study, we engineered a diverse library of multireceptor cell-cell recognition circuits by using synthetic Notch receptors to transcriptionally interconnect multiple molecular recognition events. These synthetic circuits allow engineered T cells to integrate extra- and intracellular antigen recognition, are robust to heterogeneity, and achieve precise recognition by integrating up to three different antigens with positive or negative logic. A three-antigen AND gate composed of three sequentially linked receptors shows selectivity in vivo, clearing three-antigen tumors while ignoring related two-antigen tumors. Daisy-chaining multiple molecular recognition events together in synthetic circuits provides a powerful way to engineer cellular-level recognition.