| Contributors: |
Spiga, M.; Potenza, A.; Magnani, Z.; Beretta, S.; Camisa, B.; Conte, L.; Airaghi, A.; Mohammadi, N.; Perani, L.; Doglioni, C.; Ponzoni, M.; Sanvito, F.; Balestrieri, C.; Sergi Sergi, L.; Botrugno, O. A.; Giovannoni, G.; Tonon, G.; Abbati, D.; Iozzi, C.; Reichert, M.; Algul, H.; Pocaterra, A.; Fiumara, M.; Ferrari, S.; Ugolini, A.; Grometto, A.; Di Lullo, G.; Sitia, G.; Belfiori, G.; Protti, M. P.; Ostuni, R.; Mondino, A.; Reni, M.; Crippa, S.; Falconi, M.; Naldini, L.; Ruggiero, E.; Bonini, C. |
| Description: |
T-cell avidity is a major determinant of Adoptive T cell therapy (ACT) efficacy for cancer treatment. However, high-avidity tumor-specific T cells can rarely be isolated from cancer patients, highlighting the need for strategies to enhance the cytotoxic capacity of low-avidity cells. Here, we rescue the anti-tumor functions of low-avidity T cells against pancreatic ductal adenocarcinoma (PDAC) by knocking-out TIGIT, a key inhibitory molecule expressed on exhausted CD8+ T cells infiltrating gastrointestinal tumors. We uncover that TIGIT disruption by base editing boosts the intracellular signal transduction derived from a weak T cell receptor (TCR) engagement enforcing cytoskeletal rearrangements, thus increasing T cell avidity and stabilizing the immunological synapse. Accordingly, TIGIT disruption enables low-avidity T cells to exert robust degranulation, comparable to that of high-avidity T cells, and potent and durable anti-tumor capacity in vivo in male mice. These results highlight TIGIT knockout as a potential strategy to enhance low-avidity T cell function and broaden the repertoire of TCR engineered T cells in the treatment of pancreatic cancer and other solid malignancies. |