Journal Article

TIGIT disruption rescues the antitumor activity of low avidity TCR-engineered T cells by increasing TCR signal strength

Di Lullo, Giulia, Crippa, Stefano, Naldini, Luigi, Balestrieri, Chiara, Protti, Maria Pia, Algul, Hana, Doglioni, Claudio, Pocaterra, Arianna, Abbati, Danilo, Falconi, Massimo, Iozzi, Chiara, Conte, Laura, Botrugno, Oronza A., Grometto, Alice, Spiga, Martina, Magnani, Zulma, Bonini, Chiara, Mohammadi, Neda, Perani, Laura, Giovannoni, Giulio, Potenza, Alessia, Mondino, Anna, Ostuni, Renato, Ruggiero, Eliana, Airaghi, Alessia, Camisa, Barbara, Ponzoni, Maurilio, Reichert, Maximilian, Sanvito, Francesca, Tonon, Giovanni, Reni, Michele, Belfiori, Giulio, Fiumara, Martina, Beretta, Stefano, Ferrari, Samuele, Sergi Sergi, Lucia, Ugolini, Alessia, Sitia, Giovanni

2026

Overview

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. Anti-tumor functions of low-avidity T cells are often suboptimal. Here the authors show that genetic disruption of TIGIT in TCR-engineered T cells enhances their anti-tumor activity against pancreatic and other gastrointestinal cancers by increasing TCR signal strength.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13/1 / 13/106 / 13/109 / 13/21 / 13/31 / 13/51 / 14/1 / 14/5 / 14/63 / 38/1 / 38/22 / 38/23 / 38/39 / 38/43 / 38/44 / 38/77 / 38/90 / 38/91 / 45/29 / 631/250/580 / 631/67/1059/2325 / 64/110 / 692/4017 / Adenocarcinoma / Animals / Anticancer properties / Antigens / Antitumor activity / Antitumor agents / Avidity / Cancer / Cancer therapies / Carcinoma, Pancreatic Ductal - genetics / Carcinoma, Pancreatic Ductal - immunology / Carcinoma, Pancreatic Ductal - therapy / CD8 antigen / CD8-Positive T-Lymphocytes - immunology / Cell Line, Tumor / Cell therapy / Cells / Cloning / Cytoskeleton / Cytotoxicity / Degranulation / Disruption / Editing / Humanities and Social Sciences / Humans / Immunohistochemistry / Immunological synapses / Immunology / Immunotherapy, Adoptive - methods / Independent sample / Lymphocytes / Lymphocytes T / Male / Malignancy / Metastasis / Mice / Mice, Inbred C57BL / Mice, Knockout / multidisciplinary / Pancreatic cancer / Pancreatic Neoplasms - genetics / Pancreatic Neoplasms - immunology / Pancreatic Neoplasms - therapy / Protein expression / Proteins / Receptors, Antigen, T-Cell - genetics / Receptors, Antigen, T-Cell - immunology / Receptors, Antigen, T-Cell - metabolism / Receptors, Immunologic - genetics / Receptors, Immunologic - immunology / Receptors, Immunologic - metabolism / Science / Science (multidisciplinary) / Signal strength / Signal transduction / Signal Transduction - immunology / T cell receptors / Tumor-infiltrating lymphocytes / Tumors