TIGIT disruption rescues the antitumor activity of low avidity TCR-engineered T cells by increasing TCR signal strength
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<sup>+</sup> 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.
Authors
- Martina Fiumara (ORCID: https://orcid.org/0009-0007-5934-9273)
- F. Sanvito
- Hana Algül (ORCID: https://orcid.org/0000-0002-5067-7031)
- Mirco Ponzoni (ORCID: https://orcid.org/0000-0002-6164-4286)
- Laura Perani (ORCID: https://orcid.org/0000-0001-8616-3377)
- Eliana Ruggiero (ORCID: https://orcid.org/0000-0002-2954-8278)
- Samuele Ferrari (ORCID: https://orcid.org/0000-0003-1122-1231)
- Chiara Balestrieri (ORCID: https://orcid.org/0000-0001-7362-3530)
- Neda Mohammadi (ORCID: https://orcid.org/0000-0002-9196-0503)
- Stefano Crippa
- Arianna Pocaterra (ORCID: https://orcid.org/0000-0002-5571-6394)
- Claudio Doglioni (ORCID: https://orcid.org/0000-0002-4969-5216)
- Giulia Di Lullo (ORCID: https://orcid.org/0000-0002-9358-920X)
- Massimo Falconi (ORCID: https://orcid.org/0000-0001-9654-7243)
- Giovanni Sitia (ORCID: https://orcid.org/0000-0003-1024-9128)
- Renato Ostuni (ORCID: https://orcid.org/0000-0003-0460-3426)
- Danilo Abbati (ORCID: https://orcid.org/0000-0001-8517-7937)
- Alessia Potenza (ORCID: https://orcid.org/0000-0003-0298-7315)
- Oronza A. Botrugno (ORCID: https://orcid.org/0000-0002-2568-9815)
- Maximilian Reichert (ORCID: https://orcid.org/0000-0002-8611-5639)
- Martina Spiga
- Laura Conte (ORCID: https://orcid.org/0000-0003-4319-010X)
- Stefano Beretta (ORCID: https://orcid.org/0000-0003-4375-004X)
- Barbara Camisa (ORCID: https://orcid.org/0000-0002-3867-2457)
- Chiara Bonini (ORCID: https://orcid.org/0000-0002-5070-9726)
- Chiara Iozzi
- Alessia Airaghi
- Luigi Naldini
- Tonon
- Alessia Ugolini
- Michele Reni
- Alice Grometto
- Giulio Giovannoni
- Lucia Sergi Sergi
- Giulio Belfiori
- Anna Mondino
- Zulma Magnani
- Maria Pia Protti
Institutions
- Vita-Salute San Raffaele University (IT)
- TUM Klinikum (DE)
- The San Raffaele Telethon Institute for Gene Therapy (IT)
- Istituti di Ricovero e Cura a Carattere Scientifico (IT)
- Pancreas Centre (Canada) (CA)
- Istituto di Ricovero e Cura a Carattere Scientifico San Raffaele (IT)
- Technical University of Munich (DE)
Publication Details
- Journal
- Nature Communications
- Published
- 2026-01-08
- DOI
- https://doi.org/10.1038/s41467-025-67263-w
- Citations
- 1
- Primary Topic
- CAR-T cell therapy research
- Type
- article
- Field-Weighted Citation Impact
- 24.20