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<p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月8日

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

摘要

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.