Open AccessTumor FAK orchestrates immunosuppression in ovarian cancer via the CD155/TIGIT axis
Author(s) -
Duygu Ozmadenci,
Jayanth S. Shankara Narayanan,
Jacob R. Andrew,
Marjaana Ojalill,
A. Barrie,
Shulin Jiang,
Samhita Iyer,
Xiao Lei Chen,
Michael Rose,
Mónica V. Estrada,
Alfredo Molinolo,
Thomas Bertotto,
Zbigniew Mikulski,
Michael C. McHale,
Rebekah R. White,
Denise C. Connolly,
Jonathan A. Pachter,
Vijay K. Kuchroo,
Dwayne G. Stupack,
David D. Schlaepfer
Publication year - 2022
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.2117065119
Subject(s) - tigit , cancer research , focal adhesion , ovarian cancer , biology , immunotherapy , immunology , medicine , cancer , signal transduction , immune system , microbiology and biotechnology
Significance High-grade serous ovarian carcinoma (HGSOC) is an immunotherapy-resistant lethal cancer. An HGSOC hallmark is elevated checkpoint pathway ligand expression that limits antitumor immune responses. Computational, preclinical, and patient tumor multiplexed analyses revealed that tumor-associated focal adhesion kinase (FAK) activation regulates CD155 expression, a checkpoint ligand for TIGIT (T cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domains). Using an aggressive mouse ovarian tumor model, we find that combined oral FAK inhibitor plus function-blocking TIGIT antibody immunotherapy reduced tumor burden, prolonged mouse survival, and led to immune cell activation and tertiary lymphoid structure formation, hallmarks of an antitumor immune response. As FAK is commonly overexpressed in HGSOC tumors, targeting FAK and TIGIT may limit tumor immune evasion.