Tumor FAK orchestrates immunosuppression in ovarian cancer via the CD155/TIGIT axis

• DOI: 10.1073/pnas.2117065119
• Publication Date: 2022-04-25T19:07:45Z
• Authors: Duygu Ozmadenci; Jayanth S. Shanka...; Jacob Andrew; Marjaana Ojalill; Allison M. Barrie; Shulin Jiang; Samhita Iyer; Xiao Lei Chen; Michael Rose; Valeria 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
• Keywords: Oncology and Carcinogenesis; Immunology; 610; Carcinoma, Ovarian Epithelial; Ligands; Mice; 03 medical and health sciences; Cancer Genomics; Rare Diseases; Clinical Research; Immunologic; Ovarian Epithelial; high-grade serous ovarian cancer; Receptors; Genetics; 2.1 Biological and endogenous factors; Animals; Humans; CD155; Receptors, Immunologic; Cancer; Immunosuppression Therapy; Ovarian Neoplasms; 0303 health sciences; Biomedical and Clinical Sciences; FAK; Human Genome; Carcinoma; Biological Sciences; Ovarian Cancer; 3. Good health; Orphan Drug; Good Health and Well Being; 5.1 Pharmaceuticals; Focal Adhesion Kinase 1; Focal Adhesion Protein-Tyrosine Kinases; Women's Health; Female; Immunotherapy; immunotherapy; Biotechnology; tertiary lymphoid structures

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.