Tumor FAK orchestrates immunosuppression in ovarian cancer via the CD155/TIGIT axis
Abstract
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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Apr 25, 2022
- Source ID
- 10.1073/pnas.2117065119
Entities
People
- Alfredo A Molinolo
- Allison M. Barrie
- David D Schlaepfer
- Denise C. Connolly
- Duygu Ozmadenci
- Dwayne Stupack
- Jacob Andrew
- Jayanth S. Shankara Narayanan
- Jonathan A. Pachter
- Marjaana Ojalill
- Michael C. Mchale
- Michael J Rose
- Mónica Valeria Estrada
- Rebekah R. White
- Samhita Iyer
- Shulin Jiang
- Thomas Bertotto
- Vijay K. Kuchroo
- Xiao Lei Chen
- Zbigniew Mikulski
Organizations
- Congressionally Directed Medical Research Programs
- Department of Surgery
- Fox Chase Cancer Center
- Harvard Medical School
- La Jolla Institute for Allergy and Immunology
- National Cancer Institute
- Ovarian Cancer Research Alliance
- Verastem Oncology
- Xiamen University