1. Tumor FAK orchestrates immunosuppression in ovarian cancer via the CD155/TIGIT axis
- Author
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Ozmadenci, Duygu, Narayanan, Jayanth S Shankara, Andrew, Jacob, Ojalill, Marjaana, Barrie, Allison M, Jiang, Shulin, Iyer, Samhita, Chen, Xiao Lei, Rose, Michael, Estrada, Valeria, Molinolo, Alfredo, Bertotto, Thomas, Mikulski, Zbigniew, McHale, Michael C, White, Rebekah R, Connolly, Denise C, Pachter, Jonathan A, Kuchroo, Vijay K, Stupack, Dwayne G, and Schlaepfer, David D
- Subjects
Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Immunology ,Clinical Research ,Biotechnology ,Immunotherapy ,Rare Diseases ,Cancer Genomics ,Cancer ,Genetics ,Orphan Drug ,Women's Health ,Ovarian Cancer ,Human Genome ,5.1 Pharmaceuticals ,2.1 Biological and endogenous factors ,Good Health and Well Being ,Animals ,Carcinoma ,Ovarian Epithelial ,Female ,Focal Adhesion Kinase 1 ,Focal Adhesion Protein-Tyrosine Kinases ,Humans ,Immunosuppression Therapy ,Ligands ,Mice ,Ovarian Neoplasms ,Receptors ,Immunologic ,high-grade serous ovarian cancer ,immunotherapy ,FAK ,CD155 ,tertiary lymphoid structures - Abstract
High-grade serous ovarian cancer (HGSOC) is a lethal malignancy characterized by an immunosuppressive tumor microenvironment containing few tumor infiltrating lymphocytes (TILs) and an insensitivity to checkpoint inhibitor immunotherapies. Gains in the PTK2 gene encoding focal adhesion kinase (FAK) at Chr8 q24.3 occur in ∼70% of HGSOC tumors, and elevated FAK messenger RNA (mRNA) levels are associated with poor patient survival. Herein, we show that active FAK, phosphorylated at tyrosine-576 within catalytic domain, is significantly increased in late-stage HGSOC tumors. Active FAK costained with CD155, a checkpoint receptor ligand for TIGIT (T cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domains), in HGSOC tumors and a selective association between FAK and TIGIT checkpoint ligands were supported by patient transcriptomic database analysis. HGSOC tumors with high FAK expression were associated with low CD3 mRNA levels. Accordingly, late-stage tumors showed elevated active FAK staining and significantly lower levels of CD3+ TILs. Using the KMF (Kras, Myc, FAK) syngeneic ovarian tumor model containing spontaneous PTK2 (FAK) gene gains, the effects of tumor intrinsic genetic or oral small molecule FAK inhibitior (FAKi; VS-4718) were evaluated in vivo. Blocking FAK activity decreased tumor burden, suppressed ascites KMF-associated CD155 levels, and increased peritoneal TILs. The combination of FAKi with blocking TIGIT antibody (1B4) maintained elevated TIL levels and reduced TIGIT+ T regulatory cell levels, prolonged host survival, increased CXCL13 levels, and led to the formation of omental tertiary lymphoid structures. Collectively, our studies support FAK and TIGIT targeting as a rationale immunotherapy combination for HGSOC.
- Published
- 2022