Major finding: Nuclear FAK stimulates cytokine transcription and Treg recruitment, promoting tumor immune evasion.
Mechanism: CCL5 induction by nuclear FAK promotes tumor growth by inducing Tregs and inhibiting CD8+ T cells.
Impact: FAK inhibitors in clinical development may cause immune-mediated squamous cell carcinoma regression.
Focal adhesion kinase (FAK) is a tyrosine kinase involved in focal adhesions, migration, invasion, survival, and proliferation, and is required for tumorigenesis in multiple tumor types. FAK contains putative nuclear localizations signals, and can translocate to the nucleus under conditions of cellular stress. However, the role of nuclear FAK has not been well defined. Serrels, Lund, and colleagues showed that, in a syngeneic mouse model of squamous cell carcinoma (SCC), FAK-deficient cells exhibited an initial growth period followed by complete tumor regression in immunocompetent mice, whereas in immunodeficient mice, FAK deletion had only a small effect on growth. The tumor regression in FAK-deficient mice required CD8+ T cells; in contrast, infiltrating CD8+ T cells in FAK wild-type tumors were characterized by increased expression of markers of T-cell exhaustion and were associated with increased numbers of regulatory T cells (Treg), suggesting that FAK promotes the formation of an immunosuppressive microenvironment that promotes tumor growth. Mechanistically, nuclear FAK regulated Tregs via its association with transcriptional regulators on chromatin, leading to upregulation of chemokines and cytokines, including Tgfb2 and chemokine (C-C motif) ligand 5 (Ccl5), which has a known role in the recruitment and expansion of Tregs. The effects of nuclear FAK in promoting SCC tumorigenesis required its catalytic activity, as expression of a catalytically inactive FAK mutant or inhibition of FAK with a small-molecule inhibitor (VS-4718) led to SCC tumor regression. Consistent with these findings, VS-4718 reduced the number of Tregs, and its antitumor activity was dependent on CD8+ T cells. Together, these results indicate that nuclear FAK promotes immune evasion in SCC by generating an immunosuppressive microenvironment, and provide a rationale for further study of FAK kinase inhibitors including VS-4718, which is already in early clinical development.
- ©2015 American Association for Cancer Research.
Volume 5, Issue 12
