Leader cells promote immunosuppression to drive ovarian cancer progression in vivo
Amy L. Wilson,
Laura R. Moffitt,
Brittany R. Doran,
Bashira Basri,
Jennie Do,
Thomas W. Jobling,
Magdalena Plebanski,
Andrew N. Stephens,
Maree Bilandzic
Affiliations
Amy L. Wilson
Hudson Institute of Medical Research, Clayton, VIC, Australia; Department of Molecular and Translational Sciences, Monash University, Clayton, VIC, Australia
Laura R. Moffitt
Hudson Institute of Medical Research, Clayton, VIC, Australia; Department of Molecular and Translational Sciences, Monash University, Clayton, VIC, Australia
Brittany R. Doran
Hudson Institute of Medical Research, Clayton, VIC, Australia; Department of Molecular and Translational Sciences, Monash University, Clayton, VIC, Australia
Bashira Basri
Hudson Institute of Medical Research, Clayton, VIC, Australia
Jennie Do
Hudson Institute of Medical Research, Clayton, VIC, Australia; Department of Molecular and Translational Sciences, Monash University, Clayton, VIC, Australia
Thomas W. Jobling
Monash Medical Centre, Department of Gynecology Oncology, Monash Health, 823-865 Centre Rd, Bentleigh East, VIC 3165, Australia
Magdalena Plebanski
School of Health and Biomedical Sciences, RMIT University, Bundoora, VIC, Australia
Andrew N. Stephens
Hudson Institute of Medical Research, Clayton, VIC, Australia; Department of Molecular and Translational Sciences, Monash University, Clayton, VIC, Australia
Maree Bilandzic
Hudson Institute of Medical Research, Clayton, VIC, Australia; Department of Molecular and Translational Sciences, Monash University, Clayton, VIC, Australia; Corresponding author
Summary: Over 75% of patients with ovarian cancer present with late-stage disease, often accompanied by extensive metastasis. The metastatic cascade is driven by a sub-population of transcriptionally plastic cells known as ''leader cells'' (LCs), which play a critical role in collective invasion yet remain poorly understood. LCs are marked by the expression of keratin-14 (KRT14), which determines their migratory and invasive capacity in ovarian cancer. This study demonstrates that KRT14+ LCs promote tumor progression through immunosuppression and immune privilege in vivo. In the ID8 syngeneic epithelial ovarian cancer mouse model, tumor-specific loss of KRT14+ LCs impairs tumor progression and metastatic spread without affecting cellular proliferation. Immune profiling shows reduced immunosuppressive regulatory T cells (Tregs) and M2 macrophages and improved CD8+ T cell/Treg ratios in LC knockout (LCKO) mice. Conversely, forced LC overexpression accelerates metastasis and increases the secretion of immunosuppressive chemokines, such as CCL22 and CCL5, highlighting the role of KRT14+ LCs in immune suppression and metastatic progression.
