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

doi:10.1016/j.celrep.2024.114979

Leader cells promote immunosuppression to drive ovarian cancer progression in vivo

Cell Rep. 2024 Nov 13;43(11):114979. doi: 10.1016/j.celrep.2024.114979. Online ahead of print.

Authors

Amy L Wilson¹, Laura R Moffitt¹, Brittany R Doran¹, Bashira Basri², Jennie Do¹, Thomas W Jobling³, Magdalena Plebanski⁴, Andrew N Stephens¹, Maree Bilandzic⁵

Affiliations

¹ Hudson Institute of Medical Research, Clayton, VIC, Australia; Department of Molecular and Translational Sciences, Monash University, Clayton, VIC, Australia.
² Hudson Institute of Medical Research, Clayton, VIC, Australia.
³ Monash Medical Centre, Department of Gynecology Oncology, Monash Health, 823-865 Centre Rd, Bentleigh East, VIC 3165, Australia.
⁴ School of Health and Biomedical Sciences, RMIT University, Bundoora, VIC, Australia.
⁵ Hudson Institute of Medical Research, Clayton, VIC, Australia; Department of Molecular and Translational Sciences, Monash University, Clayton, VIC, Australia. Electronic address: maree.bilandzic@hudson.org.au.

PMID: 39541210
DOI: 10.1016/j.celrep.2024.114979

Abstract

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 (LC^KO) 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.

Keywords: CP: Cancer; T regulatory cells; cancer metastasis; chemokines; immunosuppression; keratin-14; leader cells; ovarian cancer.