TY - JOUR
T1 - Triple-negative breast cancer cells rely on kinase-independent functions of CDK8 to evade NK-cell-mediated tumor surveillance
AU - Knab, Vanessa Maria
AU - Gotthardt, Dagmar
AU - Klein, Klara
AU - Grausenburger, Reinhard
AU - Heller, Gerwin
AU - Menzl, Ingeborg
AU - Prinz, Daniela
AU - Trifinopoulos, Jana
AU - List, Julia
AU - Fux, Daniela
AU - Witalisz-Siepracka, Agnieszka
AU - Sexl, Veronika
N1 - Publisher Copyright:
© 2021, The Author(s).
PY - 2021/11
Y1 - 2021/11
N2 - Triple-negative breast cancer (TNBC) is an aggressive malignant disease that is responsible for approximately 15% of breast cancers. The standard of care relies on surgery and chemotherapy but the prognosis is poor and there is an urgent need for new therapeutic strategies. Recent in silico studies have revealed an inverse correlation between recurrence-free survival and the level of cyclin-dependent kinase 8 (CDK8) in breast cancer patients. CDK8 is known to have a role in natural killer (NK) cell cytotoxicity, but its function in TNBC progression and immune cell recognition or escape has not been investigated. We have used a murine model of orthotopic breast cancer to study the tumor-intrinsic role of CDK8 in TNBC. Knockdown of CDK8 in TNBC cells impairs tumor regrowth upon surgical removal and prevents metastasis. In the absence of CDK8, the epithelial-to-mesenchymal transition (EMT) is impaired and immune-mediated tumor-cell clearance is facilitated. CDK8 drives EMT in TNBC cells in a kinase-independent manner. In vivo experiments have confirmed that CDK8 is a crucial regulator of NK-cell-mediated immune evasion in TNBC. The studies also show that CDK8 is involved in regulating the checkpoint inhibitor programmed death-ligand 1 (PD-L1). The CDK8-PD-L1 axis is found in mouse and human TNBC cells, underlining the importance of CDK8-driven immune cell evasion in these highly aggressive breast cancer cells. Our data link CDK8 to PD-L1 expression and provide a rationale for investigating the possibility of CDK8-directed therapy for TNBC.
AB - Triple-negative breast cancer (TNBC) is an aggressive malignant disease that is responsible for approximately 15% of breast cancers. The standard of care relies on surgery and chemotherapy but the prognosis is poor and there is an urgent need for new therapeutic strategies. Recent in silico studies have revealed an inverse correlation between recurrence-free survival and the level of cyclin-dependent kinase 8 (CDK8) in breast cancer patients. CDK8 is known to have a role in natural killer (NK) cell cytotoxicity, but its function in TNBC progression and immune cell recognition or escape has not been investigated. We have used a murine model of orthotopic breast cancer to study the tumor-intrinsic role of CDK8 in TNBC. Knockdown of CDK8 in TNBC cells impairs tumor regrowth upon surgical removal and prevents metastasis. In the absence of CDK8, the epithelial-to-mesenchymal transition (EMT) is impaired and immune-mediated tumor-cell clearance is facilitated. CDK8 drives EMT in TNBC cells in a kinase-independent manner. In vivo experiments have confirmed that CDK8 is a crucial regulator of NK-cell-mediated immune evasion in TNBC. The studies also show that CDK8 is involved in regulating the checkpoint inhibitor programmed death-ligand 1 (PD-L1). The CDK8-PD-L1 axis is found in mouse and human TNBC cells, underlining the importance of CDK8-driven immune cell evasion in these highly aggressive breast cancer cells. Our data link CDK8 to PD-L1 expression and provide a rationale for investigating the possibility of CDK8-directed therapy for TNBC.
KW - Animals
KW - Cyclin-Dependent Kinase 8/metabolism
KW - Humans
KW - Killer Cells, Natural/metabolism
KW - Mice
KW - Triple Negative Breast Neoplasms/genetics
UR - http://www.scopus.com/inward/record.url?scp=85117817186&partnerID=8YFLogxK
U2 - 10.1038/s41419-021-04279-2
DO - 10.1038/s41419-021-04279-2
M3 - Journal article
C2 - 34689158
SN - 2041-4889
VL - 12
SP - 991
JO - Cell Death and Disease
JF - Cell Death and Disease
IS - 11
M1 - 991
ER -