Aberrant upregulation of PDK1 in ovarian cancer cells impairs CD8⁺ T cell function and survival through elevation of PD-L1

Abstract

Blockade of the programmed cell death 1(PD-1)/PD-1 ligand-1(PD-L1) pathway has been exploited therapeutically in many cancer types. Upregulation of PD-L1 in tumor cells contributes to malignancy through suppression of the T cell-mediated antitumor response. Pyruvate dehydrogenase kinase 1 (PDK1), a glycolytic gate-keeping enzyme, is also known to promote tumor development. Here, we have uncovered a mechanism of regulation of PD-L1 by PDK1 through activation of c-Jun-NH 2-kinase (JNK)-c-Jun in ovarian cancer cells. Elevated PDK1 expression was correlated with that of PD-L1 in the TCGA ovarian cancer dataset and ovarian cancer tissue array. Overexpression of PDK1 in ovarian cancer cells impaired CD8 + T cell function by suppressing IFN-γ secretion through the PD-1/PD-L1 pathway. Conversely, knockdown of PDK1 in ovarian cancer cells relieved suppression of CD8 + T cell function. CD8 + T cell apoptosis induced by binding of PD-1 with PD-L1 was increased after co-culture with ovarian cancer cells overexpressing PDK1, while depletion of PDK1 exerted the opposite effect. In vivo experiments revealed synergistic improved overall survival and enhanced inhibition of tumor growth upon co-treatment with dichloroacetate (DCA), a PDK inhibitor, and PD-L1 antibody, accompanied by increased IFN-γ secretion by monocytes infiltrating tumor islets. Moreover, PDK1 expression and CD8 + T cell infiltration were inversely correlated in the ovarian cancer tissue array. Our collective findings provide a novel explanation of how PDK1 contributes to upregulation of PD-L1 in ovarian cancer and highlight its potential as a target therapeutic molecule that cooperates with the immune checkpoint blockade.

The Perfect Combination: Enhancing Patient Response to PD-1-Based Therapies in Epithelial Ovarian Cancer

“…Remarkably, a study by Wang et al determined that the glycolytic enzyme, pyruvate dehydrogenase kinase-1 (PDK1) correlates to levels of PD-L1 in EOC patient tissue [ 126 ]. It was also discovered that PDK1 overexpression resulted in reduced IFNγ secretion leading to reduced CD8+ T cell function, with a PDK1 knockdown reversing this effect.…”

<p>Programmed Death-1 Receptor (PD-1) as a Potential Prognosis Biomarker for Ovarian Cancer Patients</p>

“…15 Considering the foregoing clinical trials and the drug efficiency in many cancers, including melanoma, leukemia, renal, gastric, lung, and bladder cancer, immunotherapy is also a promising approach in ovarian cancer treatment. 2,17,[29][30][31][32] Moreover, data suggest that the response to PD-1/PD-L1 pathway inhibitors may be dependent on the OC histological type. 31,33 Currently, no PD-1/PD-L1 pathway inhibitors have been approved by FDA in OC treatment.…”

Wnt5b-induced PCP/JNK&nbsp;Activation Promotes PD-L1&nbsp;Expression and the Malignant Phenotype of Non-small Cell Lung Cancer&nbsp;

“…expression is a predictor of the response to immune checkpoint inhibitors and the survival of the patients [56]. JNK signaling contributes to the upregulation of PD-L1 expression in malignant tumors [18,39].…”

“…JNK could upregulate PD-L1 expression in malignant tumors [18,39]. So we explored whether Wnt5b regulated PD-L1 through JNK signaling.…”

“…As a major signaling cassette of the mitogen-activated protein kinase (MAPK), the c-Jun N-terminal kinase (JNK) takes part in Wnt/PCP signaling [15][16][17]. Previous study confirmed that Dvl-3 could activate JNK in NSCLC [13], and also JNK activation is crucial for PD-L1 regulation in ovarian cancer cells [18]. Frizzled (Fzd) family belongs to seven transmembrane receptors, including ten isoforms (Fzd1-10).…”