Targeting Plk1 Sensitizes Pancreatic Cancer to Immune Checkpoint Therapy.

Polo-like kinase 1 (Plk1) plays an important role in cell-cycle regulation. Recent work has suggested that Plk1 could be a biomarker of gemcitabine response in pancreatic ductal adenocarcinoma (PDAC). Although targeting Plk1 to treat PDAC has been attempted in clinical trials, the results were not promising, and the mechanisms of resistance to Plk1 inhibition is poorly understood. In addition, the role of Plk1 in PDAC progression requires further elucidation. Here, we showed that Plk1 was associated with poor outcomes in patients with PDAC. In an inducible transgenic mouse line with specific expression of Plk1 in the pancreas, Plk1 overexpression significantly inhibited caerulein-induced acute pancreatitis and delayed development of acinar-to-ductal metaplasia and pancreatic intraepithelial neoplasia. Bioinformatics analyses identified the regulatory networks in which Plk1 is involved in PDAC disease progression, including multiple inflammation-related pathways. Unexpectedly, inhibition or depletion of Plk1 resulted in upregulation of PD-L1 via activation of the NF-κB pathway. Mechanistically, Plk1-mediated phosphorylation of RB at S758 inhibited the translocation of NF-κB to nucleus, inactivating the pathway. Inhibition of Plk1 sensitized PDAC to immune checkpoint blockade therapy through activation of an antitumor immune response. Together, Plk1 suppresses PDAC progression and inhibits NF-κB activity, and targeting Plk1 can potentiate the efficacy of immunotherapy in PDAC. SIGNIFICANCE: Inhibition of Plk1 induces upregulation of PD-L1 expression in pancreatic ductal adenocarcinoma, stimulating antitumor immunity and sensitizing tumors to immunotherapy.

Adenosinergic Signaling Alters Natural Killer Cell Functional Responses.

Adenosine is a potent immunosuppressive purine metabolite contributing to the pathogenesis of solid tumors. Extracellular adenosine signals on tumor-infiltrating NK cells to inhibit their proliferation, maturation, and cytotoxic function. Cytokine priming imparts upon NK cells distinct activation statuses, which modulate NK anti-tumor immunity and responses to purinergic metabolism. Here, for the first time, we investigated human NK cell responses to adenosinergic signaling in the context of distinct cytokine priming programs. NK cells were shown to be hyper-responsive to adenosine when primed with IL-12 and IL-15 compared to IL-2, exhibiting enhanced IFN-γ expression from CD56bright and CD56dim subsets while modulating the expression of activation marker NKG2D. These responses resulted in signaling that was dependent on mTOR. Adenosine induced upregulation of transcriptional signatures for genes involved in immune responses while downregulating cellular metabolism and other protein synthesis functions that correlate to inhibited oxidative phosphorylation and glycolysis. Overall, our findings show that adenosine acts on specific cellular pathways rather than inducing a broad inhibition of NK cell functions. These responses are dependent on cytokine priming signatures and are important in designing therapeutic interventions that can reprogram NK cell immunometabolism for improved immunotherapies of solid tumors.