Targeting Plk1 Sensitizes Pancreatic Cancer to Immune Checkpoint Therapy

Abstract

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 PDAC patients. 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 (ADM) and pancreatic intraepithelial neoplasia (PanIN). 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 NFκB pathway. Mechanistically, Plk1-mediated phosphorylation of RB at S758 inhibited the translocation of NFκB to nucleus, inactivating the pathway. Inhibition of Plk1 sensitized PDAC to immune checkpoint blockade therapy through activation of an anti-tumor immune response. Together, Plk1 suppresses PDAC progression and inhibits NFκB activity, and targeting Plk1 can potentiate the efficacy of immunotherapy in PDAC.

Single-cell analysis characterizes PLK1 as a catalyst of an immunosuppressive tumor microenvironment in LUAD

“…Both our lab and others have proven that PLK1 overexpression in LUAD leads to cancer progression and is associated with poor overall survival [18,19]. Interestingly, recent studies have validated PLK1 as a potential target to improve the efficacy of immunotherapies in lung cancer [20], consistent with our finding in pancreatic cancer that targeting PLK1 in pancreatic cancer enhances the effectiveness of immune checkpoint blockade [21]. While these results suggest that PLK1 may be an important modulator of tumor immunity, whether and how PLK1 functions in the TME of LUAD is largely unknown.…”

“…Considering the predominant immunosuppressive functions of PLK1 in LUAD and other cancer types, treatment focuses on targeting PLK1 may decelerate tumor growth by boosting immune response in TME. However, it is noteworthy that PLK1 may be negatively correlated with PD-L1 in certain situations [20, 21], devaluing the monotherapy with PLK1 inhibitor as this approach will unexpectedly elevate immune checkpoints. Thus, combination treatment with PLKi and immune checkpoints blockade should exhibit premium effect, and this assumption remains to be investigated by future studies.…”

Concurrent targeting of GSK3 and MEK as a therapeutic strategy to treat pancreatic ductal adenocarcinoma

“…Consistent with this idea, inhibition of PLK1 was reported to sensitize PDAC xenografts to immune checkpoint therapy through the activation of anti-tumor immune responses. 67…”

Identifying M1-like macrophage related genes for prognosis prediction in lung adenocarcinoma based on a gene co-expression network

“…Volasertib, the most advanced and most potent PLK1 inhibitor is currently being tested in Phase I-III trials [ 47 ]. Beyond that, inhibition of Plk1 sensitized pancreatic ductal adenocarcinoma to immune checkpoint blockade therapy through activation of an antitumor immune response [ 48 ]. The model associated patient prognosis with these four genes; to the best of our knowledge, this has not been reported previously.…”