When targeting post-translational modification of PD-L1 meets pancreatic cancer immunotherapy: a story about synergistic inhibition

Xing Huang, Xueli Bai, Tingbo Liang

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Pancreatic cancer is highly malignant with an insidious onset, resulting in a low rate of early diagnosis. Consequently, only a few patients are suitable for surgery when the tumor is discovered. Moreover, the special anatomical position of the pancreas makes the operation particularly difficult, and patients are prone to recurrence and metastasis after surgery. Therefore, the long-term survival rate of pancreatic cancer patients continues to be the lowest among all solid tumors, and thus pancreatic cancer has been dubbed the “King of Cancer”.

Under the leadership of Professor Tingbo Liang, the Zhejiang Provincial Key Laboratory of Pancreatic Disease (Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang, China) has been committed to systematically meliorating the treatment of pancreatic cancer from multiple perspectives. We have implemented initiatives to significantly improve the prognosis of pancreatic cancer patients and achieve a cure wherever possible. In the early stages of this program, we conducted a series of investigations and made some exciting and important progress. For example, we were the first to establish the high-efficiency and low-toxicity mFOLFIRINOX chemotherapy regimen, which is suitable for the characteristics of the Chinese physiology and has significantly increased the surgical resection rate and patient prognosis. In addition, we adopted a creative approach involving the combination of neoadjuvant chemotherapy with autologous small bowel transplantation, to provide more patients with the opportunity to undergo surgery, and further improve the radical cure rate of pancreatic cancer.

In recent years, immunotherapy, in the form of immune checkpoint inhibitors, has gradually become a new method of tumor treatment following surgical resection, radiotherapy and chemotherapy, as well as targeted therapy, bringing new hope to patients with pancreatic cancer. The interaction between programmed cell death receptor 1 (PD-1) and its ligand 1 (PD-L1), as well as the activation of its downstream signalings, promote tumor immune escape by inhibiting the function and proliferation of T cells. As a result, this interplay has now become the main immunotherapeutic target, and blocking this pathway can reverse the immunosuppressive state of tumors. However, the variety of PD-1/PD-L1 inhibitors currently on the market has not achieved satisfactory outcomes in pancreatic cancer therapy. The reasons for these inadequacies have been explained from the perspective of the special immune microenvironment of pancreatic cancer, such as the lack of immunogenicity and effector T cells in the tumor tissue, as well as the massive infiltration of immunosuppressive cells. Intriguingly, one of our recent studies published in Nature Communications (https://doi.org/10.1038/s41467-021-24769-3; https://rdcu.be/csaZa) revealed for the first time that the post-translational modification (phosphorylation in this case) of PD-L1 is the key reason for the poor efficacy of the PD-L1 targeting antibody in pancreatic cancer therapy.

At the start of this research, we preliminarily identified that PD-L1 has two conventional and evolutionarily-conserved motifs of never in mitosis gene A-related kinase (NEK) family. More interestingly, these two motifs are located among the three glycosylation sites of PD-L1, which have been proven to be critical to the stability of the PD-L1 protein. Based on this discovery, we speculated that PD-L1 stability is maintained by NEK kinase-mediated phosphorylation, and inhibition of NEK kinase is likely to significantly enhance the effectiveness of the PD-L1 targeting antibody in the treatment of pancreatic cancer. Based on this concept, we launched a series of studies. We first discovered that NEK2, a representative member of the NEK family, is highly expressed in pancreatic cancer and is negatively correlated with the prognosis of pancreatic cancer (especially immune “hot” tumors) as well as the quantity and activity of tumor-infiltrating lymphocytes. Furthermore, we found that the deletion of NEK2 can significantly increase the immunogenicity of pancreatic cancer, and that NEK2 inhibitors can inhibit tumor growth in an immune system-dependent manner. Subsequently, by analyzing paired pancreatic tumor tissues and adjacent normal tissues, as well as pancreatic cancer tissue microarrays, we observed a significant positive correlation between the expression levels of NEK2 and PD-L1. Further studies demonstrated that NEK2 inhibits the ubiquitin-proteasome pathway-mediated degradation of PD-L1 through binding and phosphorylating PD-L1, thereby maintaining its stability. Finally, we confirmed that the combination of the NEK2 inhibitor and PD-L1 targeting antibody can indeed significantly enhance the effectiveness of pancreatic cancer immunotherapy.

Our review of the history of NEK2 research revealed that, in addition to regulating the efficacy of cancer immunotherapy, NEK2 is also closely related to tumor chemotherapeutic resistance. In fact, in recent years, accumulating evidence has shown that a few specific proteins that regulate cell cycle (such as CDK4/5/6, including NEK2) can affect the outcomes of both chemotherapy and immunotherapy, which may provide the possibility and opportunity to enhance the comprehensive treatment effect on tumors, while simultaneously reducing potentially toxic side-effects. We will strive to establish a dual regimen of chemotherapy and immunotherapy aimed at a single target for the treatment of pancreatic cancer in the near future.

Xing Huang

Editorial Board Member & Principle Investigator, Zhejiang University School of Medicine

I am interested in all-sided reciprocal control among cancer, immunity, metabolism and resistance, including but not limited to:

1 Tumor immunity:

1.1 regulatory factors and mechanisms of tumor immune checkpoints

1.2 interactive components and mechanisms of tumor immune microenvironment

1.3 influencing elements and mechanisms of tumor immunogenicity

2 Tumor typing:

2.1 local pathological characteristics and pathological typing of tumor

2.2 local metabolic characteristics and metabolic typing of tumor

2.3 local immune characteristics and immune typing of tumor

3 Diagnosis and treatment of tumors:

3.1 biomarkers for early diagnosis and prognosis of tumors

3.2 mechanisms of drug resistance in tumor therapies

3.3 novel techniques and strategies for diagnosis and treatment of tumors