Abstract
BackgroundDysregulated expression and activation of receptor tyrosine kinases (RTKs) are associated with a range of human cancers. However, current RTK-targeting strategies exert little effect on pancreatic cancer, a highly malignant tumor with complex immune microenvironment. Given that immunotherapy for pancreatic cancer still remains challenging, this study aimed to elucidate the prognostic role of RTKs in pancreatic tumors with different immunological backgrounds and investigate their targeting potential in pancreatic cancer immunotherapy.MethodsKaplan–Meier plotter was used to analyze the prognostic significance of each of the all-known RTKs to date in immune “hot” and “cold” pancreatic cancers. Gene Expression Profiling Interactive Analysis-2 was applied to assess the differential expression of RTKs between pancreatic tumors and normal pancreatic tissues, as well as its correlation with immune checkpoints (ICPs). One hundred and fifty in-house clinical tissue specimens of pancreatic cancer were collected for expression and correlation validation via immunohistochemical analysis. Two pancreatic cancer cell lines were used to demonstrate the regulatory effects of RTKs on ICPs by biochemistry and flow cytometry. Two in vivo models bearing pancreatic tumors were jointly applied to investigate the combinational regimen of RTK inhibition and immune checkpoint blockade for pancreatic cancer immunotherapy.ResultsMET was identified as a pancreatic cancer-specific RTK, which is significantly associated with prognosis in both immune “hot” and “cold” pancreatic cancers. MET was observed to be highly upregulated in pancreatic cancer tissues, and positively correlated with PD-L1 levels. Elevated MET and PD-L1 expressions were closely associated with lymph node metastasis, tumor TNM stage, and overall survival in pancreatic cancer. Mechanistically, MET could interact with PD-L1, and maintain its expression level in multiple ways. MET deficiency was found to facilitate lymphocyte infiltration into pancreatic tumors. Finally, significant benefits of combining MET inhibition with PD-1/PD-L1 blockage were verified in both orthotopic and subcutaneous mouse models of pancreatic cancer.ConclusionsThis study systematically investigated the potential effectiveness of a novel pancreatic cancer immunotherapy targeting RTKs, and revealed the function of MET in PD-L1 regulation as well as the combined therapeutic efficacy of MET and PD-L1 in pancreatic cancer.
Highlights
Dysregulated expression and activation of receptor tyrosine kinases (RTKs) are associated with a range of human cancers
We identified pancreatic cancer-specific RTKs, which are significantly upregulated in pancreatic tumors and associated with Immune checkpoint (ICP)
We focused on the RTKs that were upregulated in pancreatic cancer tissues compared with normal pancreatic tissues, and six most well-established inhibitory ICPs on the tumor side were selected and integrated as the ICP signature in our study; these included PD-1 ligand 1 (PD-L1), CD276, CD155, CD112, LGALS9, and HVEM
Summary
Dysregulated expression and activation of receptor tyrosine kinases (RTKs) are associated with a range of human cancers. Current RTK-targeting strategies exert little effect on pancreatic cancer, a highly malignant tumor with complex immune microenvironment. Given the late diagnosis, rapid metastatic progression, resistance to conventional therapeutics, and increased incidence rate of pancreatic cancer, it is expected to become the second leading cause of cancerrelated deaths in the United States by 2030 [6]. This poses a grave threat to human health and survival. To enhance our understanding of the efficacy of RTK-targeting therapy, further investigation with regard to the selection of targets and therapeutic strategies is warranted
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