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Published on: October 9, 2018
Combinational blockade of MET and PD-L1 improves pancreatic cancer immunotherapeutic efficacy
Enliang Li1,2,3,4,5,6, Xing Huang7,8,9,10,11,12, Gang Zhang1,2,3,4,5,6
1Zhejiang Provincial Key Laboratory of Pancreatic Disease, the First Affiliated Hospital, School of Medicine, Zhejiang University, 310009, Hangzhou, Zhejiang, China.
Background:
Dysregulated 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.
Methods:
Kaplan-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.
Results:
MET 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.
Conclusions:
This 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.
Insights
MET receptor tyrosine kinase (RTK) is a promising target for pancreatic cancer immunotherapy. Targeting MET and PD-L1 together can improve treatment outcomes for pancreatic cancer patients.
Area of Science:
- Oncology
- Immunotherapy
- Molecular Biology
Background:
- Receptor tyrosine kinases (RTKs) are dysregulated in many cancers, but current therapies are ineffective against pancreatic cancer.
- Pancreatic cancer presents a complex immune microenvironment, making immunotherapy challenging.
- Understanding RTK roles in pancreatic tumors is crucial for developing effective immunotherapies.
Purpose of the Study:
- To investigate the prognostic significance of RTKs in pancreatic tumors with varying immune profiles.
- To explore the potential of targeting RTKs in pancreatic cancer immunotherapy.
- To elucidate the relationship between RTKs, immune checkpoints, and treatment response.
Main Methods:
- Kaplan-Meier plotter analysis for RTK prognostic significance in immune-hot and -cold tumors.
- Gene Expression Profiling Interactive Analysis (GEPIA-2) for RTK differential expression and correlation with immune checkpoints.
- Immunohistochemical analysis of 150 clinical pancreatic cancer specimens.
- Biochemistry and flow cytometry in pancreatic cancer cell lines to assess RTK effects on immune checkpoints.
- In vivo studies to evaluate combined RTK inhibition and immune checkpoint blockade.
Main Results:
- MET was identified as a pancreatic cancer-specific RTK, prognostic in both immune-hot and -cold tumors.
- MET is upregulated in pancreatic cancer and positively correlates with PD-L1 expression.
- Elevated MET and PD-L1 correlate with advanced tumor stage, metastasis, and poorer survival.
- MET regulates PD-L1 expression and its inhibition promotes lymphocyte infiltration.
- Combination therapy of MET inhibition and PD-1/PD-L1 blockade showed significant benefits in preclinical models.
Conclusions:
- MET plays a key role in regulating PD-L1 expression in pancreatic cancer.
- Targeting MET in combination with PD-L1 blockade offers a promising therapeutic strategy for pancreatic cancer.
- This study provides a rationale for novel immunotherapies targeting RTKs in pancreatic cancer.
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