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ANGPTL3 in the Peripheral Circulation Is Associated with Resistance to Anti-PD1 Therapy in Advanced Gastric Cancer
Chie Kudo-Saito1, Hirokazu Shoji2, Kengo Nagashima3
1Department of Immune Medicine, National Cancer Center Research Institute, Tokyo, Japan.
Abstract:
Anti-PD1/-PDL1 therapy has attracted great attention in cancer therapy in recent years, but a serious problem remains that only a small portion of patients can benefit from it. In this study, we attempted to identify a molecule that is associated with anti-PD1/-PDL1 therapeutic efficacy through proteomic profiling of plasma obtained from patients with advanced gastric cancer (AGC) receiving anti-PD1 nivolumab monotherapy. We collected peripheral blood from 91 patients with AGC before and after nivolumab treatment, and plasma was analyzed by the SomaScan v4.1 and ELISA. Relationships between the levels and patient prognosis were statistically analyzed. To evaluate antitumor effects induced by blocking the identified molecule for which high levels were significantly associated with poor prognosis, in vivo therapeutic experiments using mouse tumor models were conducted. Proteomic data revealed that the levels of 14 molecules both before and after treatment were significantly higher in patients with progressive disease (PD) than those in non-PD patients. Among them, angiopoietin-like 3 (ANGPTL3) levels were notably higher in PD patients than those in non-PD patients, and patients with high levels of ANGPTL3 either before or after treatment showed significantly worse prognosis. In mouse tumor models with increased ANGPTL3, anti-ANGPTL3 therapy significantly reduced tumor growth and synergistically enhanced anti-PD1 therapeutic efficacy. These suggest that high levels of ANGPTL3 in plasma are a significant risk factor associated with unresponsiveness to anti-PD1 treatment and poor prognosis. Targeting ANGPTL3 in the peripheral circulation may be a promising strategy to improve clinical outcomes in anti-PD1/-PDL1 therapy for AGC.
Significance:
This study provides valuable evidence suggesting the importance of targeting peripheral ANGPTL3 in the anti-PD1/-PDL1 therapy for AGC and will encourage and accelerate the development of a useful biomarker to predict responders/nonresponders to the therapy, leading to improved clinical outcomes in the treatment of gastric cancer.
Insights
High levels of Angiopoietin-like 3 (ANGPTL3) in gastric cancer patients predict poor response to anti-PD1 therapy. Targeting ANGPTL3 may improve treatment efficacy for these patients.
Area of Science:
- Oncology
- Immunotherapy
- Proteomics
Background:
- Anti-programmed cell death protein 1 (PD1)/programmed death-ligand 1 (PDL1) therapy shows promise in cancer treatment.
- However, only a subset of patients benefit from these immunotherapies, necessitating biomarkers for efficacy prediction.
Purpose of the Study:
- To identify plasma molecules associated with anti-PD1 therapeutic efficacy in advanced gastric cancer (AGC).
- To investigate the role of Angiopoietin-like 3 (ANGPTL3) in predicting response to nivolumab therapy.
Main Methods:
- Proteomic profiling of plasma from 91 AGC patients before and after nivolumab treatment using SomaScan v4.1 and ELISA.
- Statistical analysis of molecule levels and patient prognosis.
- In vivo experiments using mouse tumor models to assess anti-tumor effects of ANGPTL3 blockade.
Main Results:
- 14 molecules were significantly elevated in patients with progressive disease (PD) compared to non-PD patients.
- ANGPTL3 levels were notably higher in PD patients and associated with worse prognosis.
- Anti-ANGPTL3 therapy reduced tumor growth and enhanced anti-PD1 efficacy in mouse models.
Conclusions:
- Elevated plasma ANGPTL3 is a risk factor for unresponsiveness to anti-PD1 therapy and poor prognosis in AGC.
- Targeting ANGPTL3 could be a viable strategy to improve outcomes for patients receiving anti-PD1/PDL1 therapy.
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