Lenvatinib Combined with PD-1 Blockade Therapy Benefits Gastric Cancers through Immunosuppressive Macrophage
Nina Yi-Tzu Lin1, Hirotomo Machiyama2,3, Akihito Kawazoe4
1Division of Cancer Immunology, Research Institute/Exploratory Oncology Research and Clinical Trial Center (EPOC), National Cancer Center, Tokyo, Japan.
Abstract:
The combination of multikinase inhibitors with PD-1 blockade therapy has emerged as a promising strategy to overcome resistance to PD-1 blockade monotherapy across multiple cancer types, including gastric cancer. In this study, we report that the multikinase inhibitor lenvatinib selectively reduced the number of CD206+CD163+ immunosuppressive macrophages in the tumor microenvironment (TME) and increased antitumor immunity. Longitudinal immunoprofiling was conducted with paired (pre- and posttreatment) tumor samples from patients with advanced gastric cancer who received first- or second-line combination therapy with lenvatinib and pembrolizumab in the EPOC1706 clinical trial. Patients with abundant CD206+CD163+ immunosuppressive macrophage infiltration exhibited favorable responses to combination therapy, accompanied by a significant posttreatment reduction in these cells. Although this immunosuppressive macrophage infiltration was associated with resistance to PD-1 blockade monotherapy, it predicted a response to combination treatment: 8 of the 9 patients with >440 CD206+CD163+ immunosuppressive macrophages/mm2 responded, whereas none of the 8 patients who received monotherapy responded. Mechanistically, lenvatinib inhibited platelet-derived growth factor receptor α (PDGFRα)/fibroblast growth factor receptor (FGFR)-dependent p38 mitogen-activated protein kinase (MAPK) and AKT signaling pathways in F4/80highCD11bint immunosuppressive macrophages, triggering endoplasmic reticulum stress and an unresolved unfolded protein response, resulting in their apoptosis. Furthermore, in multiple animal models, the therapeutic efficacy of the combination was observed in tumors with abundant immunosuppressive macrophages with activated PDGFR/FGFR-AKT/p38 MAPK signaling. Therefore, we propose that the abundance of immunosuppressive macrophages in the TME could serve as a predictive biomarker for patient stratification to guide rational anti-PD-1-based combination therapy in gastric cancer, enabling mechanism-based combination cancer immunotherapy.
Insights
Combining lenvatinib with PD-1 blockade therapy effectively targets immunosuppressive macrophages in gastric cancer. This combination enhances antitumor immunity and shows promise as a predictive biomarker for patient stratification in cancer immunotherapy.
Area of Science:
- Immunology
- Oncology
- Pharmacology
Background:
- Resistance to PD-1 blockade monotherapy is a significant challenge in gastric cancer (GC) treatment.
- Combination therapy with multikinase inhibitors and PD-1 blockade shows promise for overcoming this resistance.
- Immunosuppressive macrophages within the tumor microenvironment (TME) play a crucial role in cancer progression and treatment resistance.
Purpose of the Study:
- To investigate the mechanism by which lenvatinib, a multikinase inhibitor, affects immunosuppressive macrophages in the TME.
- To evaluate the efficacy of lenvatinib in combination with PD-1 blockade (pembrolizumab) in patients with advanced GC.
- To identify potential predictive biomarkers for response to combination immunotherapy in GC.
Main Methods:
- Longitudinal immunoprofiling of tumor samples from GC patients treated with lenvatinib and pembrolizumab.
- Analysis of CD206+CD163+ immunosuppressive macrophage infiltration and its correlation with treatment response.
- Mechanistic studies involving PDGFRα/FGFR signaling pathways and endoplasmic reticulum stress in macrophages.
- Evaluation of combination therapy efficacy in preclinical animal models.
Main Results:
- Lenvatinib selectively reduced CD206+CD163+ immunosuppressive macrophages in the TME, enhancing antitumor immunity.
- Patients with abundant immunosuppressive macrophages responded favorably to lenvatinib and pembrolizumab combination therapy.
- High infiltration of these macrophages predicted response to combination therapy but was associated with resistance to PD-1 monotherapy.
- Lenvatinib inhibited PDGFRα/FGFR-dependent signaling, inducing apoptosis in immunosuppressive macrophages via endoplasmic reticulum stress.
Conclusions:
- Abundance of immunosuppressive macrophages in the TME can serve as a predictive biomarker for patient stratification in GC.
- Mechanism-based combination immunotherapy, such as lenvatinib plus anti-PD-1, offers a rational approach to overcome resistance and improve treatment outcomes in GC.
- Targeting immunosuppressive macrophages represents a promising strategy for enhancing cancer immunotherapy efficacy.
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