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PD-L2 drives resistance to EGFR-TKIs: dynamic changes of the tumor immune environment and targeted therapy
Simeng Wang1,2, Dongliang Su1,2, Han Chen1,2
1Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, 110016, PR China.
Abstract:
There is a lack of effective treatments to overcome resistance to EGFR-TKIs in EGFR mutant tumors. A deeper understanding of resistance mechanisms can provide insights into reducing or eliminating resistance, and can potentially deliver targeted treatment measures to overcome resistance. Here, we identified that the dynamic changes of the tumor immune environment were important extrinsic factors driving tumor resistance to EGFR-TKIs in EGFR mutant cell lines and syngeneic tumor-bearing mice. Our results demonstrate that the acquired resistance to EGFR-TKIs is accompanied by aberrant expression of PD-L2, leading a dynamic shift from an initially favorable tumor immune environment to an immunosuppressive phenotype. PD-L2 expression significantly affected EGFR mutant cell apoptosis that depended on the proportion and function of CD8+ T cells in the tumor immune environment. Combined with single-cell sequencing and experimental results, we demonstrated that PD-L2 specifically inhibited the proliferation of CD8+ T cells and the secretion of granzyme B and perforin, leading to reduced apoptosis mediated by CD8+ T cells and enhanced immune escape of tumor cells, which drives EGFR-TKIs resistance. Importantly, we have identified a potent natural small-molecule inhibitor of PD-L2, zinc undecylenate. In vitro, it selectively and potently blocks the PD-L2/PD-1 interaction. In vivo, it abolishes the suppressive effect of the PD-L2-overexpressing tumor immune microenvironment by blocking PD-L2/PD-1 signaling. Moreover, the combination of zinc undecylenate and EGFR-TKIs can synergistically reverse tumor resistance, which is dependent on CD8+ T cells mediating apoptosis. Our study uncovers the PD-L2/PD-1 signaling pathway as a driving factor to mediate EGFR-TKIs resistance, and identifies a new naturally-derived agent to reverse EGFR-TKIs resistance.
Insights
Acquired resistance to EGFR-TKIs in EGFR mutant tumors is driven by PD-L2, which suppresses CD8+ T cells. A natural inhibitor, zinc undecylenate, combined with EGFR-TKIs, synergistically reverses this resistance by restoring T cell-mediated apoptosis.
Area of Science:
- Immunology
- Oncology
- Pharmacology
Background:
- Effective treatments for EGFR-TKI resistance in EGFR mutant tumors are lacking.
- Understanding resistance mechanisms is crucial for developing targeted therapies.
- Tumor immune microenvironment dynamics are implicated as extrinsic factors in resistance.
Purpose of the Study:
- To investigate the role of the tumor immune environment in EGFR-TKI resistance.
- To identify mechanisms by which resistance develops.
- To discover novel therapeutic strategies to overcome EGFR-TKI resistance.
Main Methods:
- Utilized EGFR mutant cell lines and syngeneic tumor-bearing mouse models.
- Analyzed dynamic changes in the tumor immune environment.
- Investigated the role of PD-L2 expression and its interaction with CD8+ T cells.
- Employed single-cell sequencing and in vitro/in vivo experiments.
- Evaluated the efficacy of zinc undecylenate, a PD-L2 inhibitor, alone and in combination with EGFR-TKIs.
Main Results:
- Acquired resistance to EGFR-TKIs is associated with aberrant PD-L2 expression, shifting the tumor immune environment to an immunosuppressive state.
- PD-L2 inhibits CD8+ T cell proliferation and cytotoxic function (granzyme B, perforin), reducing T cell-mediated apoptosis and promoting tumor immune escape.
- Zinc undecylenate selectively blocks PD-L2/PD-1 interaction, reversing the immunosuppressive tumor microenvironment.
- Combination therapy of zinc undecylenate and EGFR-TKIs synergistically overcomes resistance, dependent on CD8+ T cell-mediated apoptosis.
Conclusions:
- The PD-L2/PD-1 signaling pathway is a key driver of EGFR-TKI resistance in EGFR mutant tumors.
- Aberrant PD-L2 expression creates an immunosuppressive tumor microenvironment that impairs anti-tumor immunity.
- Zinc undecylenate, a natural PD-L2 inhibitor, demonstrates potential as a therapeutic agent to reverse EGFR-TKI resistance, particularly in combination with EGFR-TKIs.
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