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Therapeutic induction of ferroptosis in tumors using PD-L1 targeting antibody nanogel conjugates
Mengdie Wang1, Theeraphop Prachyathipsakul2, Christi A Wisniewski1
1Department of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA, USA.
Abstract:
Although programmed cell death ligand 1 (PD-L1) is best known for its role in immune suppression, tumor-intrinsic functions are emerging. Here, we report that tumor cells that express PD-L1 are sensitive to ferroptosis inducers such as imidazole ketone erastin (IKE). PD-L1 promotes ferroptosis sensitivity because it suppresses SLC7A11 expression and diminishes glutathione levels. Although the use of anti-PD-L1 antibody drug conjugates (ADCs) could be effective for the delivery of ferroptosis inducers to specific tumor populations, the chemistry of most ferroptosis inducers precludes their incorporation in ADCs. To overcome this challenge, we synthesized an antibody nanogel conjugate (ANC) comprised of an anti-PD-L1 antibody conjugated to a nanogel encapsulated with IKE. This ANC targets PD-L1-expressing cells in vitro and in vivo and induces ferroptosis, resulting in tumor suppression. Importantly, this approach is superior to systemic administration of IKE because it enables enhanced delivery of IKE specifically to tumor cells and it requires lower drug doses for efficacy.
Insights
Tumor cells expressing programmed cell death ligand 1 (PD-L1) are susceptible to ferroptosis. Researchers developed an antibody nanogel conjugate (ANC) to deliver ferroptosis inducers specifically to PD-L1-expressing tumor cells, enhancing efficacy and reducing dosage.
Area of Science:
- Oncology
- Immunology
- Biochemistry
Background:
- Programmed cell death ligand 1 (PD-L1) is primarily known for immune suppression.
- Emerging evidence highlights crucial tumor-intrinsic functions of PD-L1.
- PD-L1 expression in tumor cells influences their sensitivity to specific cell death pathways.
Purpose of the Study:
- To investigate the role of PD-L1 in ferroptosis sensitivity.
- To develop a targeted delivery system for ferroptosis inducers to PD-L1-expressing tumors.
- To evaluate the efficacy of this novel delivery system in tumor suppression.
Main Methods:
- Assessed ferroptosis sensitivity of PD-L1-expressing tumor cells using imidazole ketone erastin (IKE).
- Investigated the mechanism by which PD-L1 influences ferroptosis, focusing on SLC7A11 and glutathione levels.
- Synthesized an anti-PD-L1 antibody nanogel conjugate (ANC) encapsulating IKE.
- Evaluated the in vitro and in vivo targeting and tumor-suppressive efficacy of the ANC.
Main Results:
- Tumor cells expressing PD-L1 demonstrated heightened sensitivity to ferroptosis inducers like IKE.
- PD-L1 was found to suppress SLC7A11 expression, leading to reduced glutathione levels and increased ferroptosis susceptibility.
- The developed ANC effectively targeted PD-L1-expressing cells both in vitro and in vivo.
- ANC treatment resulted in ferroptosis induction and significant tumor suppression, outperforming systemic IKE administration.
Conclusions:
- PD-L1 expression confers sensitivity to ferroptosis by downregulating SLC7A11 and glutathione.
- An antibody nanogel conjugate (ANC) provides a novel and effective strategy for targeted delivery of ferroptosis inducers.
- This targeted approach enhances drug delivery specifically to tumor cells, improves efficacy, and allows for lower therapeutic doses.
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