Mandy's paper on induction of ferroptosis using PD-L1 targeting nanogel conjugates is published in Cell Chemical Biology!

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.

Wang M, Prachyathipsakul T, Wisniewski CA, Xiong C, Goel S, Goel HL, Karner ER, Mukhopadhyay D, Gupta P, Majee A, Thayumanavan S, Mercurio AM. Therapeutic induction of ferroptosis in tumors using PD-L1 targeting antibody nanogel conjugates. Cell Chem Biol. 2024 Nov 26.

Ayush's paper on NRP2 expressing cells mitigating radiation-induced oxidative stress is published!

Abstract

The high rate of recurrence after radiation therapy in triple-negative breast cancer (TNBC) indicates that novel approaches and targets are needed to enhance radiosensitivity. Here, we report that neuropilin-2 (NRP2), a receptor for vascular endothelial growth factor (VEGF) that is enriched on sub-populations of TNBC cells with stem cell properties, is an effective therapeutic target for sensitizing TNBC to radiotherapy. Specifically, VEGF/NRP2 signaling induces nitric oxide synthase 2 (NOS2) transcription by a mechanism dependent on Gli1. NRP2-expressing tumor cells serve as a hub to produce nitric oxide (NO), an autocrine and paracrine signaling metabolite, which promotes cysteine-nitrosylation of Kelch-like ECH-asssociated protein 1 (KEAP1) and, consequently, nuclear factor erythroid 2-related factor 2 (NFE2L2)-mediated transcription of antioxidant response genes. Inhibiting VEGF binding to NRP2, using a humanized monoclonal antibody (mAb), results in NFE2L2 degradation via KEAP1 rendering cell lines and organoids vulnerable to irradiation. Importantly, treatment of patient-derived xenografts with the NRP2 mAb and radiation resulted in significant tumor necrosis and regression compared to radiation alone. Together, these findings reveal a targetable mechanism of radioresistance and they support the use of NRP2 mAb as an effective radiosensitizer in TNBC.

Kumar A, Goel HL, Wisniewski CA, Wang T, Geng Y, Wang M, Goel S, Hu K, Li R, Zhu LJ, Clark JL, Ferreira LM, Brehm M, Fitzgerald TJ, Mercurio AM. Neuropilin-2 expressing cells in breast cancer are S-nitrosylation hubs that mitigate radiation-induced oxidative stress. J Clin Invest. 2024 Oct 1. PMID: 39352757