Abstract 4053: NRP1 drives a novel cross-presentation pathway exploitable by peptide-linked antibodies to redirect viral memory T-cells against solid tumors

Abstract Background: Although NRP1 is known to regulate tumor angiogenesis [1,2] and immune suppression [3,4], its role in antigen processing has not been defined. We discovered that NRP1 engagement triggers a previously unrecognized pathway enabling cross-presentation of exogenous peptides on MHC-I. We exploited this biology using a peptide-linked anti-NRP1 monoclonal antibody (5D6) to redirect antiviral CD8+ T cells against NRP1-expressing tumors. Methods: HLA-A2-restricted CMV, SARS-CoV-2, and tumor-associated peptides were chemically conjugated or recombinantly fused to 5D6 through a pH-sensitive cleavable linker. Internalization, trafficking, and antigen processing were evaluated by confocal microscopy and mass spectrometry. Functional cross-presentation was assessed using peptide-specific CD8+ T cells in breast, lung and renal cancer cells in vitro, and in NSG mice bearing human carcinoma xenografts dosed with peptide-linked 5D6 followed by adoptive transfer of peptide-specific TCR-T cells. Results: NRP1 ligation induced rapid antibody internalization into endosomal and lysosomal compartments, enabling efficient liberation of peptide cargo and high-density MHC-I cross-presentation on tumor cells. Pep-5D6-treated tumor cells were selectively killed by cognate CD8+ T cells. In vivo, pep-5D6 followed by a single dose of peptide-specific TCR-T cells eradicated established tumors across multiple xenograft models within 1-4 weeks. These data reveal that NRP1 can function as a receptor for antigen delivery and cross-presentation, demonstrating its potential for therapeutic exploitation. Conclusions: We identify a previously unrecognized NRP1-mediated cross-presentation pathway and introduce a first-in-class strategy that repurposes abundant viral memory T cells for targeted tumor elimination. This mechanistic insight defines new immunobiology for NRP1 and establishes a translational platform for redirecting pre-existing antiviral immunity toward NRP1-expressing cancers. References: 1.Niland S, Eble JA. Neuropilins in the context of Tumor Vasculature. Int J Mol.Sci. 2019: 20(3) 2.Domingues A, Fantin A. Neuropilin-1 Regulation of Vascular Permeability Signaling. Biomolecules 2021 11(5) 666 3.Roy S, Bag AK, Singh RK, Talmadge JE, Batra SK, Datta K. Multifaceted Role of Neuropilins in the Immune System. Front. Immunol. 2017; Vol 8 4. Kawaguchi K, Suzuki E, Nishie M, Kii I, Kataoka TR, Hirata M, Inoue M, Pu F, Iwaisako K, Tsuda M, Yamaguchi A, Haga H, Hagiwara M, Toi M. Downregulation of Neuropilin-1 on Macrophages modulates Antibody-mediated Tumoricidal Activity. Cancer Immunol Immunother. 2017 Sep:66(9):1131-1142 An AI tool was used for general language editing purposes. Citation Format: Anne V. Philips, Celine Kerros, Helen He, Lisa St. John, Noah Tubo, Ho Ngai, Qiyang Zhou, Chunhua Shi, Anthony Sump, Gheath Alatrash, Jeffrey J. Molldrem, . NRP1 drives a novel cross-presentation pathway exploitable by peptide-linked antibodies to redirect viral memory T-cells against solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 4053.