Immune landscape characterization of neurofibromas with atypical features in Neurofibromatosis1 reveals PD-1 and the Tim-3/Galectin-9 pathway as potential therapeutic targets

作者：Anaïs Brunet, Fanny Coulpier, Audrey Onfroy, Nouhoum Sako, Katarzyna J. Radomska, Valérie Aftimos, Laetitia Lacroix, Audrey Briand‐Suleau, Pascale Maillé, Oana Hermeziu, Ingrid Laurendeau, Éric Pasmant, Pierre Wolkenstein, Piotr Topilko, Nicolás Ortonne · 发表于：Acta Neuropathologica Communications · 年份：2026 · DOI：10.1186/s40478-026-02310-1 · 研究领域：Neurofibromatosis and Schwannoma Cases、Galectins and Cancer Biology、Signaling Pathways in Disease

Neurofibromatosis type 1 (NF1) is a genetic disorder that predisposes individuals to the development of plexiform neurofibromas (pNF), benign tumors of the nerve sheath that can progress to malignant peripheral nerve sheath tumors (MPNST). Some pNFs exhibit atypical characteristics, particularly atypical neurofibromatous neoplasms of uncertain biological potential (ANNUBP), which meet recently defined criteria. These are pNFs with concerning histological and/or molecular features and uncertain behavior, leading to their consideration as potential precursors of MPNSTs. In this study, we characterized the immune landscape of a series of atypical neurofibromas (exhibiting increased cellularity or atypical cells) and ANNUBPs (ANF/ANNUBP) compared to cutaneous neurofibromas (cNF), pNFs, and MPNSTs, all from patients with NF1, using immunohistochemistry and single-cell RNA sequencing (scRNA-seq). Our findings revealed that ANF/ANNUBPs are heavily infiltrated with CD3+ T-lymphocytes and CD163+ macrophages. Transcriptomic profiling using the NanoString technology demonstrated that ANF/ANNUBPs exhibit a distinct immune signature compared to both pNFs and MPNSTs. This includes overexpression of two inhibitory immune checkpoints (ICs): HAVCR2 (encoding the IC receptor Tim-3) and its primary ligand Galectin-9 (Gal9). Subsequent analyses of scRNA datasets corroborated these findings with Prss56 Cre/+ , Nf1 fl/fl , R26 tdTom/+ mouse model-derived tumors. Using multiplex immunofluorescence,...