Intratumoural plasma cells mediate a pro-inflammatory response to kinase inhibition and successful immune checkpoint blockade therapy in malignant peripheral nerve sheath tumours

作者：Joshua J. Lingo, Ryan Reis, Altay Koyaş, Ellen Voigt, Zeb R. Zacharias, Chantal Allamargot, Emma L. Hornick, Juan A Raygoza Garay, Courtney A. Kaemmer, E. Elias, A. Jabbari, Connor R. Wilhelm, Alexander W. Boyden, Nitin J. Karandikar, Patrick Breheny, David K. Meyerholz, Rebecca D. Dodd, Jon C. D. Houtman, Benjamin W. Darbro, Dawn E. Quelle · 发表于：EBioMedicine · 年份：2026 · DOI：10.1016/j.ebiom.2026.106413 · 研究领域：Neurofibromatosis and Schwannoma Cases、Cancer Immunotherapy and Biomarkers、CAR-T cell therapy research

BACKGROUND: The role of intratumoural plasma cells in immune checkpoint blockade (ICB) therapy has never been tested although their presence is linked with improved response and survival in people with cancer. Malignant peripheral nerve sheath tumours (MPNSTs) are deadly sarcomas with minimal responsiveness to ICB therapies. Strikingly, drugs inhibiting cyclin-dependent kinases 4/6 (CDK4/6) and MEK sensitise de novo MPNSTs to immunotherapy targeting programmed death-ligand 1 (PD-L1), which correlates with increased intratumoural plasma cells. Here, we tested if plasma cells mediate MPNST response to anti-PD-L1 therapy and how they modulate tumour immune responsiveness to CDK4/6-MEK inhibition. METHODS: Anti-tumour activity of PD-L1 inhibition, with or without CDK4/6-MEK inhibition, was measured in de novo MPNSTs within wild-type versus plasma cell-deficient mice. Plasma cell-dependent effects of CDK4/6-MEK inhibition on priming the MPNST immune environment were determined by single cell transcriptomics and immune cell analyses. FINDINGS: Plasma cell-deficient MPNSTs failed to respond to anti-PD-L1 monotherapy and were no longer sensitised by CDK4/6-MEK inhibition to immunotherapy. Following kinase inhibitor treatment, plasma cells were necessary for a pro-inflammatory response marked by increased tumour infiltration and activation of natural killer (NK) and CD8+ T cells, major histocompatibility class I antigen presentation, and decreased M2 macrophages. By comparison, elevat...