Intratumoral plasma cells mediate CD8+ T cell infiltration and successful immune checkpoint blockade therapy in de novo MPNSTs

作者：Joshua J. Lingo, Ryan J. Reis, Chantal Allamargot, Juan A Raygoza Garay, Courtney A. Kaemmer, E. Elias, Ellen Voigt, 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：bioRxiv (Cold Spring Harbor Laboratory) · 年份：2026 · DOI：10.64898/2026.02.18.706680 · 研究领域：Neurofibromatosis and Schwannoma Cases、CAR-T cell therapy research、Cancer Immunotherapy and Biomarkers

Background The role of intratumoral plasma cells in immune checkpoint blockade (ICB) therapy has never been tested although their presence is linked with improved patient response and survival. Malignant peripheral nerve sheath tumors (MPNSTs) are deadly sarcomas with minimal responsiveness to ICB therapies. Strikingly, drugs inhibiting cyclin-dependent kinases 4/6 (CDK4/6) and MEK sensitize de novo MPNSTs to immunotherapy targeting programmed death-ligand 1 (PD-L1), which correlates with increased intratumoral plasma cells. Here, we tested if plasma cells mediate the MPNST response to anti-PD-L1 therapy. Methods Anti-tumor 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 immunostaining. Findings MPNSTs lacking plasma cells failed to respond to anti-PD-L1 monotherapy and were no longer sensitized to immunotherapy by CDK4/6-MEK inhibition. Plasma cell-deficient MPNSTs exposed to CDK4/6-MEK inhibitors had impaired antigen presentation on major histocompatibility class I (MHC-I) and decreased CD8+ T cell infiltration and activation. Complementary analyses of human sarcomas showed increased intratumoral plasma cell signatures prognose better patient survival. Interpretation Plasma cells favorably remodel the tumor immune environment by...