Journal article
Intratumoural plasma cells mediate a pro-inflammatory response to kinase inhibition and successful immune checkpoint blockade therapy in malignant peripheral nerve sheath tumours
EBioMedicine, Vol.131, 106413
08/01/2026
DOI: 10.1016/j.ebiom.2026.106413
PMID: 42541926
Abstract
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 sensitize 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.
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.
Plasma cell-deficient MPNSTs failed to respond to anti-PD-L1 monotherapy and were no longer sensitized by CDK4/6-MEK inhibition to immunotherapy. Following kinase inhibitor treatment, plasma cells were necessary for a pro-inflammatory response marked by increased tumor infiltration and activation of natural killer (NK) and CD8+ T cells, major histocompatibility class I antigen presentation, and decreased M2 macrophages. By comparison, elevated CD4+ T cell and B cell infiltration dominated the plasma cell knockout phenotype.
Plasma cells favorably remodel the tumour immune environment for anti-tumour immunity and are critical for successful ICB therapy in MPNSTs. These findings may inform ICB treatment strategies and patient stratification for therapy of many tumour types.
This research was supported by University of Iowa Sarcoma Research Program awards and NIH grants T34-GM141143, T32-GM067795, F31-CA281312, P30-CA086862, and R01-NS119322.
Details
- Title: Subtitle
- Intratumoural plasma cells mediate a pro-inflammatory response to kinase inhibition and successful immune checkpoint blockade therapy in malignant peripheral nerve sheath tumours
- Creators
- Joshua J. Lingo - University of IowaRyan Reis - University of IowaAltay Koyas - University of IowaEllen Voigt - University of IowaZeb R. Zacharias - University of IowaChantal Allamargot - University of IowaEmma L. Hornick - University of IowaJuan A. Raygoza Garay - University of Iowa Holden Comprehensive Cancer CenterCourtney A. Kaemmer - University of IowaElizabeth C. Elias - University of IowaAli Jabbari - University of IowaConnor R. Wilhelm - University of IowaAlexander W. Boyden - University of IowaNitin J. Karandikar - University of IowaPatrick Breheny - University of IowaDavid K. Meyerholz - University of IowaRebecca D. Dodd - University of IowaJon C.D. Houtman - University of IowaBenjamin W. Darbro - University of IowaDawn E. Quelle - University of Iowa
- Resource Type
- Journal article
- Publication Details
- EBioMedicine, Vol.131, 106413
- DOI
- 10.1016/j.ebiom.2026.106413
- PMID
- 42541926
- ISSN
- 2352-3964
- eISSN
- 2352-3964
- Publisher
- Elsevier B.V
- Grant note
- University of Iowa Sarcoma Research Program awards Gilbert Family Foundation NIH grants: T34-GM141143, T32-GM067795, F31-CA281312, P30-CA086862, R01-NS119322
This research was supported by University of Iowa Sarcoma Research Program awards, the Gilbert Family Foundation, and NIH grants T34-GM141143, T32-GM067795, F31-CA281312, P30-CA086862, and R01-NS119322.
- Language
- English
- Date published
- 08/01/2026
- Academic Unit
- Dermatology; Microbiology and Immunology; Hematology, Oncology, and Blood & Marrow Transplantation; Stead Family Department of Pediatrics; Core Research Facilities; Pathology; Biostatistics; Medical Genetics and Genomics; Neuroscience and Pharmacology; Holden Comprehensive Cancer Center; Internal Medicine
- Record Identifier
- 9985217074002771
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