CELL INTELLIGENCE · 肿瘤细胞治疗研究

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, elevated CD4+ T cell and B cell infiltration dominated the plasma cell knockout phenotype. INTERPRETATION: Plasma cells favourably 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. FUNDING: 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.