| Abstract: |
Purpose: Malignant peripheral nerve sheath tumors (MPNST) are aggressive soft-tissue sarcomas and the leading cause of mortality in individuals with neurofibromatosis type 1 (NF1). Despite many clinical trials, outcomes for patients with MPNST have remained stagnant, and most succumb to their disease; thus, novel therapeutic approaches are needed. A better understanding of the MPNST immune ecosystem will aid in the development of strategies to activate the immune system against the tumor. In this study, we profile the tumor immune microenvironment (TIME) in NF1-associated peripheral nerve sheath tumors (PNST) to discover insights on the role played by tumor-infiltrating immune cells in malignant transformation. Experimental Design: Using fresh and formalin-fixed paraffinembedded tissue from patients diagnosed with NF1-PNST, we dissected the TIME through IHC, multiparameter flow cytometry, and comparative transcriptomic studies. Results: Immunophenotyping confirmed increased immune cell infiltration during malignant progression, with a predominance of infiltrating myeloid cells, particularly CD163+ tumorassociated macrophages (TAM). The T cells within MPNST exhibited signs of tumor activation, characterized by high programmed cell death 1 expression. Additionally, MPNST specimens demonstrated elevated levels of immunosuppressive TAM, with heightened PD-L1 expression. The proportion of CD163+ myeloid cells within the TIME correlated with poorer progression-free survival. Notably, loss of H3K27 trimethylation correlated with low immune cell infiltration in MPNST. Conclusions: Malignant transformation of NF1-PNST is characterized by an immunosuppressive microenvironment comprising TAM with high expression of PD-L1, which is associated with inferior outcomes. These findings suggest the clinical potential of immune-modulating therapeutics that can unleash an antitumor immune response. © 2024 American Association for Cancer Research. |
| Keywords: |
adult; human tissue; genetics; flow cytometry; cd8 antigen; transcription factor foxp3; tumor associated leukocyte; lymphocytes, tumor-infiltrating; metabolism; neurofibromatosis; neurofibromatosis 1; progression free survival; immune system; cell infiltration; genetic association; pathology; angiogenesis; retrospective study; t lymphocyte receptor; immunological tolerance; th2 cell; immunology; fluorescence in situ hybridization; immunophenotyping; oligodendroglioma; antigens, cd; malignant transformation; malignant peripheral nerve sheath tumor; nerve sheath tumor; nerve sheath neoplasms; disease specific survival; leukocyte antigen; leukocyte; t lymphocyte subpopulation; cd163 antigen; cell surface receptor; differentiation antigen; antigens, differentiation, myelomonocytic; receptors, cell surface; programmed death 1 ligand 1; tumor microenvironment; immune evasion; complication; tumor-associated macrophage; demographics; neurofibromatosis type 1; tumor escape; tumor-associated macrophages; arginase 1; high throughput sequencing; thymic stromal lymphopoietin; humans; human; male; female; article; rna sequencing; neurofibrosarcoma; cd274 protein, human; pexidartinib; b7-h1 antigen
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