Multi-dimensional immunotyping of human NF1-associated peripheral nerve sheath tumors uncovers tumor-associated macrophages as key drivers of immune evasion in the tumor microenvironment

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. Herein, we profile the tumor immune microenvironment (TIME) in NF1-associated peripheral nerve sheath tumors (PNST) to discover insights on the role that tumor-infiltrating immune cells play in malignant transformation. Experimental design: Utilizing fresh and formalin-fixed, paraffin-embedded tissue from patients diagnosed with NF1-PNST, we dissected the TIME by using immunohistochemistry, multiparameter flow cytometry, and comparative transcriptomic studies. Results: Immunophenotyping confirmed increased immune cells infiltration during malignant progression, with a predominance of infiltrating myeloid cells, particularly CD163+ tumor-associated macrophages (TAM). The T cells within MPNST exhibited signs of tumor activation, characterized by high PD-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 of TAM with high expression of PD-L1, which are associated with inferior outcomes. These findings suggest a clinical potential of immune modulating therapeutics that can unleash an anti-tumor immune response.