Multidimensional Immunotyping of Human NF1-Associated Peripheral Nerve Sheath Tumors Uncovers Tumor-Associated Macrophages as Key Drivers of Immune Evasion in the Tumor Microenvironment.

Autor:	Zhang L; Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.; Cellular and Molecular Medicine Graduate Program, Johns Hopkins University School of Medicine, Baltimore, Maryland.; Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland.; Bloomberg-Kimmel Institute for Cancer Immunotherapy, Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland., Maalouf A; Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.; Bloomberg-Kimmel Institute for Cancer Immunotherapy, Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland., Makri SC; Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland., Banerjee J; Sage Bionetworks, Seattle, Washington., Suru A; Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.; Bloomberg-Kimmel Institute for Cancer Immunotherapy, Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland., Tam AJ; Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.; Bloomberg-Kimmel Institute for Cancer Immunotherapy, Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland., Calizo A; Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.; Cellular and Molecular Medicine Graduate Program, Johns Hopkins University School of Medicine, Baltimore, Maryland., Pollard K; Laboratory Corporation of America (Labcorp), Burlington, North Carolina., Wang J; Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland., Danilova L; Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.; Bloomberg-Kimmel Institute for Cancer Immunotherapy, Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland., Ioannou M; Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland., Levin AS; Department of Orthopedic Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland., Morris CD; Orthopedic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York., Rhee DS; Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland., Belzberg AJ; Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, Maryland., Blakeley JO; Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland., Ladle BH; Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.; Cellular and Molecular Medicine Graduate Program, Johns Hopkins University School of Medicine, Baltimore, Maryland.; Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland.; Bloomberg-Kimmel Institute for Cancer Immunotherapy, Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland., Pardoll DM; Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.; Bloomberg-Kimmel Institute for Cancer Immunotherapy, Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland., Lucas CG; Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland., Rodriguez FJ; Department of Pathology, University of California Los Angeles, Los Angeles, California., Gross JM; Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland., Anders RA; Bloomberg-Kimmel Institute for Cancer Immunotherapy, Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland.; Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland., Pratilas CA; Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.; Cellular and Molecular Medicine Graduate Program, Johns Hopkins University School of Medicine, Baltimore, Maryland.; Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland., Llosa NJ; Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.; Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland.; Bloomberg-Kimmel Institute for Cancer Immunotherapy, Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland.
Jazyk:	angličtina
Zdroj:	Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2024 Dec 02; Vol. 30 (23), pp. 5459-5472.
DOI:	10.1158/1078-0432.CCR-24-1454
Abstrakt:	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 paraffin-embedded 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+ tumor-associated 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.)
Databáze:	MEDLINE
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