Programmed death ligand 1 expression and tumor infiltrating lymphocytes in neurofibromatosis type 1 and 2 associated tumors

Wang, Shiyang; Liechty, Benjamin; Patel, Seema; Weber, Jeffrey S.; Hollmann, Travis J.; Snuderl, Matija; Karajannis, Matthias A.

doi:10.1007/s11060-018-2788-6

Cited by 61 publications

(56 citation statements)

References 27 publications

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“…The accumulation of these cells is pathological, because they were not detected in normal peripheral nerves. T cells have recently begun to be characterized as a component of human benign neurofibroma, but no work has been done to examine DCs as a distinct myeloid cell population in neurofibroma (54)(55)(56).…”

Section: Discussionmentioning

confidence: 99%

Cxcr3-expressing leukocytes are necessary for neurofibroma formation in mice

Fletcher

Jessen

et al. 2019

JCI Insight

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macrophage subpopulations with distinct activities (24,25). Further characterization of these neurofibroma leukocytes and their contributions to tumor initiation and growth is necessary for the development of safe and effective immunomodulatory therapies.In the Dhh-Cre Nf1 fl/fl mouse neurofibroma model, biallelic deletion of Nf1 in the Schwann cell lineage mimics the biallelic loss of NF1 in human NF1 and sporadic plexiform neurofibroma (26). The peripheral nerves of these mice appear normal at 1 month of age, but pathological changes, including mast cell and macrophage infiltration and abnormal Schwann cell proliferation, are evident at 2 months of age (26,27). By 4 months of age, these mice invariably form MRI-detectable paraspinal neurofibromas that histologically and transcriptionally resemble human plexiform neurofibroma (26,28,29). Schwann cell-specific deletion of Nf1 using other drivers can also induce nerve pathology and neurofibroma development in mice (19,(30)(31)(32). In contrast, CNPase-human EGFR (CNPase-hEGFR) mice have increased Ras activity driven by overexpression of hEGFR and develop similar nerve pathology to Nf1 mouse models but have reduced myeloid cell infiltration, and only approximately 1 in 20 develop a neurofibroma (20,33).Here, we compare nerves from these mouse models transcriptionally and identify a chemokine, Cxcl10, that is uniquely overexpressed in 2-month Dhh-Cre Nf1 fl/fl nerves. CXCL10 and its receptor, CXCR3, are important modulators of neuroinflammation and tumor biology (34)(35)(36). In this study, we identify Cxcl10and Cxcr3-expressing cell populations in nerves and neurofibroma and demonstrate the necessity of Cxcr3 for neurofibroma development in Dhh-Cre Nf1 fl/fl mice. Results Differential gene expression analyses identify Cxcl10 as a potential modulator of plexiform neurofibroma development.Peripheral nerves from GEMMs of NF1 (GEMM-NF1) (P0-CreB Nf1 fl/fl , P0-CreB Nf1 fl/-, Dhh-Cre Nf1 fl/fl ) invariably develop neurofibromas (26,31). P0-CreB and Dhh-Cre are transgenic mouse strains that express Cre recombinase in peripheral nerve Schwann cells; when used to recombine Nf1 in mice, peripheral nerves show pathological mast cell recruitment, disruption of axon and nonmyelinating Schwann cell (axon/ Remak bundle) interactions, and collagen deposition (nerve disruption). This nerve disruption phenotype precedes plexiform neurofibroma development. Although several of these changes have been proposed to contribute to neurofibroma development, similar nerve pathology is also observed in CNPase-hEGFR/ + and CNPase-hEGFR/CNPase-hEGFR mice, which recruit fewer macrophages and rarely form neurofibromas (33,37). In contrast, this pathology is not observed in Npcis mice (Nf1 +/− Trp53 +/− deletions in cis) that progress directly to malignant peripheral nerve sheath tumor (ref. 38 and Supplemental Figure 1; supplemental material available online with this article; https://doi.org/10.1172/jci.insight.98601DS1) or in CNPase-HRas12V mice that do not develop plexiform neurofibroma (39)....

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Section: Discussionmentioning

confidence: 99%

Cxcr3-expressing leukocytes are necessary for neurofibroma formation in mice

Fletcher

Jessen

et al. 2019

JCI Insight

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Section: Tumor Immune Microenvironmentmentioning

confidence: 99%

“…Additionally, the NF2 gene may have implications for the tumor microenvironment ( 26 , 93 ). Wang et al find that a proportion of NF2-associated meningiomas expressed PD-L1 on tumoral cells and 100% had tumor-infiltrating lymphocytes ( 93 ). In combination with the predominance of M1 pro-inflammatory macrophage infiltrate in meningiomas with 22q deletions, CI could be more efficacious in meningiomas with NF2 inactivation or deletions ( 42 ).…”

Section: Tumor Immune Microenvironmentmentioning

confidence: 99%

Basis for Immunotherapy for Treatment of Meningiomas

et al. 2020

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Meningiomas are common tumors that account for approximately one third of CNS tumors diagnosed every year. They are classified by the World Health Organization in grades I-III. Higher grades have an increased rate of growth, invasiveness, rate of recurrence, and worse outcomes than lower grades. Most meningiomas are grade I, while ~18% of meningiomas are grade II and III in hospital-based series. Meningiomas are typically “benign” tumors that are treated with surgery and radiation. However, when they recur or are unresectable, treatment options are very limited, especially since they are chemotherapy-resistant. Recent advances in the treatment of cancers with immunotherapy have focused on checkpoint blockade as well as other types of immunotherapy. There is emerging evidence supporting the use of immunotherapy as a potentially effective treatment strategy for meningioma patients. The immune microenvironment of meningiomas is a complex interplay of genetic alterations, immunomodulatory protein expression, and tumor-immune cell interactions. Meningiomas are known to be infiltrated by immune cells including microglia, macrophages, B-cells, and T-cells. Several mechanisms contribute to decreased an ti-tumor immune response, allowing tumor growth and evasion of the immune system. We discuss the most current knowledge on the immune micro-environment of meningiomas, preclinical findings of immunotherapy in meningiomas, meningioma immunotherapy clinical trials, and also offer insight into future prospects for immunotherapies in meningiomas.

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“…Tumors with infiltration of CD8+ cells are considered good candidates for therapy with anti-PD-1 drugs. The tumor infiltrating lymphocytes (TILs) or high expression of PD-L1 on PNF cells suggest that patients can be responsive to treatment with immune checkpoint inhibitors (64).…”

Section: Pd1-inhibitors Programmed Death-ligand 1 (Pd-l1)mentioning

confidence: 99%

New Frontiers in Therapy of Peripheral Nerve Sheath Tumors in Patients With Neurofibromatosis Type 1: Latest Evidence and Clinical Implications

et al. 2020

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Almost all individuals with neurofibromatosis type 1 (NF1) develop peripheral nerve sheath tumors (PNSTs), mainly benign neurofibromas, however about 10% of PNSTs will undergo transformation to malignant peripheral nerve sheath tumors (MPNSTs). Surgical treatment of PNSTs has traditionally been regarded as a standard approach. The availability of new agents that target specific molecular pathways involved in the pathogenesis of PNST has led to a number of clinical trials, which resulted in increased chances for better survival and quality of life. This review presents the latest evidence and clinical implications for new therapies of PNSTs in patients with NF1 emphasizing the potential benefit from the use of Ras/MAPK pathway inhibitors, immunotherapy, chemotherapy or radiation therapy. We present evaluation of current knowledge on available treatment modalities. Neurofibromatosis type 1 (NF1) is an autosomal dominant neurocutaneous disease affecting about 1 in 3500 people worldwide (1). The hallmark clinical features of NF1 include multiple café-au-lait macules, neurofibromas, intertriginous freckling, osseous lesions, Lisch nodules and optic pathway gliomas. The disorder is typified by the presence of multisystem tumors, which carries a high risk of malignant transformation (2, 3). Nearly 100% of individuals with NF1 develop benign peripheral nerve sheath tumors (BPNSTs) and in approximately 30-50% of them atypical and plexiform neurofibromas (PNFs) are found. In about 10% of NF1 patients, neurofibromas may undergo transformation to malignant peripheral nerve sheath tumors (MPNSTs), which are highly aggressive. The differentiation between atypical neurofibroma and low grade MPNST is probably the most challenging issue in the pathology of peripheral nerve sheath tumors (PNSTs), particularly in NF1 patients. Clinically, atypical tumors often develop as extensive, slowly growing neoplasms, and pain can be a characteristic feature (4, 5). The poor response to currently available therapies underlines the need for more effective, targeted treatment methods for NF1-associated PNSTs (6, 7). In this review, we analyzed the latest evidence and clinical implications of new therapies of PNSTs in patients with NF1 emphasizing the importance of patient risk stratification to identify those who are likely to benefit from the use of Ras/MAPK pathway inhibitors, immunotherapy, chemotherapy or radiotherapy. We also analyzed the limitations of administering these therapies to all individuals with NF1-associated PNSTs together with future perspectives. Methodology PubMed searches were performed to identify potentially clinically relevant English-language studies published in the last 15 years. The searches were based on a combination of indexed terms and free text terms ("peripheral nerve sheath tumors"

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Programmed death ligand 1 expression and tumor infiltrating lymphocytes in neurofibromatosis type 1 and 2 associated tumors

Cited by 61 publications

References 27 publications

Cxcr3-expressing leukocytes are necessary for neurofibroma formation in mice

Cxcr3-expressing leukocytes are necessary for neurofibroma formation in mice

Basis for Immunotherapy for Treatment of Meningiomas

New Frontiers in Therapy of Peripheral Nerve Sheath Tumors in Patients With Neurofibromatosis Type 1: Latest Evidence and Clinical Implications

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