Midkine activation of CD8+ T cells establishes a neuron-immune-cancer axis responsible for low-grade glioma growth.

Brain tumors (gliomas) are heterogeneous cellular ecosystems, where non-neoplastic monocytic cells have emerged as key regulators of tumor maintenance and progression. However, relative to macrophages/microglia, comparatively less is known about the roles of neurons and T cells in glioma pathobiology. Herein, we leverage genetically engineered mouse models and human biospecimens to define the axis in which neurons, T cells, and microglia interact to govern Neurofibromatosis-1 (NF1) low-grade glioma (LGG) growth. NF1-mutant human and mouse brain neurons elaborate midkine to activate naïve CD8+ T cells to produce Ccl4, which induces microglia to produce a key LGG growth factor (Ccl5) critical for LGG stem cell survival. Importantly, increased CCL5 expression is associated with reduced survival in patients with LGG. The elucidation of the critical intercellular dependencies that constitute the LGG neuroimmune axis provides insights into the role of neurons and immune cells in controlling glioma growth, relevant to future therapeutic targeting.

Lymphocyte Subpopulations in Patients With Neurofibromatosis Type 1-associated Optic Pathway Gliomas and Plexiform Neurofibromas.

BACKGROUND/AIM: Neurofibromatosis type 1 (NF1) is characterized by the occurrence of multisystem tumors, among which the most characteristic are optic pathway gliomas (OPGs) and plexiform neurofibromas (PNFs). With the development of new anticancer drugs targeting the immune system, it is important to examine the immunological status of patients with NF1. Furthermore, the immune system has been suggested as a probable modulator of NF1-associated phenotypes. The objective of this study was the analysis of lymphocyte subset populations with respect to the presence of PNFs and OPGs. PATIENTS AND METHODS: Fifty-three patients with NF1 diagnosed with OPG/PNF were analyzed for lymphocyte subpopulations. RESULTS: Significantly lower levels of B-cells, T-cells and natural killer (NK) cells were observed in the group of patients with PNFs compared to those with OPG. CONCLUSION: Our observation may indicate a correlation between weakened functioning of the immune system and the formation of PNFs.

Genetic and genomic alterations differentially dictate low-grade glioma growth through cancer stem cell-specific chemokine recruitment of T cells and microglia.

BACKGROUND: One of the clinical hallmarks of low-grade gliomas (LGGs) arising in children with the neurofibromatosis type 1 (NF1) cancer predisposition syndrome is significant clinical variability with respect to tumor growth, associated neurologic deficits, and response to therapy. Numerous factors could contribute to this clinical heterogeneity, including the tumor cell of origin, the specific germline NF1 gene mutation, and the coexistence of additional genomic alterations. Since human specimens are rarely acquired, and have proven difficult to maintain in vitro or as xenografts in vivo, we have developed a series of Nf1 mutant optic glioma mouse strains representing each of these contributing factors. METHODS: Optic glioma stem cells (o-GSCs) were generated from this collection of Nf1 genetically engineered mice, and analyzed for their intrinsic growth properties, as well as the production of chemokines that could differentially attract T cells and microglia. RESULTS: The observed differences in Nf1 optic glioma growth are not the result of cell autonomous growth properties of o-GSCs, but rather the unique patterns of o-GSC chemokine expression, which differentially attract T cells and microglia. This immune profile collectively dictates the levels of chemokine C-C ligand 5 (Ccl5) expression, the key stromal factor that drives murine Nf1 optic glioma growth. CONCLUSIONS: These findings reveal that genetic and genomic alterations create murine LGG biological heterogeneity through the differential recruitment of T cells and microglia by o-GSC-produced chemokines, which ultimately determine the expression of stromal factors that drive tumor growth.

Anti-vimentin antibodies and neuron-specific enolase in children with neurofibromatosis type-1.

OBJECTIVES: The aim of the study was to investigate the relationship of serum levels of neuron-specific enolase, anti-vimentin IgG, and anti-vimentin IgM antibodies in patients with neurofibromatosis type 1 and associated tumors (optic glioma, and plexiform neurofibroma). METHODS: Measurement of neuron-specific enolase and anti-vimentin antibodies were performed in 131 children and adolescents (67 males, mean age 10 years, range 4-19 years; 64 females, mean age 11 years, range 1-20 years) with three different forms of neurofibromatosis type 1 and in control group of 40 individuals (20 males, mean age 9 years, range 1-19 years and 20 females, mean age 12 years, range 3-18 years). RESULTS: Anti-vimentin IgG, IgM antibodies and NSE showed similar ability to distinguish between neurofibromatosis type 1 and tumors associated with neurofibromatosis type 1. (AUC=0.57, AUC=0.52 and AUC=0.59 respectively). NSE showed better diagnostic efficiency (AUC=0.68) than the anti-vimentin IgG and anti-vimentin IgM. (AUC=0.63 and AUC=0.56 respectively). Anti-vimentin IgG and IgM antibodies showed higher sensitivity (87.5% and 87.2%) at the cut off value than the NSE (54%). On the contrary, NSE showed higher specificity at the cut off value than both the anti-vimentin IgG and IgM (71% vs. 22.5% and 16% respectively). CONCLUSIONS: Anti-vimentin IgG and IgM and neuron-specific enolase are relevant markers in investigation of the patients with neurofibromatosis type 1 and associated tumors.

Associations between allergic conditions and pediatric brain tumors in Neurofibromatosis type 1.

Individuals with Neurofibromatosis type 1 (NF1) are at increased risk for pediatric brain tumors (PBTs), especially optic gliomas; however, factors influencing their development are largely unknown. Extensive research suggests that allergic conditions protect against brain tumors, particularly gliomas in individuals without NF1. In this large cross-sectional study, we employed two different data sources to evaluate evidence for the hypothesis that allergic conditions (allergies, asthma, and eczema) may protect against PBT development in individuals with NF1. We used self- and parent/legal guardian reported questionnaire data from participants in the NF1 Patient Registry Initiative (NPRI, n = 1660) born from 1933 to 2014 to ascertain allergic condition and PBT diagnosis histories. Medical records (MRs) of 629 NF1 patients at a large medical center born from 1930 to 2012 were also reviewed for PBT and allergic condition diagnoses to evaluate additional evidence for our hypothesis. We used logistic regression to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for associations between allergic condition diagnoses and PBTs. Both data sources provided limited to no support for a protective effect of allergies or eczema on PBT development. Non-significant inverse associations between asthma and PBTs were observed (NPRI: OR = 0.80, 95% CI 0.55-1.17; MR: OR = 0.71, 95% CI 0.40-1.28) with stronger associations for optic gliomas specifically. Additionally, a significant inverse association was observed in an NPRI subgroup analysis where the reported asthma diagnosis age was younger than the reported PBT diagnosis age (OR = 0.57; 95% CI 0.36-0.89). Our study supports the hypothesis that asthma protects against PBT development in NF1.

CXCL12 alone is insufficient for gliomagenesis in Nf1 mutant mice.

Tumorigenesis requires interactions between tumor progenitors and their microenvironment. We found that low cAMP levels were sufficient for tumorigenesis in a mouse model of Neurofibromatosis-1 (NF1)-associated optic pathway glioma (OPG). We hypothesized that the distinct pattern of glioma in NF1 reflected spatiotemporal differences in CXCL12 effects on cAMP levels. Thus, we sought to alter the pattern of gliomagenesis through manipulation of CXCL12-CXCR4 pathway activation in Nf1 OPG mice. Forced CXCL12 expression induced glioma at a low frequency. Further, treatment of Nf1 OPG mice with AMD3100, a CXCR4 antagonist, did not attenuate glioma growth. Thus, it appears, CXCL12 alone cannot promote gliomagenesis in NF1 mice.

Outpatient carboplatin desensitization in a pediatric patient with bilateral optic glioma.

OBJECTIVE: To report a case of successful outpatient carboplatin desensitization in a pediatric patient with bilateral optic glioma. CASE SUMMARY: A 10-year-old white girl with bilateral optic glioma developed a hypersensitivity reaction to carboplatin after nine courses. She had received 18 courses six years earlier without incident. A desensitization regimen was administered, and she has tolerated all subsequent courses of carboplatin therapy. DISCUSSION: Carboplatin is an important chemotherapeutic agent in the treatment of a variety of pediatric brain tumors. It is usually given in an outpatient setting. Hypersensitivity to this agent appears to develop after frequent exposure such as with the once-weekly regimens often used to treat brain tumors in pediatric patients. CONCLUSIONS: Carboplatin desensitization can be successfully performed on an outpatient basis with close observation and cardiorespiratory monitoring. This regimen could prove useful for other patients who develop hypersensitivity reactions to carboplatin and allow therapy to continue.