Phase I/II Study of a Vascular Endothelial Growth Factor Receptor Vaccine in Patients With NF2-Related Schwannomatosis.

PURPOSE: The humanized antivascular endothelial growth factor (VEGF) antibody bevacizumab (Bev) is efficacious for the treatment of NF2-related schwannomatosis (NF2), previously known as neurofibromatosis type 2. This study evaluated the safety and efficacy of a VEGF receptor (VEGFR) vaccine containing VEGFR1 and VEGFR2 peptides in patients with NF2 with progressive schwannomas (jRCTs031180184). MATERIALS AND METHODS: VEGFR1 and VEGFR2 peptides were injected subcutaneously into infra-axillary and inguinal regions, once a week for 4 weeks and then once a month for 4 months. The primary end point was safety. Secondary end points included tolerability, hearing response, imaging response, and immunologic response. RESULTS: Sixteen patients with NF2 with progressive schwannomas completed treatment and were assessed. No severe vaccine-related adverse events occurred. Among the 13 patients with assessable hearing, word recognition score improved in five patients at 6 months and two at 12 months. Progression of average hearing level of pure tone was 0.168 dB/mo during the year of treatment period, whereas long-term progression was 0.364 dB/mo. Among all 16 patients, a partial response was observed in more than one schwannoma in four (including one in which Bev had not been effective), minor response in 5, and stable disease in 4. Both VEGFR1-specific and VEGFR2-specific cytotoxic T lymphocytes (CTLs) were induced in 11 patients. Two years after vaccination, a radiologic response was achieved in nine of 20 assessable schwannomas. CONCLUSION: This study demonstrated the safety and preliminary efficacy of VEGFR peptide vaccination in patients with NF2. Memory-induced CTLs after VEGFR vaccination may persistently suppress tumor progression.

Difference in the hypoxic immunosuppressive microenvironment of patients with neurofibromatosis type 2 schwannomas and sporadic schwannomas.

BACKGROUND: Neurofibromatosis type 2 (NF2) patients uniformly develop multiple schwannomas. The tumor-microenvironment (TME) is associated with hypoxia and consists of immunosuppressive cells, including regulatory T cells (Tregs) and tumor-associated macrophages (TAMs). The hypoxic TME of NF2 schwannomas remains unclear. In addition, no comparative study has investigated immunosuppressive cells in NF2 and sporadic schwannomas. METHODS: In 22 NF2 and 21 sporadic schwannomas, we analyzed the immunohistochemistry for Ki-67, hypoxia-inducible factor-1α (HIF-1α), vascular endothelial growth factor receptor 1 (VEGFR1) and VEGFR2, platelet derived growth factor receptor-beta (PDGFR-ß), programmed cell death-1 (PD-1)/ programmed cell death ligand-1 (PD-L1), Foxp3, CD163, CD3, and CD8 to assess the immunosuppressive TME. RESULTS: Most vessels in sporadic schwannomas exhibited slight or negative VEGFR1 and 2 expressions with pericytes coverage. In contrast, large vessels in NF2 schwannomas exhibited strong VEGFR1 and 2 expressions without pericytes. The number of CD3+, CD8+, and CD163+ cells was significantly higher in NF2 schwannomas than in sporadic ones. The expression of PD-L1 and nestin positive cell ratio was higher in NF2 schwannomas than that in sporadic ones. The number of CD163+ cells, nestin positive cell ratio, and HIF-1α expression were significantly associated with shorter progression-free survival in NF2 schwannomas. CONCLUSIONS: This study presents the clinicopathological features of the differences in immunosuppressive cells and the expression of immune checkpoint molecules between NF2 and sporadic schwannomas. Hypoxic TME was first detected in NF2-schwannomas, which was associated with the tumor progression.

Prognostic Analysis of Clinical and Immunohistochemical Factors for Patients with Spinal Schwannoma.

BACKGROUND: Schwannoma comprises approximately 25% of all spinal tumors, but there is little information published in the literature regarding this subject. Our aim in this study was to discuss diagnostic and prognostic factors for spinal schwannoma. METHODS: A retrospective study was performed to analyze the clinical and immunohistochemical data of patients with spinal schwannoma surgically treated in our center between 2005 and 2013. RESULTS: A total of 524 patients with spinal schwannoma were included in the study. The mean follow-up period was 58.3 months. Forty-eight patients developed recurrence, and 26 died. Findings from the statistical analyses suggested duration of preoperative symptoms, Sridhar classification, tumor size, bone damage, Ki67 labeling index, and S100 expression were different between benign schwannoma and the malignant subtype. Recurrence was associated with resection mode, segments of involvement, pathology grade, CD57 expression, Ki67 labeling index, and S100 expression. The overall survival was closely related with recurrence, location in sacrum, pathology grade, Ki67 labeling index, and P53 expression. CONCLUSIONS: Compared with the benign subtype, malignant schwannoma has a shorter duration of preoperative symptoms, larger tumor size, greater Sridhar classification, and poorer prognosis. Total resection can significantly reduce recurrence but not guarantee a better survival, which is associated location and pathology grade. A Ki67 labeling index >5% was not only an index for malignant subtype but also a prognostic indicator for recurrence and poor survival. Moreover, S100-negative was a prognostic indicator for recurrence, whereas P53-positive was associated with a poor prognosis.

Immune Pathobiology of Schwannomas: A Concise Review.

Schwannomas are benign tumors treatable with neurosurgery or radiosurgery, yet a small subset may exhibit aggressive growth. Hence illuminating their immune features can help develop better treatments. A tumor-promoting inflammation exists in schwannomas. Transcription factor NF-κB triggers synthesis of inflammatory cytokines and chemokines. NF-κB is suppressed by NF2/merlin, yet it is mutated or repressed in schwannomas, and therefore MCP-1/CCL2, MIP-1α/CCL3, CXCL16, and CXCR6/Bonzo are likely expressed in these tumors. CD68+ and CD163+ macrophages may infiltrate schwannomas and promote their growth. Anti-inflammatory salicylates inhibit schwannomas in cell culture and clinically. Schwannomas that cannot be completely removed by neurosurgery or controlled by radiosurgery may be suitable targets of pharmacologic interventions focusing on immune mechanisms.

TIM-3 plays a more important role than PD-1 in the functional impairments of cytotoxic T cells of malignant Schwannomas.

Cancer immunotherapy using cytotoxic T cells demonstrates dramatic survival benefits in lymphomas, but its efficacy in solid tumors is limited. Here, we investigated the possibility of using cytotoxic T cells to treat malignant Schwannoma, a rare but aggressive nerve sheath tumor, by examining the native T-cell immunity in the host. We found that compared to CD8+ T cells from healthy controls or benign Schwannoma patients, the CD8+ T cells from malignant Schwannoma patients were present at normal frequencies but were substantially enriched with PD-1-TIM-3+ and PD-1+TIM-3+ cells. Compared to the PD-1-TIM-3- CD8+ T cells, the PD-1-TIM-3+ and PD-1+TIM-3+ CD8+ T cells presented significantly lower proliferation capacity, reduced interleukin 2 and interferon gamma expression, and/or dramatically decreased perforin and granzyme B secretion, indicating a whole-spectrum immunosuppression and reduced cytotoxicity. TIM-3 expression alone was associated with lower proliferation and less perforin and granzyme B secretion, whereas PD-1 expression alone was not associated with functional impairments, suggesting that TIM-3 expression was a better marker of exhausted CD8+ T cells. The expression of galectin 9, a TIM-3 ligand, in CD4+ Th cells was significantly elevated in malignant, but not benign, Schwannoma patients and were enriched in CD25+ Treg cells. Both the PD-1-TIM-3+ and PD-1+TIM-3+ CD8+ T cells responded to Treg-mediated and galectin 9-mediated suppression, whereas the PD-1+TIM-3- CD8+ T cells only responded to Treg-mediated suppression. In resected tumors, the malignant Schwannomas had more tumor-infiltrating CD4+ and CD8+ T cells than the benign Schwannomas, but a large fraction of these tumor-infiltrating CD4+ and CD8+ T cells expressed PD-1 and/or TIM-3, which indicated that their antitumor immunity was compromised. Together, our results suggested that PD-1 and TIM-3 blockade might be necessary in developing effective immunotherapeutic strategies in malignant Schwannoma, in which TIM-3 may play a more important role.

Schwannoma-like tumor in the anterior cranial fossa immunonegative for Leu7 but immunopositive for Schwann/2E.

Schwannoma arising from the olfactory system, often called olfactory groove schwannoma (OGS), is rare, as the olfactory bulb and tract, belonging to the central nervous system, should lack Schwann cells. Another rare entity called olfactory ensheathing cell tumor (OECT) has been reported, which mimics clinical and radiological characteristics of OGS. Here, we report two rare cases of schwannoma-like tumor in the anterior cranial fossa that showed negative staining for Leu7, but positive staining for Schwann/2E, and discuss their origin. Two cases of mass lesions in the anterior cranial fossa in a 26-year-old man and a 24-year-old woman were successfully removed. Morphological examination of these tumors was compatible with a diagnosis of schwannoma. Immunohistochemically, both cases were negative for Leu7, yielding a diagnosis of OECT, but were positive for the schwannoma-specific marker, Schwann/2E. Immunohistochemical staining results in our two cases question the current assumption that OGS and OECT can be distinguished only by Leu7 staining pattern. In conclusion, the origins of OGS and OECT remain to be determined, and further studies in larger numbers of cases are needed to characterize these rare tumors in the anterior cranial fossa.

Characterizing the immune microenvironment of malignant peripheral nerve sheath tumor by PD-L1 expression and presence of CD8+ tumor infiltrating lymphocytes.

BACKGROUND: Malignant peripheral nerve sheath tumor (MPNST) is an aggressive sarcoma with few treatment options. Tumor immune state has not been characterized in MPNST, and is important in determining response to immune checkpoint blockade. Our aim was to evaluate the expression of programmed death-ligand 1 (PD-L1), programmed cell death protein 1 (PD-1), and presence of CD8+ tumor infiltrating lymphocytes (TILs) in MPNST, and correlate these findings with clinical behavior and outcome. RESULTS: PD-L1 staining of at least 1% was seen in 0/20 nerves, 2/68 benign lesions and 9/53 MPNST. Two of 68 benign lesions and 7/53 (13%) MPNST had at least 5% PD-L1 staining. CD8 staining of at least 5% was seen in 1/20 (5%) nerves, 45/68 (66%) benign lesions and 30/53 (57%) MPNST. PD-L1 was statistically more prevalent in MPNST than both nerves and benign lesions (p=0.049 and p=0.008, respectively). Expression of PD-1 was absent in all tissue specimens. There was no correlation of PD-L1 or CD8 expression with disease state (primary versus metastatic) or patient survival. METHODS: A comprehensive PNST tissue microarray was created from 141 surgical specimens including primary, recurrent, and metastatic MPNST (n=53), neurofibromas (n=57), schwannoma (n=11), and normal nerve (n=20). Cores were stained in triplicate for PD-L1, PD-1, and CD8, and expression compared between tumor types. These data were then examined for survival correlates in 35 patients with primary MPNST. CONCLUSIONS: MPNST is characterized by low PD-L1 and absent PD-1 expression with significant CD8+ TIL presence. MPNST immune microenvironment does not correlate with patient outcome.

Elevated serum IL-17A but not IL-6 in glioma versus meningioma and schwannoma.

BACKGROUND: There is a Th1/Th2 cytokine imbalance and expression of IL-17 in patients with brain tumours. We aimed to compare the levels of IL-17A and IL-6 in sera of glioma, meningioma and schwannoma patients as well as in healthy individuals. MATERIALS AND METHODS: IL-17A and IL-6 levels were measured in sera of 38 glioma, 24 meningioma and 18 schwannoma patients for comparison with 26 healthy controls by commercial ELISA assays. RESULTS: We observed an increase in the IL-17A in 30% of glioma patients while only 4% and 5.5% of meningioma and schwannoma patients and none of the healthy controls showed elevated IL-17A in their sera (0.29 ± 0.54, 0.03 ± 0.15 and 0.16 ± 0.68 vs. 0.00 ± 0.00 pg/ml; p=0.01, p=0.01 and p=0.001, respectively). There was also a significant decrease in the level of IL-6 in glioma patients compared to healthy controls (2.34 ± 4.35 vs. 4.67 ± 4.32 pg/ml; p=0.01). There was a direct correlation between the level of IL-17A and age in glioma patients (p=0.005). Glioma patients over 30 years of age had higher IL-17A and lower IL-6 in their sera compared to the young patients. In addition, a non-significant grade-specific inverse trend between IL-17A and IL-6 was observed in glioma patients, where high-grade gliomas had higher IL-17A and lower IL-6. CONCLUSIONS: Our data suggest a Th17 mediated inflammatory response in the pathogenesis of glioma. Moreover, tuning of IL-6 and IL-17A inflammatory cytokines occurs during progression of glioma. IL-17A may be a potential biomarker and/or immunotherapeutic target in glioma cases.

Primary brain tumours and specific serum immunoglobulin E: a case-control study nested in the European Prospective Investigation into Cancer and Nutrition cohort.

BACKGROUND: Case-control studies suggest that patients with allergic diseases have a lower risk of developing glioma but not meningioma or schwannoma. However, those data can be differentially biased. Prospective studies with objective measurements of immunologic biomarkers, like immunoglobulin E (IgE), in blood obtained before cancer diagnosis could help to clarify whether an aetiological association exists. METHODS: The present case-control study nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) measured specific serum IgE as a biomarker for the most common inhalant allergens in 275 glioma, 175 meningioma and 49 schwannoma cases and 963 matched controls using the ImmunoCAP specific IgE test. Subjects with an IgE level ≥0.35 kUA/l (kilo antibody units per litre) were classified as sensitized by allergens. Odds ratios (OR) and 95% confidence intervals (CI) were estimated by adjusted conditional logistic regression models for each tumour subtype. The effect of dose-response relationship was assessed in five increasing IgE level categories to estimate P-values for trend. RESULTS: The risk of glioma was inversely related to allergic sensitization (OR = 0.73; 95% CI 0.51-1.06), especially pronounced in women (OR = 0.53; 95% CI 0.30-0.95). In dose-response analyses, for high-grade glioma, the lowest OR was observed in sera with the highest IgE levels (P for trend = 0.04). No association was seen for meningioma and schwannoma. CONCLUSION: The results, based on serum samples prospectively collected in a cohort study, provide some support for the hypothesis that individuals with allergic sensitization are at reduced risk of glioma and confirm results from previous case-control studies.

Schwannoma intraósseo da coluna vertebral cervical: relato de caso / Intra-osseous cervical vertebral schwannoma: case report

Apresenta-se o caso clínico de um indivíduo do gênero masculino, de 75 anos de idade, com alterações clínicas compatíveis com um quadro de mielopatia cervical. A investigação por imagem revelou uma estenose do canal vertebral em C2-C3 e C3-C4, por alterações degenerativas nesses níveis, e a presença de uma lesão expansiva centrada aos corpos de C5 e C6. A tomografia axial computadorizada (TC) e a ressonância magnética (RM) mostraram ainda um componente paravertebral com características de sinal idênticas às da lesão vertebral. O doente foi operado e o exame histopatológico da massa tumoral demonstrou tratar-se de um schwannoma. Contudo, foram notadas algumas diferenças entre os dois componentes, intraósseo e paravertebral. O caso apresentado reveste-se de interesse especial pela localização e distribuição tumoral particularmente invulgares. Do nosso conhecimento, trata-se do primeiro caso descrito de schwannoma intraósseo com destruição simultânea de dois corpos vertebrais adjacentes. Salienta-se, ainda, a ocorrência de dois componentes tumorais anatomicamente distintos, um intraósseo e outro paravertebral, sem nítida continuidade entre si, como observado intraoperatoriamente e demonstrado pelas imagens de TC e RM. Julgamos importante considerar esse tipo de tumor no diagnóstico diferencial de lesões expansivas vertebrais, de forma a planejar adequadamente a abordagem terapêutica...

Laparoscopic resection of a retroperitoneal degenerative schwannoma: a case report and review of the literature.

Degenerative schwannomas are rare benign tumors. The patient presented in this case report complained of a dull left upper quadrant pain for several months. A computed tomography scan revealed a low-density lesion at the level of T12. The lesion was laparoscopically resected and pathologic examination revealed a degenerative schwannoma.

Immunoreactivity of bovine schwannomas.

Thirty schwannomas from 22 cows were examined immunohistochemically. All were positive for vimentin and Ki-67 but negative for pancytokeratin, neurofilament, and desmin. S-100 immunolabelling varied between and within lesions. The numbers of tumours giving positive results for S-100, neuron-specific enolase (NSE) and glial fibrillary acidic protein (GFAP) were 16, 30 and 25, respectively. It was concluded that vimentin-positive tumours suspected to be schwannomas should also be immunolabelled for NSE and GFAP to confirm the diagnosis.

The interaction mode of premalignant Schwann and immune effector cells during chemically induced carcinogenesis in the rat peripheral nervous system is strongly influenced by genetic background.

Contrary to rats of the highly sensitive inbred strain BDIX, BDIV rats are resistant to the induction of malignant schwannomas by N-ethyl-N-nitrosourea, arising predominantly in the trigeminal nerves. A point mutation of the neu/erbB-2 gene diagnostic of N-ethyl-N-nitrosourea-induced rat schwannomas is an early marker of Schwann precursor cells at high risk of subsequent malignant transformation. Neu-mutant cells initially arise at a similar frequency in sensitive and resistant animals. However, these cells disappear from the trigeminal nerves of resistant rats while giving rise to highly malignant schwannomas in susceptible animals. The resistance of BDIV rats obviously includes mechanisms to recognize and eliminate premalignant cells. The involvement of a cellular immune response was investigated in trigeminal nerves of both strains at different times after neonatal carcinogen exposure. An inflammatory reaction involving sequentially CD4(+) macrophages and T helper cells, CD8(+) cytotoxic T cells, and ED1(+) and ED2(+) macrophages was detected as a consequence of N-ethyl-N-nitrosourea treatment as early as postnatal day 40, briefly after the emergence of premalignant neu-mutant Schwann cells. It persisted throughout the observation period (40-250 days). However, there were no gross differences in immune cell counts between tumor-susceptible and tumor-resistant rats, except for a moderate increase of ED2(+) macrophages in N-ethyl-N-nitrosourea-treated BDIX rats only. Differential interactions of immune effector cells with premalignant Schwann cells may thus be involved in genetically determined tumor susceptibility or resistance, which could include functional differences of immune effector cells and/or a differential capability of premalignant Schwann cells to escape or counteract the cellular immune response.

Alpha-synuclein immunoreactivity in normal and neoplastic Schwann cells.

Alpha-synuclein is known to play an important role in several neurodegenerative diseases. Moreover, it is expressed in central nervous system neuronal tumors, and another member of the synuclein family, gamma-synuclein, is overexpressed in breast and ovarian carcinomas. However, the expression of alpha-synuclein has not been reported hitherto in the peripheral nervous system (PNS). In the present study, we investigated normal PNS tissue and schwannomas in human postmortem and biopsy samples using both immunocytochemistry and immunoelectron microscopy with antibodies against alpha-, beta- and gamma-synuclein. In normal PNS tissue, Schwann cells, but not axons or myelin, were immunopositive for alpha-synuclein. In schwannomas, almost all of the tumor cells showed diffuse cytoplasmic staining for alpha-synuclein (30 cases). Ultrastructurally, alpha-synuclein immunoreactivity was found in the cytoplasm of normal and neoplastic Schwann cells, in association with the plasma membrane, ribosomes, rough endoplasmic reticulum, small vesicles, Golgi apparatus and the nuclear outer membrane. No beta- or gamma-synuclein immunoreactivity was found in those cells. These results indicate that in the PNS, alpha-synuclein is a useful marker of Schwann cells and that it is not involved in tumorigenesis.

Adult T-cell lymphoma involving the leptomeninges associated with a spinal cord schwannoma.

Adult T-cell lymphoma (ATL-L) developing initially in the meninges is rare. An autopsy case of ATL-L with an acute onset of meningitis and generalized lymphadenopathy in association with a cervical cord schwannoma is reported here. A 78-year-old woman with sensori-motor weakness of both arms over a 1-year period, developed febrile episodes and drowsiness with neck stiffness. Lumbar puncture revealed an increased protein content (161 mg/dL) and increased cell count (463/3) consisting of 99% of lymphocytes which contained atypical lymphocytes with multilobulated nuclei ('flower cells'), which are characteristic of ATL-L. Viral titers were positive only for HTLV-I antibodies (serum X 640: CSF X 16). Biopsy of an enlarged retroperitoneal lymph node revealed malignant lymphoma of the T-cell type. Brain MRI was negative, whereas an intradural extramedullary mass was found at the C4 level. With a diagnosis of ATL-L stage IV, chemotherapy was commenced, which was effective in reducing the generalized lymphadenopathy as well as the cervical mass and restoring the CSF findings to normality. The cervical cord mass was verified to be a solitary schwannoma, and ATL-L involvement was found not only in the leptomeninges, but also within the cervical cord schwannoma.

What are the CD34+ cells in benign peripheral nerve sheath tumors? Double immunostaining study of CD34 and S-100 protein.

To determine whether CD34 expression in nerve sheath lesions was found in a unique cell population or in a subset of nerve sheath cells, we performed double immunohistochemical staining using a standard avidinbiotin complex method with 2 separate color developing systems. We studied 40 neurofibromas and 16 neurilemomas. All lesions strongly expressed S-100 in nuclei and cytoplasm. CD34 was detected in cells having ameboid dendritic cytoplasm present in greatest numbers in Antoni B zones of neurilemomas, myxoid zones of neurofibromas, at the periphery of lobules in both tumor types, and condensed in apposition to perineurium. The CD34+ cells also were detected in normal nerves. They were infrequent in Antoni A zones of neurilemomas. No dual S-100 and CD34 expression was seen. This double immunostaining confirms the presence of a CD34-reactive non-Schwannian cell type in these neural neoplasms. As the CD34+, S-100-negative cell population is present also in normal nerves and infrequently seen in the areas of cellular neoplastic Schwann cells, CD34+, S-100-negative cells in peripheral nerve sheath tumors most likely are nonneoplastic and may have a supportive function.

Immunoblotting analysis of schwannomin/merlin in human schwannomas.

HYPOTHESIS: Absent or reduced expression of schwannomin/merlin is associated with tumorigenesis of sporadic schwannomas. BACKGROUND: The neurofibromatosis type 2 (NF2) gene frequently is mutated in sporadic vestibular schwannomas. The protein product of the NF2 gene is called schwannomin or merlin. Little is known about the mutated forms of schwannomin/merlin present in schwannomas. METHODS: To investigate further the role of schwannomin/merlin in schwannoma tumorigenesis, immunoblotting experiments were performed. Antischwannomin/merlin-specific antibody that recognizes amino terminus of the protein was used to determine the expression levels of schwannomin/merlin in 16 sporadic vestibular schwannomas, 1 NF2-related vestibular schwannoma, and 5 spinal schwannomas. RESULTS: The antibody detects a protein of approximately 66 kDa in the Triton X-100-insoluble fraction of tumors. The expression of schwannomin/merlin was severely reduced, <35% of control, in 11 (50%) of 22 sporadic schwannomas and in 1 NF2-related vestibular schwannoma. The intensity of 66-kDa schwannomin/merlin band was moderately reduced, from 35-60%, in 7 (32%) of 22 schwannomas compared to the expression levels found in the human brain. Truncated forms of schwannomin/merlin were identified in three tumors with moderately reduced schwannomin/merlin. CONCLUSIONS: These results provide new evidence that inactivation of schwannomin/merlin is an important factor in tumorigenesis of sporadic schwannomas.

Factor XIIIa-immunoreactivity in tumors of the central nervous system.

The clotting factor XIIIa (FXIIIa) has been shown to be present both in tumor cells and in tumor-associated macrophages of different neoplasms such as Hodgkin's disease, giant cell tumor of bone, malignant fibrous histiocytoma, meningeal tumors, and hemangiopericytoma. The biological significance of these findings, however, are still unclear. This study investigates the immunohistochemical distribution of FXIIIa in 186 tumors of the central nervous system (CNS) in order to evaluate its possible diagnostic or prognostic significance in neuro-oncology. High-grade gliomas such as glioblastoma, gliosarcoma, astrocytoma (grade III WHO), and ependymoma (III) as well as meningiomas and meningeal hemangiopericytomas consistently contained factor XIIIa-positive cells, whereas low-grade glial tumors did not do so. One desmoplastic medulloblastoma and one anaplastic schwannoma also showed FXIIIa-positive cells. With the exception of hemangiopericytomas, however, the major source of FXIIIa expression in all these tumors consisted of a subpopulation of tumor-associated macrophages, the exact role of which still remains unclear. Because of its non-discriminatory staining in a wide variety of CNS tumors, the differential diagnostic contribution of FXIIIa in neuro-oncology seems to be limited.

Immunohistochemical and ultrastructural investigation of the human vestibular dark cell area: roles of subepithelial capillaries and T lymphocyte-melanophage interaction in an immune surveillance system.

BACKGROUND: The aim of the present study was to morphologically characterize the structure of the subepithelial blood vessels in the dark cell area of the human vestibular organs, and to determine whether immunocompetent cells such as macrophages and lymphocytes could be found around these small blood vessels. MATERIALS AND METHODS: All 31 surgical specimens (semicircular canals and utricles) were obtained from patients with vestibular schwannoma. Formalin fixed specimens were stained with hematoxylin and eosin (H&E), and with antibodies to von Willebrand Factor (vWF), leukocyte common antigen (LCA), and UCHL-1, and were examined with light microscope. Specimens fixed with glutaraldehyde were examined with a transmission electron microscope (TEM). OBJECTIVES: Subepithelial blood vessels stained positive for vWF. By TEM observation, these blood vessels were observed to be capillaries that consisted of non-fenestrated endothelium, occasional pericytes, and a basement membrane. They were usually accompanied by melanophages with a number of secondary lysosomes containing phagocytosed degraded melanosomes and lipid droplets. Moreover, melanocytes and their cell processes directly surrounded these subepithelial capillaries. The fact that cells which were positively stained with LCA and UCHL-1 were present both in the intra- and subepithelial layer of the specimens, and that by TEM the intra- and subepithelial mononuclear cells with a lymphoid appearance had clustered dense bodies in their cytoplasm, suggested that they were a population of T lymphocytes. CONCLUSIONS: Results suggested the possibility of a T lymphocyte-melanophage (macrophage) interaction, both originating from and harbored around subepithelial capillaries, which suggests the presence of an immune surveillance system in the human vestibular organs.

Schwannoma cells induce a tumor-cell-specific cytotoxic-T-cell response upon transplantation into syngeneic rats but escape elimination through the secretion of immunosuppressive factors.

Tumor cells often express antigens that can be recognized by the immune system. Despite induction of an immune response, the tumor cells escape their elimination. We have studied the mechanisms and factors which mediate these events in a syngeneic tumor model. NV2Cd rat schwannoma cells were transplanted into BDIX rats. After injection of 10(7) to 2 x 10(7) cells, tumors grew very slowly for 10 to 12 days. After that time, rapid growth was observed. The tumors consisted of compact areas of spindle-shaped cells with small cysts, many blood vessels and central necrotic areas. During tumor growth, the number of spleen cells and T lymphocytes increased, and cytotoxic T cells with specificity for the NV2Cd tumor cells were detected. The strong specific cellular immune response did not prevent the increase in tumor volume. We studied the biological activity of the fluid present in the cysts of the tumor. At a concentration of 1 ng to 10 microg protein per ml, the cyst fluid inhibited the proliferation of splenic T lymphocytes and B lymphocytes and of lymphoma cells, but enhanced the proliferation of NV2Cd tumor cells. The cyst fluids contain the immunosuppressive transforming growth factors (TGF)-beta1, -beta2 and -beta3, also the vascular endothelial growth factor (VEGF) and epidermal growth factor (EGF). Antibodies directed against TGF-beta relieved the suppression of T-cell growth by cyst fluid, but did not influence the proliferation of NV2Cd cells. The growth-modulating factors present in the tumor cyst fluid were also detected in conditioned medium from NV2Cd cells cultured in vitro. Our data suggest that tumors can escape the cellular immune response by the production of factors that inhibit lymphocytes. They also enhance their own growth environment by secreted factors.