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Transoral vs. endoscopic endonasal approach for clival/upper cervical chordoma

Shidoh Satoka, Toda Masahiro, Kawase Takeshi, Nakajima Hideo, Tomita Toshiki, Ogawa Kaoru, Yoshida Kazunari

Neurologia Medico-Chirurgica 54 （ 12 ） 991 - 998 2014年12月

ISSN 0470-8105

The surgical results of 18 cases of clival/upper cervical chordoma treated in the last decade via the endoscopic endonasal approach (EEA, 9 cases) and the transoral-transpalatal approach (TO-TPA, 9 cases) were compared. Each group showed the same incidence of subdural invasion, with 5 cases each. The superior (frontal base) and lateral surgical fields were wider by EEA, but the inferior view lower than the cranio-vertebral junction (CVJ) was wider by TO-TPA. Gross total removal was achieved in 3 cases in the EEA group, but in only 1 case in the TO-TPA group. Differences in radicality might be due to the extent of the lateral and subdural overview. However for large tumors extending below the CVJ, TO-TPA was the only viable approach for surgical removal. Surgical complications were higher in the EEA (4 cases) than the TO-TPA group (1 case), and were mainly caused by aggressive management of subdural invasion in the EEA group. Post-operative oral intake was earlier and the operative time was shorter in the EEA group. The surgical results were more radical and less invasive in the EEA group than the TO-TPA group. However in tumors extending below the CVJ, the surgical field in EEA was limited, indicating the need to use the transoral route or a combination of routes. A higher complication rate following subdural management was a negative factor that requires improvement in the EEA group and two-staged EEA followed by a transcranial approach may be considered for the cases with subdural invasion.

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Analysis of the bacterial flora in the nasal cavity and the sphenoid sinus mucosa in patients operated on with an endoscopic endonasal transsphenoidal approach

Shibao Shunsuke, Toda Masahiro, Tomita Toshiki, Ogawa Kaoru, Yoshida Kazunari

Neurologia Medico-Chirurgica 54 （ 12 ） 1009 - 1013 2014年12月

ISSN 0470-8105

The aim of this study was to analyze the bacterial flora in the nasal cavity and sphenoid sinus and evaluate the sensitivity of these bacteria to antibiotics that can be used to prevent postoperative meningitis. Bacteria of the preoperative nasal cavity and intraoperative sphenoid sinus mucosa were cultured and analyzed in 40 patients (20 men and 20 women; mean age, 52.2 years) who underwent endoscopic transsphenoidal surgery. The sensitivity of these bacteria to cephalosporin, a representative prophylactic antibiotic, was examined. Staphylococcus epidermidis was the most frequently detected species in both spaces; 24 (38.7%) of 62 isolates in the nasal cavity and 26 (37.1%) of 70 isolates in the sphenoid sinus. In contrast, Corynebacterium species were found mainly in the nasal cavity, and anaerobic bacteria were found only in the sphenoid sinus. Bacteria that were resistant to cephalosporin were found in the nasal cavity in 3.2% of patients and in the sphenoid sinus in 20% of patients. In conclusion, the composition of bacterial flora, including bacteria that are resistant to prophylactic antibiotics, differs between the nasal cavity and the sphenoid sinus.

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Functional analysis of a novel glioma antigen, EFTUD1

Saito Katsuya, Iizuka Yukihiko, Ohta Shigeki, Takahashi Satoshi, Nakamura Kenta, Saya Hideyuki, Yoshida Kazunari, Kawakami Yutaka, Toda Masahiro

Neuro-Oncology 16 （ 12 ） 1618 - 1629 2014年12月

ISSN 1522-8517

BACKGROUND: A cDNA library made from 2 glioma cell lines, U87MG and T98G, was screened by serological identification of antigens by recombinant cDNA expression (SEREX) using serum from a glioblastoma patient. Elongation factor Tu GTP binding domain containing protein 1 (EFTUD1), which is required for ribosome biogenesis, was identified. A cancer microarray database showed overexpression of EFTUD1 in gliomas, suggesting that EFTUD1 is a candidate molecular target for gliomas.METHODS: EFTUD1 expression in glioma cell lines and glioma tissue was assessed by Western blot, quantitative PCR, and immunohistochemistry. The effect on ribosome biogenesis, cell growth, cell cycle, and induction of apoptosis and autophagy in glioma cells during the downregulation of EFTUD1 was investigated. To reveal the role of autophagy, the autophagy-blocker, chloroquine (CQ), was used in glioma cells downregulating EFTUD1. The effect of combining CQ with EFTUD1 inhibition in glioma cells was analyzed.RESULTS: EFTUD1 expression in glioma cell lines and tissue was higher than in normal brain tissue. Downregulating EFTUD1 induced G1 cell-cycle arrest and apoptosis, leading to reduced glioma cell proliferation. The mechanism underlying this antitumor effect was impaired ribosome biogenesis via EFTUD1 inhibition. Additionally, protective autophagy was induced by glioma cells as an adaptive response to EFTUD1 inhibition. The antitumor effect induced by the combined treatment was significantly higher than that of either EFTUD1 inhibition or CQ alone.CONCLUSION: These results suggest that EFTUD1 represents a novel therapeutic target and that the combination of EFTUD1 inhibition with autophagy blockade may be effective in the treatment of gliomas.

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Pilocytic astrocytoma with anaplastic features presenting good long-term clinical course after surgery alone

Saito Katsuya, Toda Masahiro, Yoshida Kazunari

Child's Nervous System 2014年08月

ISSN 0256-7040

Purpose Pilocytic astrocytomas (PAs) are the most common brain tumor in children and typically have an excellent prognosis. However, some PAs show histologically anaplastic features. It is reported that PAs with anaplastic features often need the postoperative radiation and chemotherapy due to aggressiveness such as early local recurrence and dissemination. We describe an interesting case of primary anaplastic PA with good clinical course in the long-term. Methods A 10-year-old man presented with worsening headache and vomiting. Magnetic resonance imaging (MRI) showed a large cystic tumor with contrast-enhanced solid component in a right occipital lobe. Magnetic resonance spectroscopy (MRS) showed the decrease of N-acetylaspartate (NAA) and the increase of choline and lipids, which suggested the malignancy. Results The patient was operated with an occipital lobectomy. The tumor was incompletely resected due to the deep invasion to the inner wall of lateral ventricle. Pathological diagnosis was a pilocystic astrocytoma with anaplastic features. Although aggressive features were suspected from magnetic resonance spectroscopy and pathological findings, the remnant tumor showed no recurrence for 8 years without any postoperative treatments. Conclusion PAs could exhibit variable behavior, and careful managements including wait-and-scan should be considered, because adjuvant therapies may cause child's growth disorder and malignant transformation. © 2014 Springer-Verlag Berlin Heidelberg.

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Primary dural closure and anterior cranial base reconstruction using pericranial and nasoseptal multi-layered flaps in endoscopic-assisted skull base surgery

Tomio Ryosuke, Toda Masahiro, Tomita Toshiki, Yazawa Masaki, Kono Maya, Ogawa Kaoru, Yoshida Kazunari

Acta Neurochirurgica 156 （ 10 ） 1911 - 1915 2014年

ISSN 0001-6268

Introduction: Dural and anterior cranial base reconstruction is essential in the surgical resection of a craniofacial tumor that extends from the paranasal sinuses to the subdural space. Watertight reconstruction of vascularized tissue is essential to prevent postoperative liquorrhea, especially under conditions that prevent wound healing (e.g., postoperative irradiation therapy).Method: We successfully treated two cases of olfactory neuroblastoma by endoscopic-assisted craniotomy with primary dural closure and anterior cranial base reconstruction using a multi-layered flap technique. Dural defects were closed using temporal fascia or fascia lata in a conventional fashion, immediately after detaching the subdural tumor, in order to isolate and prevent contamination of subdural components and cerebrospinal fluid (CSF) from the tumor and nasal sinuses. Tumor removal and anterior cranial base reconstruction were performed without any concern of CSF contamination after dural closure by craniotomy and endoscopic endonasal approach (EEA). Vascularized pericranial flaps (PCF) and nasoseptal flaps (NSF) were used simultaneously as doubled-over layers for reconstruction.Results: The tumor was completely removed macroscopically and the anterior cranial base was reconstructed in both cases. CSF leak and postoperative meningitis were absent. Postoperative and irradiation therapy courses were successful and uneventful.Conclusions: This multi-layered anterior cranial base reconstruction consisted of three layers: a fascia for dural plasty and double-layered PCF and NSF. This surgical reconstruction technique is suitable to treat craniofacial tumors extending into the subdural space through the anterior cranial base dura mater.

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Anterior petrosal approach

Tomio Ryosuke, Toda Masahiro, Yoshida Kazunari, Borghei-Razavi Hamid

Journal of Neurosurgery 120 （ 5 ） 1249 - 1250 2014年

ISSN 0022-3085

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Isolated Pituitary Tuberculoma - Case Reports –

Saito K, Toda M, Shido S, Tomita T, Ogawa K, Yoshida K.

NMC Case Report Journal 2013 （ 0330 ） 2014年

研究論文（学術雑誌）, 共著

Sox6 Up-Regulation by Macrophage Migration Inhibitory Factor Promotes Survival and Maintenance of Mouse Neural Stem/Progenitor Cells

Ohta Shigeki, Misawa Aya, Lefebvre Véronique, Okano Hideyuki, Kawakami Yutaka, Toda Masahiro

PLoS ONE 8 （ 9 ） 2013年09月

Macrophage migration inhibitory factor (MIF) has important roles in supporting the proliferation and/or survival of murine neural stem/progenitor cells (NSPCs), but downstream effectors remain unknown. We show here that MIF robustly increases the expression of Sox6 in NSPCs in vitro. During neural development, Sox6 is expressed in the ventricular zone of the ganglionic eminence (GE) of mouse brains at embryonic day 14.5 (E14.5), cultured NSPCs from E14.5 GE, and NSPCs in the subventricular zone (SVZ) around the lateral ventricle (LV) of the adult mouse forebrain. Retroviral overexpression of Sox6 in NSPCs increases the number of primary and secondary neurospheres and inhibits cell differentiation. This effect is accompanied with increased expression of Hes1 and Bcl-2 and Akt phosphorylation, thus suggesting a role for Sox6 in promoting cell survival and/or self-renewal ability. Constitutive activation of the transcription factor Stat3 results in up-regulation of Sox6 expression and chromatin immunoprecipitation analysis showed that MIF increases Stat3 binding to the Sox6 promoter in NSPCs, indicating that Stat3 stimulates Sox6 expression downstream of MIF. Finally, the ability of MIF to increase the number of primary and secondary neurospheres is inhibited by Sox6 gene silencing. Collectively, our data identify Sox6 as an important downstream effector of MIF signaling in stemness maintenance of NSPCs. © 2013 Ohta et al.

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Infratentorial low-grade oligoastrocytoma with aggressive clinical behavior in an adult

Sano Keisho, Toda Masahiro, Sasaki Hikaru, Kitamura Yohei, Mikami Shuji, Hirato Junko, Inoue Satoshi, Kawase Takeshi, Yoshida Kazunari

Brain Tumor Pathology 30 （ 2 ） 99 - 103 2013年04月

ISSN 1433-7398

Oligoastrocytoma preferentially arises in the cerebral hemisphere, and a cerebellar location is unusual. We report the case of a 35-year-old woman with an aggressive cerebellar tumor histopathologically diagnosed as oligoastrocytoma World Health Organization (WHO) grade II. After partial removal of the tumor, she underwent concomitant temozolomide (TMZ) therapy with local irradiation followed by additional TMZ monotherapy. However, her symptoms gradually worsened, and chronological magnetic resonance imaging showed remarkable tumor enlargement. In accordance with the aggressive clinical course, unfavorable genetic characteristics such as the gain of the entire chromosome 7, loss of 9p, absence of 1p/19q codeletion, absence of methylation of the O6- methylguanine-deoxyribonucleic acid methyltransferase promoter, and absence of the isocitrate dehydrogenase-1 mutation were observed. The present case illustrates that these molecular characteristics represent the biological features of gliomas more closely than the histopathological diagnosis and may also suggest that infratentorial gliomas arise through a distinct tumorigenic pathway from their supratentorial counterparts. © The Japan Society of Brain Tumor Pathology 2012.

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Our experience in anterior petrosal approach. Letter to the editor.

Tomio R, Borghei-Razavi H, Toda M, Yoshida K.

J Neurosurg 2013年

研究論文（学術雑誌）, 共著

Transoral-transpalatal approach and endoscopic endonasal approach for chordomas of the craniovertebral junction

Shidoh S, Toda M, Nakajima H, Tomita T, Ogawa K, Kawase T, Yoshida K

J Neurophysiol 4 （ 4 ） 162 2013年

研究論文（学術雑誌）, 共著, 査読有り

Macrophage migration inhibitory factor (MIF) promotes cell survival and proliferation of neural stem/progenitor cells

Ohta Shigeki, Misawa Aya, Fukaya Raita, Inoue Satoshi, Kanemura Yonehiro, Okano Hideyuki, Kawakami Yutaka, Toda Masahiro

Development (Cambridge) 139 （ 19 ） 2012年10月

ISSN 0950-1991

In a previous study, we showed that murine dendritic cells (DCs) can increase the number of neural stem/progenitor cells (NSPCs) in vitro and in vivo. In the present study, we identified macrophage migration inhibitory factor (MIF) as a novel factor that can support the proliferation and/or survival of NSPCs in vitro. MIF is secreted by DCs and NSPCs, and its function in the normal brain remains largely unknown. It was previously shown that in macrophages, MIF binds to a CD74-CD44 complex. In the present study, we observed the expression of MIF receptors in mouse ganglionic-eminence-derived neurospheres using flow cytometry in vitro. We also found CD74 expression in the ganglionic eminence of E14 mouse brains, suggesting that MIF plays a physiological role in vivo. MIF increased the number of primary and secondary neurospheres. By contrast, retrovirally expressed MIF shRNA and MIF inhibitor (ISO-1) suppressed primary and secondary neurosphere formation, as well as cell proliferation. In the neurospheres, MIF knockdown by shRNA increased caspase 3/7 activity, and MIF increased the phosphorylation of Akt, Erk, AMPK and Stat3 (Ser727), as well as expression of Hes3 and Egfr, the products of which are known to support cell survival, proliferation and/or maintenance of NSPCs. MIF also acted as a chemoattractant for NSPCs. These results show that MIF can induce NSPC proliferation and maintenance by multiple signaling pathways acting synergistically, and it may be a potential therapeutic factor, capable of activating NSPC, for the treatment of degenerative brain disorders. © 2012. Published by The Company of Biologists Ltd.

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Epidural anterior petrosectomy with subdural visualization of sphenobasal vein via the anterior transpetrosal approach-technical case report

Ichimura Shinya, Yoshida Kazunari, Kagami Hiroshi, Inaba Makoto, Orii Maaya, Kitamura Yohei, Saga Isako, Toda Masahiro

Neurosurgical Review 35 （ 4 ） 609 - 613 2012年10月

ISSN 0344-5607

The drainage of the superficialmiddle cerebral vein (SMCV) is classified into four subtypes. The sphenobasal vein (SBV) drains from the SMCV to the pterygoid venous plexus at the temporal skull base. Epidural procedures in the standard anterior transpetrosal approach (ATPA) may damage the route of the SBV. We report a case in which modified surgical procedures via the ATPA were used to preserve the SBV. A 45-year-old man complained of right facial pain. Magnetic resonance images revealed a right cerebellopontine tumor suggestive of an epidermoid cyst. Right carotid angiography revealed that the SMCV drained into the pterygoid venous plexus via the SBV. The convexity dura mater of the temporal lobe was cut and the anterior part of the temporal lobe was retracted subdurally. The SBV was visualized from the subdural side. The basal dura mater of the temporal lobe posterior to the SBV was cut and the posterior part of the temporal lobe was retracted epidurally. After dissecting the dura mater medial to the greater petrosal nerve and to the edge of the petrous apex, the petrous apex was exposed and drilled out without injuring the SBV. The superior petrous sinus and the tentorium were cut. The tumor compressed the root exit zone of the trigeminal nerve. The tumor was grossly totally removed. ThemodifiedATPA (epidural anterior petrosectomy with subdural visualization of the SBV) is effective in preserving the SBV. © Springer-Verlag 2012.

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Application of the endoscopic transsphenoidal approach to true type transsellar transsphenoidal meningoencephalocele in an adult

Saito Katsuya, Toda Masahiro, Sano Keisho, Tomita Toshiki, Ogawa Kaoru, Yoshida Kazunari

Acta Neurochirurgica 154 （ 8 ） 1511 - 1515 2012年08月

ISSN 0001-6268

Of the transsellar transsphenoidalmeningoencephaloceles (TTSMEs), the true type presents with the hernial sac extending from the intracranium to the epipharynx through the sellar floor. The true type is the most serious and difficult to manage, especially when the hernial sac contains vital structures, such as the anterior cerebral artery, pituitary gland, optic nerve, hypothalamus, and third ventricle. Surgical outcome for true type TTSME is reported to be poor. We describe a successful case of endoscopic repair for a 36-year-old man with true type TTSME. Our success with endoscopic repair for true type TTSME in an adult is the first reported case. We believe that the endoscopic transsphenoidal approach allows less invasive surgery and provides an acceptable operative outcome in comparison with other microsurgical approaches. © Springer-Verlag 2012.

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Surgical results of an endoscopic endonasal approach for clival chordomas

Saito Katsuya, Toda Masahiro, Tomita Toshiki, Ogawa Kaoru, Yoshida Kazunari

Acta Neurochirurgica 154 （ 5 ） 879 - 886 2012年05月

ISSN 0001-6268

Background The surgical approaches for clival chordomas remain controversial, although the extent of resection is one of the most important factors for long survival rates. Recently an endoscopic endonasal approach in good collaboration with otolaryngologists has attracted major attention as a surgical approach for clival chordomas. We describe our experience with the endoscopic endonasal approach and provide a review of the literature. Methods Between 2008 and 2011, six operations were performed via the endoscopic endonasal approach for clivus chordomas. The mean tumor size was 35 mm in diameter. The tumor location was mainly from the upper to middle clivus. The tumor extended into the cavernous sinus in five cases and intradurally in three cases. A binostril approach was performed in four cases, while a one nostril approach was performed in two cases. Results Gross total removal was achieved in three cases. The analysis of cases with incomplete resection suggested that residual tumors were observed epidurally and subdurally. The residual on the epidura was observed from the posterior clinoid to the posterior compartment of the cavernous sinus. On the other hand, the residual on the subdural was observed behind the upper part of the pituitary gland. There was no postoperative cerebrospinal fluid (CSF) leakage using vascularized nasoseptal flaps in any of the cases. Conclusions The endoscopic endonasal transclival approach allows an appropriate extent of resection with acceptable complication rates in comparison with other approaches. In our series, the accomplishment of gross total removal was associated with the relationship between the tumors and surrounding structures, such as the pituitary gland and the cavernous portion of the intracranial carotid artery (ICA). © Springer-Verlag 2012.

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Downregulation of KIF23 suppresses glioma proliferation

Takahashi Satoshi, Fusaki Noemi, Ohta Shigeki, Iwahori Yoshihiro, Iizuka Yukihiko, Inagawa Kohei, Kawakami Yutaka, Yoshida Kazunari, Toda Masahiro

Journal of Neuro-Oncology 106 （ 3 ） 519 - 529 2012年02月

ISSN 0167-594X

To identify therapeutic molecular targets for glioma, we performed modified serological identification of antigens by recombinant complementary DNA (cDNA) expression cloning using sera from a mouse glioma model. Two clones, kinesin family member 23 (Kif23) and structural maintenance of chromosomes 4 (Smc4), were identified as antigens through immunological reaction with sera from mice harboring synergic GL261 mouse glioma and intratumoral inoculation with a mutant herpes simplex virus. The human Kif23 homolog KIF23 is a nuclear protein that localizes to the interzone of mitotic spindles, acting as a plus-end-directed motor enzyme that moves antiparallel microtubules in vitro. Expression analysis revealed a higher level of KIF23 expression in glioma tissues than in normal brain tissue. The introduction of small interfering RNA (siRNA) targeting KIF23 into two different glioma cell lines, U87MG and SF126, downregulated KIF23 expression, which significantly suppressed glioma cell proliferation in vitro. KIF23 siRNA-treated glioma cells exhibited larger cell bodies with two or more nuclei compared with control cells. In vivo analysis using mouse xenograft showed that KIF23 siRNA/DNA chimeratreated tumors were significantly smaller than tumors treated with control siRNA/DNA chimera. Taken together, our results indicate that downregulation of KIF23 decreases proliferation of glioma cells and that KIF23 may be a novel therapeutic target in malignant glioma. © 2011 Springer Science+Business Media, LLC.

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Macrophage migration inhibitory factor (MIF) promotes cell survival and proliferation of neural stem/progenitor cells.

Ohta S, Misawa A, Fukaya R, Inoue S, Kanemura Y, Okano H, Kawakami Y, Toda M

J Cell Sci 125 3210 - 3220 2012年

研究論文（学術雑誌）, 共著, 査読有り

Downregulation of uPARAP mediates cytoskeletal rearrangements and decreases invasion and migration properties in glioma cells

Takahashi Satoshi, Yamada-Okabe Hisafumi, Hamada Kenji, Ohta Shigeki, Kawase Takeshi, Yoshida Kazunari, Toda Masahiro

Journal of Neuro-Oncology 103 （ 2 ） 267 - 276 2011年06月

ISSN 0167-594X

To identify molecular therapeutic targets for glioma, we performed gene expression profiling by using a complementary DNA (cDNA) microarray method and identified the urokinase plasminogen activator receptor-associated protein (uPARAP/Endo180) as a gene expressed highly in glioma tissue compared with the normal brain tissue. The uPARAP is an endocytic receptor for collagen. In certain cell types, uPARAP occurs in a complex with the urokinase plasminogen activator receptor (uPAR) where it fulfills other functions in addition to collagenolysis. Quantitative PCR analysis using a cDNA panel revealed higher expression levels of uPARAP in glioma tissue compared with normal brain tissue. Western blot analysis revealed that the uPARAP protein was expressed in glioma samples and two glioma cell lines, KNS42 and KNS81, but not expressed in control tissue from the normal brain. Introduction of small interfering RNA-targeted uPARAP into the two different glioma cell lines, KNS42 and KNS81, resulted in downregulation of uPARAP expression, and it significantly suppressed glioma cell migration and invasion in vitro. Control glioma cells showed small cell bodies, whereas uPARAP siRNA-treated glioma cells exhibited large and flat morphology. Most of the polymeric actin in the control glioma cells was concentrated in the lamellipodia that are observed in mobile cells. In contrast, in the uPARAP siRNA-treated glioma cells, polymeric actin became organized in stress fibers and the lamellipodia disappeared, characteristic of immobile cells. Our present study suggests that uPARAP may be involved in glioma cell invasiveness through actin cytoskeletal rearrangement. downregulation of uPARAP may be a novel anti-invasion therapeutic strategy for malignant gliomas. © 2010 Springer Science+Business Media, LLC.

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Functional analysis of HOXD9 in human gliomas and glioma cancer stem cells

Tabuse Masanao, Ohta Shigeki, Ohashi Yohei, Fukaya Raita, Misawa Aya, Yoshida Kazunari, Kawase Takeshi, Saya Hideyuki, Thirant Cécile, Chneiweiss Hérve, Matsuzaki Yumi, Okano Hideyuki, Kawakami Yutaka, Toda Masahiro

Molecular Cancer 10 2011年05月

Background: HOX genes encode a family of homeodomain-containing transcription factors involved in the determination of cell fate and identity during embryonic development. They also behave as oncogenes in some malignancies.Results: In this study, we found high expression of the HOXD9 gene transcript in glioma cell lines and human glioma tissues by quantitative real-time PCR. Using immunohistochemistry, we observed HOXD9 protein expression in human brain tumor tissues, including astrocytomas and glioblastomas. To investigate the role of HOXD9 in gliomas, we silenced its expression in the glioma cell line U87 using HOXD9-specific siRNA, and observed decreased cell proliferation, cell cycle arrest, and induction of apoptosis. It was suggested that HOXD9 contributes to both cell proliferation and/or cell survival. The HOXD9 gene was highly expressed in a side population (SP) of SK-MG-1 cells that was previously identified as an enriched-cell fraction of glioma cancer stem-like cells. HOXD9 siRNA treatment of SK-MG-1 SP cells resulted in reduced cell proliferation. Finally, we cultured human glioma cancer stem cells (GCSCs) from patient specimens found with high expression of HOXD9 in GCSCs compared with normal astrocyte cells and neural stem/progenitor cells (NSPCs).Conclusions: Our results suggest that HOXD9 may be a novel marker of GCSCs and cell proliferation and/or survival factor in gliomas and glioma cancer stem-like cells, and a potential therapeutic target. © 2011 Tabuse et al; licensee BioMed Central Ltd.

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Adjuvant effects of formalin-inactivated HSV through activation of dendritic cells and inactivation of myeloid-derived suppressor cells in cancer immunotherapy

Ohkusu-Tsukada Kozo, Ohta Shigeki, Kawakami Yutaka, Toda Masahiro

International Journal of Cancer 128 （ 1 ） 119 - 131 2011年01月

ISSN 0020-7136

Use of adequate adjuvant is necessary for induction of effective antitumor immune responses. To develop an effective adjuvant for cancer immunotherapy, we selected formalin-inactivated (f)-HSV as an adjuvant component, and analyzed the mechanisms underlying its adjuvant effects. First, we found that f-HSV can induce the tumor antigen-specific CTLs by enhancing antigen cross-presentation by dendritic cells (DCs), mainly through TLR2, but not TLR9. Next, f-HSV was also found to prevent the accumulation of myeloid-derived suppressor cells (MDSCs). We demonstrated that the expansion of MDSCs in the blood and spleen during tumor progression required B cells producing the inflammatory angiogenesis factors, vascular endothelial growth factor (VEGF)-A and neuropilin-1 (NRP-1), a co-receptor for VEGF receptor-2 (VEGFR-2). Interestingly, the transmembrane-type NRP-1 on B cells changed to soluble-type NRP-1 (sNRP-1) by f-HSV treatment. We further showed that the sNRP-1 and VEGF-A secreted from B cells by f-HSV treatment could abrogate the immunosuppressive ability of MDSCs. These results suggest that f-HSV can enhance antitumor immune responses as an adjuvant, not only through activation of DCs, but also inactivation of MDSCs via B cells. © 2010 UICC.

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