RESUMO
Introduction: Malignant peripheral nerve sheath tumors (MPNST) pose a significant therapeutic challenge due to high recurrence rates after surgical resection and a largely ineffective response to traditional chemotherapy. An alternative treatment strategy is oncolytic viroimmunotherapy, which can elicit a durable and systemic antitumor immune response and is Food and Drug Administration (FDA)-approved for the treatment of melanoma. Unfortunately, only a subset of patients responds completely, underscoring the need to address barriers hindering viroimmunotherapy effectiveness. Methods: Here we investigated the therapeutic utility of targeting key components of the MPNST immunosuppressive microenvironment to enhance viroimmunotherapy's antitumor efficacy in three murine models, one of which showed more immunogenic characteristics than the others. Results: Myelomodulatory therapy with pexidartinib, a small molecule inhibitor of CSF1R tyrosine kinase, and the oncolytic herpes simplex virus T-VEC exhibited the most significant increase in median survival time in the highly immunogenic model. Additionally, targeting myeloid cells with the myelomodulatory therapy trabectedin, a small molecule activator of caspase-8 dependent apoptosis, augmented the survival benefit of T-VEC in a less immunogenic MPNST model. However, tumor regressions or shrinkages were not observed. Depletion experiments confirmed that the enhanced survival benefit relied on a T cell response. Furthermore, flow cytometry analysis following combination viroimmunotherapy revealed decreased M2 macrophages and myeloid-derived suppressor cells and increased tumor-specific gp70+ CD8 T cells within the tumor microenvironment. Discussion: In summary, our findings provide compelling evidence for the potential to leverage viroimmunotherapy with myeloid cell targeting against MPNST and warrant further investigation.
Assuntos
Modelos Animais de Doenças , Terapia Viral Oncolítica , Microambiente Tumoral , Animais , Terapia Viral Oncolítica/métodos , Camundongos , Microambiente Tumoral/imunologia , Vírus Oncolíticos/imunologia , Vírus Oncolíticos/genética , Linhagem Celular Tumoral , Imunoterapia/métodos , Humanos , Terapia Combinada , Feminino , Camundongos Endogâmicos C57BL , Neoplasias de Bainha Neural/terapia , Neoplasias de Bainha Neural/imunologia , Neoplasias de Bainha Neural/genética , Aminopiridinas , PirróisRESUMO
Neurofibromatosis type 1 (NF1) is caused by mutations in the NF1 gene that encodes neurofibromin, a RAS GTPase-activating protein. Inactivating NF1 mutations cause hyperactivation of RAS-mediated signaling, resulting in the development of multiple neoplasms, including malignant peripheral nerve sheath tumors (MPNSTs). MPNSTs are an aggressive tumor and the main cause of mortality in patients with NF1. MPNSTs are difficult to resect and refractory to chemo- and radiotherapy, and no molecular therapies currently exist. Immune checkpoint blockade (ICB) is an approach to treat inoperable, undruggable cancers like MPNST, but successful outcomes require an immune cell-rich tumor microenvironment. While MPNSTs are noninflamed "cold" tumors, here, we converted MPNSTs into T cell-inflamed "hot" tumors by activating stimulator of IFN genes (STING) signaling. Mouse genetic and human xenograft MPNST models treated with a STING agonist plus ICB exhibited growth delay via increased apoptotic cell death. This strategy offers a potential treatment regimen for MPNSTs.
Assuntos
Imunoterapia , Proteínas de Membrana , Neurofibromatose 1 , Neurofibromina 1 , Microambiente Tumoral , Animais , Microambiente Tumoral/imunologia , Humanos , Camundongos , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Proteínas de Membrana/imunologia , Neurofibromatose 1/genética , Neurofibromatose 1/patologia , Neurofibromatose 1/imunologia , Neurofibromatose 1/terapia , Neurofibromatose 1/metabolismo , Neurofibromina 1/genética , Inibidores de Checkpoint Imunológico/farmacologia , Neoplasias de Bainha Neural/genética , Neoplasias de Bainha Neural/patologia , Neoplasias de Bainha Neural/terapia , Neoplasias de Bainha Neural/imunologia , Neoplasias de Bainha Neural/metabolismo , Linhagem Celular Tumoral , Ensaios Antitumorais Modelo de Xenoenxerto , Transdução de Sinais/imunologiaRESUMO
PURPOSE: Nanoparticle-encapsulated drug formulations can improve responses to conventional chemotherapy by increasing drug retention within the tumor and by promoting a more effective antitumor immune response than free drug. New drug delivery modalities are needed in sarcomas because they are often chemoresistant cancers, but the rarity of sarcomas and the complexity of diverse subtypes makes it challenging to investigate novel drug formulations. EXPERIMENTAL DESIGN: New drug formulations can be tested in animal models of sarcomas where the therapeutic response of different formulations can be compared using mice with identical tumor-initiating mutations. Here, using Cre/loxP and CRISPR/Cas9 techniques, we generated two distinct mouse models of Pten-deleted soft-tissue sarcoma: malignant peripheral nerve sheath tumor (MPNST) and undifferentiated pleomorphic sarcoma (UPS). We used these models to test the efficacy of chimeric polypeptide doxorubicin (CP-Dox), a nanoscale micelle formulation, in comparison with free doxorubicin. RESULTS: The CP-Dox formulation was superior to free doxorubicin in MPNST models. However, in UPS tumors, CP-Dox did not improve survival in comparison with free doxorubicin. While CP-Dox treatment resulted in elevated intratumoral doxorubicin concentrations in MPNSTs, this increase was absent in UPS tumors. In addition, elevation of CD8+ T cells was observed exclusively in CP-Dox-treated MPNSTs, although these cells were not required for full efficacy of the CP nanoparticle-based chemotherapy. CONCLUSIONS: These results have important implications for treating sarcomas with nanoparticle-encapsulated chemotherapy by highlighting the tumor subtype-dependent nature of therapeutic response.
Assuntos
Doxorrubicina/administração & dosagem , Portadores de Fármacos/química , Neoplasias de Bainha Neural/tratamento farmacológico , Sarcoma/tratamento farmacológico , Animais , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Linhagem Celular Tumoral , Modelos Animais de Doenças , Doxorrubicina/farmacocinética , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Camundongos , Camundongos Knockout , Micelas , Nanopartículas/química , Neoplasias de Bainha Neural/genética , Neoplasias de Bainha Neural/imunologia , Neoplasias de Bainha Neural/patologia , PTEN Fosfo-Hidrolase/genética , Peptídeos/química , Sarcoma/genética , Sarcoma/imunologia , Sarcoma/patologia , Distribuição TecidualRESUMO
Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive soft-tissue sarcomas resistant to most cancer treatments. Surgical resection remains the primary treatment, but this is often incomplete, ultimately resulting in high mortality and morbidity rates. There has been a resurgence of interest in oncolytic virotherapy because of encouraging preclinical and clinical trial results. Oncolytic herpes simplex virus (oHSV) selectively replicates in cancer cells, lysing the cell and inducing antitumor immunity. We previously showed that basal interferon (IFN) signaling increases interferon-stimulated gene (ISG) expression, restricting viral replication in almost 50% of MPNSTs. The FDA-approved drug ruxolitinib (RUX) temporarily resets this constitutively active STAT signaling and renders the tumor cells susceptible to oHSV infection in cell culture. In the studies described here, we translated our in vitro results into a syngeneic MPNST tumor model. Consistent with our previous results, murine MPNSTs exhibit a similar IFN- and ISG-mediated oHSV-resistance mechanism, and virotherapy alone provides no antitumor benefit in vivo However, pretreatment of mice with ruxolitinib reduced ISG expression, making the tumors susceptible to oHSV infection. Ruxolitinib pretreatment improved viral replication and altered the oHSV-induced immune-mediated response. Our results showed that this combination therapy increased CD8+ T-cell activation in the tumor microenvironment and that this population was indispensable for the antitumor benefit that follows from the combination of RUX and oHSV. These data suggest that JAK inhibition prior to oncolytic virus treatment augments both oHSV replication and the immunotherapeutic efficacy of oncolytic herpes virotherapy.
Assuntos
Herpesvirus Humano 1/efeitos dos fármacos , Neoplasias de Bainha Neural/terapia , Terapia Viral Oncolítica/métodos , Pirazóis/farmacologia , Animais , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Linhagem Celular Tumoral , Terapia Combinada , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Herpesvirus Humano 1/fisiologia , Interferons/metabolismo , Interferons/farmacologia , Camundongos Endogâmicos C57BL , Neoplasias de Bainha Neural/imunologia , Neoplasias de Bainha Neural/mortalidade , Nitrilas , Vírus Oncolíticos/efeitos dos fármacos , Vírus Oncolíticos/fisiologia , Pirimidinas , Taxa de Sobrevida , Replicação Viral/efeitos dos fármacosRESUMO
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.
Assuntos
Neoplasias de Bainha Neural/imunologia , Neoplasias de Bainha Neural/cirurgia , Neurilemoma/imunologia , Neurilemoma/cirurgia , Neoplasias da Coluna Vertebral/imunologia , Neoplasias da Coluna Vertebral/cirurgia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Seguimentos , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Antígeno Ki-67/análise , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Prognóstico , Estudos Retrospectivos , Análise de Sobrevida , Proteína Supressora de Tumor p53/análise , Adulto JovemAssuntos
Perna (Membro)/patologia , Neoplasias de Bainha Neural/patologia , Nervos Periféricos/patologia , Doenças do Sistema Nervoso Periférico/patologia , Neoplasias Cutâneas/patologia , Idoso , Dermoscopia/métodos , Humanos , Imuno-Histoquímica/métodos , Perna (Membro)/inervação , Masculino , Mucina-1/imunologia , Neoplasias de Bainha Neural/imunologia , Neoplasias de Bainha Neural/cirurgia , Nervos Periféricos/imunologia , Nervos Periféricos/cirurgia , Doenças do Sistema Nervoso Periférico/imunologia , Doenças do Sistema Nervoso Periférico/cirurgia , Neoplasias Cutâneas/diagnóstico por imagem , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/cirurgiaRESUMO
Peripheral nerve sheath tumors are benign tumors that have the potential to transform into malignant peripheral nerve sheath tumors (MPNSTs). Interleukin-13 receptor alpha 2 (IL13Rα2) is a cancer associated receptor expressed in glioblastoma and other invasive cancers. We analyzed IL13Rα2 expression in several MPNST cell lines including the STS26T cell line, as well as in several peripheral nerve sheath tumors to utilize the IL13Rα2 receptor as a target for therapy. In our studies, we demonstrated the selective expression of IL13Rα2 in several peripheral nerve sheath tumors by immunohistochemistry (IHC) and immunoblots. We established a sciatic nerve MPNST mouse model in NIH III nude mice using a luciferase transfected STS26T MPNST cell line. Similarly, analysis of the mouse sciatic nerves after tumor induction revealed significant expression of IL13Rα2 by IHC when compared to a normal sciatic nerve. IL13 conjugated liposomal doxorubicin was formulated and shown to bind and internalized in the MPNST cell culture model demonstrating cytotoxic effect. Our subsequent in vivo investigation in the STS26T MPNST sciatic nerve tumor model indicated that IL13 conjugated liposomal doxorubicin (IL13LIPDXR) was more effective in inhibiting tumor progression compared to unconjugated liposomal doxorubicin (LIPDXR). This further supports that IL13 receptor targeted nanoliposomes is a potential approach for treating MPNSTs.
Assuntos
Antibióticos Antineoplásicos/administração & dosagem , Doxorrubicina/análogos & derivados , Neoplasias de Bainha Neural/tratamento farmacológico , Animais , Antibióticos Antineoplásicos/farmacocinética , Linhagem Celular Tumoral , Doxorrubicina/administração & dosagem , Doxorrubicina/farmacocinética , Sistemas de Liberação de Medicamentos , Humanos , Imuno-Histoquímica , Interleucina-13/administração & dosagem , Subunidade alfa2 de Receptor de Interleucina-13/metabolismo , Antígeno Ki-67/metabolismo , Camundongos , Camundongos Nus , Neoplasias de Bainha Neural/imunologia , Neoplasias de Bainha Neural/metabolismo , Polietilenoglicóis/administração & dosagem , Polietilenoglicóis/farmacocinética , Proteínas S100/metabolismo , Neuropatia Ciática/tratamento farmacológico , Neuropatia Ciática/imunologia , Neuropatia Ciática/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND: The objective of this study was to evaluate the effect on outcomes of intraoperative recombinant human interleukin-2 injection after surgical resection of peripheral nerve sheath tumours. In this double-blind trial, 40 patients due to undergo surgical excision (<5 mm margins) of presumed peripheral nerve sheath tumours were randomized to receive intraoperative injection of interleukin-2 or placebo into the wound bed. RESULTS: There were no significant differences in any variable investigated or in median survival between the two groups. The median recurrence free interval was 874 days (range 48-2141 days), The recurrence-free interval and overall survival time were significantly longer in dogs that undergone the primary surgery by a specialist-certified surgeon compared to a referring veterinarian regardless of whether additional adjunct therapy was given. CONCLUSION: Overall, marginal excision of peripheral nerve sheath tumours in dogs resulted in a long survival time, but adjuvant treatment with recombinant human interleukin-2 (rhIL-2) did not provide a survival advantage.
Assuntos
Doenças do Cão/patologia , Imunoterapia/veterinária , Interleucina-2/uso terapêutico , Neoplasias de Bainha Neural/veterinária , Animais , Terapia Combinada/veterinária , Doenças do Cão/imunologia , Doenças do Cão/cirurgia , Cães , Método Duplo-Cego , Feminino , Interleucina-2/administração & dosagem , Estimativa de Kaplan-Meier , Masculino , Recidiva Local de Neoplasia/veterinária , Neoplasias de Bainha Neural/imunologia , Neoplasias de Bainha Neural/patologia , Neoplasias de Bainha Neural/cirurgiaRESUMO
BACKGROUND: Synovial sarcomas (SnSrcs) and malignant peripheral nerve sheath tumors (MPNSTs) are rare mesenchymal tumors of adolescence and young adulthood. Previous work from our laboratory has demonstrated that SnSrcs express epidermal growth factor receptor (EGFR) and human EGFR (HER)-2/neu. The present study extends that work to examine the expression of EGFR in MPNSTs and the characterization of potential targets of the EGFR tyrosine kinase domain. METHODS: Tissue microarrays containing 48 cases of SnSrc and 32 cases of MPNST were stained for EGFR, EGFRvIII, and activated EGFR (pY1068-EGFR). Tumor DNA was extracted from fresh and formalin-fixed, paraffin-embedded tissue blocks and sequenced for exons 17-21 of EGFR and exon 2 of K-ras and b-raf. RESULTS: Immunohistochemistry (IHC) demonstrated that EGFR is expressed in a majority of SnSrcs and MPNSTs (71% and 62.5%, respectively). EGFRvIII immunoreactivity was negative. IHC was weakly immunopositive for activated EGFR (18.7% and 3.1%, respectively). Sequence analysis of the EGFR genomic DNA did not demonstrate mutations in exons 17-21. No K-ras or b-raf mutations were observed in either tumor type. CONCLUSIONS: Expression of EGFR in SnSrcs and MPNSTs with an intact EGFR/mitogen-activated protein kinase pathway has been hypothesized to contribute to the malignant potential of these tumors. Our study reveals the absence of known activating mutations in EGFR, which suggests that trials of small-molecule inhibitors would be of little clinical benefit. A clinical study of treatment with cetuximab is ongoing and may help elucidate whether blockade of EGFR with antibodies is likely to be more active.
Assuntos
Receptores ErbB/genética , Mutação , Neoplasias de Bainha Neural/diagnóstico , Inibidores de Proteínas Quinases/uso terapêutico , Sarcoma Sinovial/diagnóstico , Adolescente , Adulto , Idoso , Criança , Análise Mutacional de DNA , Feminino , Regulação Neoplásica da Expressão Gênica , Genes ras/genética , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Neoplasias de Bainha Neural/genética , Neoplasias de Bainha Neural/imunologia , Neoplasias de Bainha Neural/patologia , Proteínas Proto-Oncogênicas B-raf/genética , Sarcoma Sinovial/genética , Sarcoma Sinovial/imunologia , Sarcoma Sinovial/patologia , Translocação GenéticaRESUMO
Mechanisms by which tumor cells evade detection by the host's immune system are thought to play a role in progression to malignancy, but this has not been investigated in the context of neurofibromatosis type 1 (NF1). NF1 is an autosomal dominant disorder, in which aggressive peripheral nerve tumors, known as malignant peripheral nerve sheath tumors (MPNSTs), develop in 5-10% of patients. Large scale gene expression profiling of a MPNST-derived cell line, T265, and normal human Schwann cells (hSCs) identified a large group of immune function genes down-regulated in T265 cells. Here we report that the aberrant expression of immune system related genes extends beyond MHC class I and II genes in T265 cells to include a transcription factor (MHC2TA) and other critical components of the antigen processing and presentation apparatus. TAP1, the transporter-activator protein that loads peptide antigens onto MHC class I molecules, is down-regulated, and CD74, a chaperone protein whose function is in processing and transport of MHC class II molecules, is down-regulated and alternatively spliced to produce an RNA transcript not evident in normal human Schwann cells. These findings reveal multiple molecular pathways and at least two cellular mechanisms acting to reduce the normal immune system molecules involved in antigen processing and presentation in cells derived from a peripheral nerve sheath tumor. Acquiring a "silent" immune signature may be a critical step in the progress towards malignancy in MPNSTs.
Assuntos
Regulação Neoplásica da Expressão Gênica/fisiologia , Sistema Imunitário/metabolismo , Neoplasias de Bainha Neural/imunologia , Neoplasias do Sistema Nervoso Periférico/imunologia , Membro 2 da Subfamília B de Transportadores de Cassetes de Ligação de ATP , Transportadores de Cassetes de Ligação de ATP/genética , Transportadores de Cassetes de Ligação de ATP/metabolismo , Antígenos de Diferenciação de Linfócitos B/metabolismo , Northern Blotting/métodos , Western Blotting/métodos , Linhagem Celular Tumoral , Antígenos de Histocompatibilidade Classe II/metabolismo , Humanos , Sistema Imunitário/fisiopatologia , Análise em Microsséries/métodos , RNA Mensageiro/biossíntese , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodosRESUMO
A majority of desmoplastic melanomas and some of the other forms of melanomas are S-100 positive and HMB45 negative; this pattern of immunoreactivity is similar to certain nerve-derived tumors such as malignant peripheral nerve sheath tumor. In this study the immunostaining profile of HMB45-negative malignant melanomas was evaluated by a panel of antibodies against markers associated with melanoma and melanocytic differentiation, including microphthalmia transcription factor, tyrosinase, Melan-A, and MAGE-1. Immunodetection was performed on paraffin sections of 22 cases of HMB45-negative malignant melanomas (including 8 spindle cell melanomas, 8 desmoplastic melanomas, and 6 epithelioid melanomas), 8 HMB45-and S-100-positive malignant melanomas, 15 malignant peripheral nerve sheath tumors, 16 schwannomas, and 11 neurofibromas. Of eight HMB45-positive malignant melanomas, all were positive for Melan-A, tyrosinase, and melanocyte-specific transcription factor, and three were positive for MAGE-1. In the 14 HMB-45 negative, nondesmoplastic melanomas, melanocyte-specific transcription factor was positive in 9, Melan-A in 9, tyrosinase in 6, and MAGE-1 in 11. In eight desmoplastic malignant melanomas, MAGE-1 was positive in three, and all other markers were negative. The five markers tested were negative in all but two schwannomas, one with focal melanocyte-specific transcription factor and the other with tyrosinase and weak MAGE-1 reactivity. MAGE-1, melanocyte-specific transcription factor, tyrosinase, and Melan-A are useful markers in the diagnosis of malignant melanocytic lesions when HMB45 is negative. MAGE-1 may be useful in differentiating melanocytic lesions from nerve-derived lesions, but its sensitivity is relatively low. The immunostaining profile of desmoplastic malignant melanomas more closely resembles that of malignant peripheral nerve sheath tumor than that of other types of malignant melanoma. Melanocyte-specific transcription factor is not a useful marker for desmoplastic melanoma.
Assuntos
Biomarcadores Tumorais , Melanoma/imunologia , Neoplasias de Bainha Neural/imunologia , Neoplasias do Sistema Nervoso Periférico/imunologia , Fatores de Transcrição , Antígenos de Neoplasias , Proteínas de Ligação a DNA/imunologia , Humanos , Imunofenotipagem , Antígeno MART-1 , Melanoma/patologia , Antígenos Específicos de Melanoma , Fator de Transcrição Associado à Microftalmia , Monofenol Mono-Oxigenase/imunologia , Proteínas de Neoplasias/imunologia , Neoplasias de Bainha Neural/patologia , Neoplasias do Sistema Nervoso Periférico/patologia , Proteínas S100/imunologiaRESUMO
Recently described entity: ossifying fibromyxoid tumour of soft parts is presented. Schwann cell nature of the proliferating cells was demonstrated by immunohistochemical means. This special kind of nerve sheath tumors is characterised by pathological differentiation of the cells, resulting bone and in some cases additional cartilage formation. As for biological behaviour: in spite of occasional histological evidences of malignancy, no distant metastases are to be expected. Local aggressivity and recurrences may occur, thus designation is preferable as semimalignant or according to more modern terms as low-grade malignant tumour.