Assuntos
Melanoma , Neoplasias Primárias Desconhecidas , Neoplasias Cutâneas , Humanos , Proteínas Proto-Oncogênicas B-raf/genética , Neoplasias Primárias Desconhecidas/diagnóstico , Neoplasias Primárias Desconhecidas/genética , Melanoma/diagnóstico , Melanoma/genética , Mutação , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/genética , Análise Mutacional de DNARESUMO
Cancer immunotherapy is now the first-line treatment for many unresectable cancers. However, it remains far from a complete cure for all patients. Therefore, it is necessary to develop innovative methods for cancer immunotherapy, and immune cell therapy could be an option. Currently, several institutions are attempting to generate immune cells from induced pluripotent stem cells (iPSCs) for use in cancer immunotherapy. A method for generating dendritic cells (DCs) and macrophages (MPs) from iPSC has been established. iPSC-derived DCs (iPS-DCs) can activate T cells via antigen presentation, and iPSC-derived macrophages (iPS-MPs) attack cancer. Since iPSCs are used as the source, genetic modification is easy, and various immune functions, such as the production of anti-tumour cytokines, can be added. Furthermore, when iPS-DCs and iPS-MPs are immortalized, cost reduction through mass production is theoretically possible. In this review, the achievements of cancer research using iPS-DCs and iPS-MPs are summarized, and the prospects for the future are discussed.
Assuntos
Células-Tronco Pluripotentes Induzidas , Neoplasias , Humanos , Imunoterapia/métodos , Macrófagos , Citocinas , Células Dendríticas , Neoplasias/terapiaAssuntos
Imunoterapia/métodos , Melanoma/terapia , Células Mieloides/transplante , Neoplasias Cutâneas/terapia , Animais , Diferenciação Celular/genética , Linhagem Celular Tumoral , Modelos Animais de Doenças , Humanos , Células-Tronco Pluripotentes Induzidas/fisiologia , Interferon beta/genética , Interferon beta/imunologia , Interferon beta/metabolismo , Interleucina-15/genética , Interleucina-15/imunologia , Interleucina-15/metabolismo , Melanoma/imunologia , Melanoma/patologia , Camundongos , Células Mieloides/imunologia , Células Mieloides/metabolismo , Receptores de Interleucina-15/genética , Receptores de Interleucina-15/imunologia , Receptores de Interleucina-15/metabolismo , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/patologia , Evasão Tumoral/imunologiaRESUMO
We have established an immune cell therapy with immortalized induced pluripotent stem-cell-derived myeloid lines (iPS-ML). The benefits of using iPS-ML are the infinite proliferative capacity and ease of genetic modification. In this study, we introduced 4-1BBL gene to iPS-ML (iPS-ML-41BBL). The analysis of the cell-surface molecules showed that the expression of CD86 was upregulated in iPS-ML-41BBL more than that in control iPS-ML. Cytokine array analysis was performed using supernatants of the spleen cells that were cocultured with iPS-ML or iPS-ML-41BBL. Multiple cytokines that are beneficial to cancer immunotherapy were upregulated. Peritoneal injections of iPS-ML-41BBL inhibited tumor growth of peritoneally disseminated mouse melanoma and prolonged survival of mice compared to that of iPS-ML. Furthermore, the numbers of antigen-specific CD8+ T cells were significantly increased in the spleen and tumor tissues treated with epitope peptide-pulsed iPS-ML-41BBL compared to those treated with control iPS-ML. The number of CXCR6-positive T cells were increased in the tumor tissues after treatment with iPS-ML-41BBL compared to that with control iPS-ML. These results suggest that iPS-ML-41BBL could activate antigen-specific T cells and promote their infiltration into the tumor tissues. Thus, iPS-ML-41BBL may be a candidate for future immune cell therapy aiming to change immunological "cold tumor" to "hot tumor".
Assuntos
Ligante 4-1BB/metabolismo , Linfócitos T CD8-Positivos/imunologia , Imunoterapia/métodos , Células-Tronco Pluripotentes Induzidas/citologia , Linfócitos do Interstício Tumoral/imunologia , Melanoma/terapia , Células Mieloides/metabolismo , Células Mieloides/transplante , Neoplasias Cutâneas/terapia , Animais , Linhagem Celular Tumoral , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Melanoma/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Receptores CXCR6/metabolismo , Neoplasias Cutâneas/patologia , Resultado do TratamentoRESUMO
Immune checkpoint inhibitors improved the survival rate of patients with unresectable melanoma. However, some patients do not respond, and variable immune-related adverse events have been reported. Therefore, more effective and antigen-specific immune therapies are urgently needed. We previously reported the efficacy of an immune cell therapy with immortalized myeloid cells derived from induced pluripotent stem cells (iPS-ML). In this study, we generated OX40L-overexpressing iPS-ML (iPS-ML-Zsgreen-OX40L) and investigated their characteristics and in vivo efficacy against mouse melanoma. We found that iPS-ML-Zsgreen-OX40L suppressed the progression of B16-BL6 melanoma, and prolonged survival of mice with ovalbumin (OVA)-expressing B16 melanoma (MO4). The number of antigen-specific CD8+ T cells was higher in spleen cells treated with OVA peptide-pulsed iPS-ML-Zsgreen-OX40L than in those without OX40L. The OVA peptide-pulsed iPS-ML-Zsgreen-OX40L significantly increased the number of tumor-infiltrating T lymphocytes (TILs) in MO4 tumor. Flow cytometry showed decreased regulatory T cells but increased effector and effector memory T cells among the TILs. Although we plan to use allogeneic iPS-ML in the clinical applications, iPS-ML showed the tumorgenicity in the syngeneic mice model. Incorporating the suicide gene is necessary to ensure the safety in the future study. Collectively, these results indicate that iPS-ML-Zsgreen-OX40L therapy might be a new method for antigen-specific cancer immunotherapy.
Assuntos
Antígenos de Neoplasias/metabolismo , Células-Tronco Pluripotentes Induzidas/patologia , Melanoma Experimental/imunologia , Melanoma Experimental/patologia , Células Mieloides/patologia , Ligante OX40/metabolismo , Neoplasias Cutâneas/imunologia , Linfócitos T/imunologia , Animais , Proliferação de Células , Apresentação Cruzada/imunologia , Citocinas/metabolismo , Linfócitos do Interstício Tumoral/imunologia , Camundongos Endogâmicos C57BL , Modelos Biológicos , Estadiamento de Neoplasias , Ovalbumina/imunologia , Peptídeos/imunologia , Peritônio/patologia , Neoplasias Cutâneas/patologia , Baço/patologia , Regulação para CimaAssuntos
Antineoplásicos Imunológicos/farmacologia , Biomarcadores Tumorais/sangue , MicroRNA Circulante/sangue , Melanoma/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/farmacologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Biomarcadores Tumorais/metabolismo , MicroRNA Circulante/metabolismo , Resistencia a Medicamentos Antineoplásicos/genética , Resistencia a Medicamentos Antineoplásicos/imunologia , Feminino , Perfilação da Expressão Gênica , Humanos , Masculino , Melanoma/sangue , Melanoma/genética , Melanoma/imunologia , Pessoa de Meia-Idade , Nivolumabe/farmacologia , Nivolumabe/uso terapêutico , Análise de Sequência com Séries de Oligonucleotídeos , Prognóstico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Neoplasias Cutâneas/sangue , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/imunologia , Resultado do TratamentoRESUMO
Type I interferons (IFNs) play important roles in antitumor immunity. We generated IFN-α-producing cells by genetically engineered induced pluripotent stem cell (iPSC)-derived proliferating myeloid cells (iPSC-pMCs). Local administration of IFN-α-producing iPSC-pMCs (IFN-α-iPSC-pMCs) alters the tumor microenvironment and propagates the molecular signature associated with type I IFN. The gene-modified cell actively influences host XCR1+ dendritic cells to enhance CD8+ T cell priming, resulting in CXCR3-dependent and STING-IRF3 pathway-independent systemic tumor control. Administration of IFN-α-iPSC-pMCs in combination with immune checkpoint blockade overcomes resistance to single-treatment modalities and generates long-lasting antitumor immunity. These preclinical data suggest that IFN-α-iPSC-pMCs might constitute effective immune-stimulating agents for cancer that are refractory to checkpoint blockade.
Assuntos
Células Dendríticas/imunologia , Imunidade/imunologia , Células-Tronco Pluripotentes Induzidas/imunologia , Interferon Tipo I/imunologia , Células Mieloides/imunologia , Receptores de Quimiocinas/imunologia , Animais , Imunoterapia/métodos , Fator Regulador 3 de Interferon/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Neoplasias/imunologia , Receptores CXCR3/imunologia , Microambiente Tumoral/imunologiaRESUMO
A 66-year-old woman with diabetes who was treated with prednisolone (15 mg/day) for autoimmune hepatitis developed multiple erythematous nodules with retention of purulent fluid on her lower right limb. Candida albicans was cultured from the nodules. She was started on oral fluconazole, and the lesions subsided. However, multiple dark-red abscesses and indurations newly appeared on the left crus. Histopathological examination showed numerous branched hyphae, and tissue culture yielded a Rhizopus microsporus-related fungus. She was treated with liposomal amphotericin B combined with drainage and debridement. However, she died because of poor control of the infection and hepatic disorder.
Assuntos
Abscesso/microbiologia , Dermatomicoses/microbiologia , Hospedeiro Imunocomprometido , Mucormicose/microbiologia , Rhizopus/isolamento & purificação , Rhizopus/patogenicidade , Abscesso/terapia , Idoso , Anfotericina B/administração & dosagem , Antifúngicos/administração & dosagem , Desbridamento , Dermatomicoses/terapia , Drenagem , Evolução Fatal , Feminino , Hepatite Autoimune/tratamento farmacológico , Humanos , Mucormicose/terapia , Prednisolona/efeitos adversos , Prednisolona/uso terapêuticoAssuntos
Antineoplásicos Imunológicos/efeitos adversos , Colite/induzido quimicamente , Melanoma/tratamento farmacológico , Nivolumabe/efeitos adversos , Neoplasias Vaginais/tratamento farmacológico , Biópsia , Colite/diagnóstico , Colite/tratamento farmacológico , Colo/diagnóstico por imagem , Colo/efeitos dos fármacos , Colo/patologia , Colonoscopia , Relação Dose-Resposta a Droga , Feminino , Humanos , Mucosa Intestinal/diagnóstico por imagem , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/patologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/secundário , Metástase Linfática/tratamento farmacológico , Melanoma/imunologia , Melanoma/secundário , Metilprednisolona/administração & dosagem , Pessoa de Meia-Idade , Tomografia Computadorizada por Raios X , Neoplasias Vaginais/imunologia , Neoplasias Vaginais/patologiaAssuntos
Mioepitelioma/cirurgia , Recidiva Local de Neoplasia/prevenção & controle , Neoplasias Cutâneas/cirurgia , Idoso , Biomarcadores Tumorais/análise , Biópsia , Antebraço , Humanos , Imageamento por Ressonância Magnética , Masculino , Mioepitelioma/diagnóstico , Mioepitelioma/patologia , Pele/diagnóstico por imagem , Pele/patologia , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/patologia , Transplante de Pele , Resultado do TratamentoRESUMO
BACKGROUND: Anti-programmed cell death protein (PD)-1 antibody treatment is associated with a notable improvement in only 30%-40% of patients. Thus, a predictive and easily measured marker of the clinical benefit of anti-PD-1 antibody treatment is necessary; therefore, in this study, we focused on the serum concentration of hepatocyte growth factor (HGF). OBJECTIVES: To evaluate whether the serum concentration of HGF can be used as a biomarker for the clinical response to anti-PD-1 antibody therapy. METHODS: This study included 29 metastatic melanoma patients receiving nivolumab or pembrolizumab. Nine patients responded to anti-PD-1 antibody treatment, whereas the other 20 patients did not. The serum concentrations of HGF were analyzed by using ELISA. In 28 patients, immunohistochemical analysis of the HGF protein in patients' cancer tissues was also performed. Peripheral blood mononuclear cells (PBMCs) from healthy donors were cultured with an anti-CD3 antibody in the presence or absence of HGF and c-MET inhibitor. The expression of perforin in CD8+ T cells were evaluated by using flow cytometry. RESULTS: Among the 29 recruited patients, the non-responders displayed higher serum concentrations of HGF than the responders (P = 0.00124). Patients with low serum concentrations of HGF showed longer overall survival (N = 28, P = 0.039; HR 0.3125, 95% CI 0.1036-0.9427) and progression-free survival (N = 24, P = 0.0068; HR 0.2087, 95% CI 0.06525-0.6676) than those with high concentrations of HGF. We observed a significant correlation between the serum concentration of HGF and immunohistochemical-positive staining (P = 0.000663). In a flow cytometry analysis of PBMCs from healthy donors, HGF was found to downregulate perforin secretion. Furthermore, the addition of capmatinib, a specific inhibitor of c-MET, increased the expression of perforin in CD8+ T cells. CONCLUSIONS: HGF concentration represents a valid biomarker that can be further developed for the evaluation of anti-PD-1 therapy. Our results suggested that c-MET inhibition promotes perforin expression in CD8+ T cells. Therefore, c-MET inhibitors can activate the immune system and may play an important role in combined immunotherapy.
Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Biomarcadores Tumorais/sangue , Fator de Crescimento de Hepatócito/sangue , Melanoma/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/farmacologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/farmacologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Estudos de Casos e Controles , Células Cultivadas , Feminino , Seguimentos , Voluntários Saudáveis , Fator de Crescimento de Hepatócito/metabolismo , Humanos , Leucócitos Mononucleares , Masculino , Melanoma/sangue , Melanoma/mortalidade , Melanoma/patologia , Pessoa de Meia-Idade , Nivolumabe/farmacologia , Nivolumabe/uso terapêutico , Perforina/metabolismo , Cultura Primária de Células , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Intervalo Livre de Progressão , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-met/metabolismo , Neoplasias Cutâneas/sangue , Neoplasias Cutâneas/mortalidade , Neoplasias Cutâneas/patologiaRESUMO
Recently emerging cancer immunotherapies combine the applications of therapeutics to disrupt the immunosuppressive conditions in tumor-bearing hosts. In this study, we found that targeting the proinflammatory cytokine IL6 enhances tumor-specific Th1 responses and subsequent antitumor effects in tumor-bearing mice. IL6 blockade upregulated expression of the immune checkpoint molecule programmed death-ligand 1 (PD-L1) on melanoma cells. This PD-L1 induction was canceled in IFNγ-deficient mice or CD4+ T cell-depleted mice, suggesting that CD4+ T cell-derived IFNγ is important for PD-L1 induction in tumor-bearing hosts. In some patients with melanoma, however, treatment with the anti-PD-1 antibody nivolumab increased systemic levels of IL6, which was associated with poor clinical responses. This PD-L1 blockade-evoked induction of IL6 was reproducible in melanoma-bearing mice. We found that PD-1/PD-L1 blockade prompted PD-1+ macrophages to produce IL6 in the tumor microenvironment. Depletion of macrophages in melanoma-bearing mice reduced the levels of IL6 during PD-L1 blockade, suggesting macrophages are responsible for the IL6-mediated defective CD4+ Th1 response. Combined blockade of the mutually regulated immunosuppressive activities of IL6 and PD-1/PD-L1 signals enhanced expression of T cell-attracting chemokines and promoted infiltration of IFNγ-producing CD4+ T cells in tumor tissues, exerting a synergistic antitumor effect, whereas PD-L1 blockade alone did not promote Th1 response. Collectively, these findings suggest that IL6 is a rational immunosuppressive target for overcoming the narrow therapeutic window of anti-PD-1/PD-L1 therapy.Significance: These findings advance our understanding of IL6-PD1/PD-L1 cross-talk in the tumor microenvironment and provide clues for targeted interventional therapy that may prove more effective against cancer. Cancer Res; 78(17); 5011-22. ©2018 AACR.
Assuntos
Antígeno B7-H1/antagonistas & inibidores , Interleucina-6/imunologia , Melanoma/imunologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Microambiente Tumoral/imunologia , Animais , Antígeno B7-H1/imunologia , Regulação Neoplásica da Expressão Gênica/imunologia , Humanos , Tolerância Imunológica , Terapia de Imunossupressão , Imunoterapia , Interferon gama/imunologia , Interleucina-6/antagonistas & inibidores , Melanoma/patologia , Melanoma/terapia , Camundongos , Nivolumabe/administração & dosagem , Receptor de Morte Celular Programada 1/imunologia , Transdução de Sinais/imunologia , Linfócitos T , Células Th1/efeitos dos fármacos , Células Th1/imunologiaAssuntos
Biomarcadores Tumorais/metabolismo , Proteínas de Ligação a DNA/metabolismo , Melanoma/metabolismo , Neoplasias Cutâneas/metabolismo , Western Blotting , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Melanoma/patologia , Estadiamento de Neoplasias , Reação em Cadeia da Polimerase em Tempo Real , Neoplasias Cutâneas/patologiaRESUMO
Immune checkpoint inhibitors have increased the median survival of melanoma patients. To improve their effects, antigen-specific therapies utilizing melanoma-associated antigens should be developed. Cell division cycle-associated protein 1 (CDCA1), which has a specific function at the kinetochores for stabilizing microtubule attachment, is overexpressed in various cancers. CDCA1, which is a member of cancer-testis antigens, does not show detectable expression levels in normal tissues. Quantitative reverse transcription polymerase chain reaction and immunoblotting analyses revealed that CDCA1 was expressed in all of the tested melanoma cell lines, 74% of primary melanomas, 64% of metastatic melanomas and 25% of nevi. An immunohistochemical analysis and a Cox proportional hazards model showed that CDCA1 could be a prognostic marker in malignant melanoma (MM) patients. CDCA1-specific siRNA inhibited the cell proliferation of SKMEL2 and WM115 cells, but did not reduce the migration or invasion activity. These results suggest that CDCA1 may be a new therapeutic target of melanoma.
Assuntos
Antígenos de Neoplasias/metabolismo , Biomarcadores Tumorais/metabolismo , Proteínas de Ciclo Celular/metabolismo , Melanoma/imunologia , Nevo/imunologia , Neoplasias Cutâneas/imunologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos de Neoplasias/genética , Biomarcadores Tumorais/genética , Proteínas de Ciclo Celular/genética , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Criança , Pré-Escolar , Feminino , Humanos , Imuno-Histoquímica , Cinetocoros/metabolismo , Metástase Linfática , Masculino , Melanoma/mortalidade , Melanoma/patologia , Pessoa de Meia-Idade , Nevo/mortalidade , Nevo/patologia , Prognóstico , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Pele/patologia , Neoplasias Cutâneas/mortalidade , Neoplasias Cutâneas/patologia , Taxa de Sobrevida , Adulto JovemRESUMO
In recent years, immunotherapy for advanced melanoma has been gaining increased attention. The efficacy of anti-cytotoxic T-lymphocyte antigen 4 antibodies, anti-programmed cell death 1 antibodies, and the BRAF(V600E) kinase inhibitor has been proven in metastatic melanoma. At the same time, adoptive cell transfer has significant effects against metastatic melanoma; however, it is difficult to apply on a broad scale because of the problems related to cell preparation. To overcome these problems, we developed immune cell therapy using induced pluripotent stem (iPS) cells. The benefit of our method is that a large number of cells can be readily obtained. We focused on macrophages for immune cell therapy because macrophage infiltration is frequently observed in solid cancers. In this study, the efficacy of human iPS cell-derived myeloid cell lines (iPS-ML) genetically modified to express type I IFNs against human melanoma cells was examined. The morphology, phagocytic ability, and surface markers of iPS-ML were similar to those of macrophages. The iPS-ML that express type I IFNs (iPS-ML-IFN) showed significant effects in inhibiting the growth of disseminated human melanoma cells in SCID mice. The infiltration of iPS-ML into the tumor nests was confirmed immunohistologically. The iPS-ML-IFNs increased the expression of CD169, a marker of M1 macrophages that can activate antitumor immunity. The iPS-ML-IFNs could infiltrate into tumor tissue and exert anticancer effects in the local tumor tissue. In conclusion, this method will provide a new therapeutic modality for metastatic melanoma.
Assuntos
Células-Tronco Pluripotentes Induzidas/fisiologia , Interferon Tipo I/fisiologia , Melanoma/terapia , Células Mieloides/metabolismo , Neoplasias Cutâneas/terapia , Animais , Diferenciação Celular , Linhagem Celular Tumoral , Humanos , Imunoterapia , Macrófagos/imunologia , Melanoma/imunologia , Melanoma/secundário , Camundongos SCID , Transplante de Neoplasias , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/patologiaRESUMO
Anaplastic large cell lymphoma (ALCL) is a high grade non-Hodgkin lymphoma (NHL) that is comprised of the malignant proliferation of large lymphoid cells, which express CD30. Primary ALCL of the skeletal muscle is extremely uncommon. A 51-year-old Japanese female presented at our hospital with a 2-month history of severe pain and swelling of the right leg. A gallium-67 SPECT/CT scan showed a large mass involving the skeletal muscles from the gluteus to femoris. A biopsy of the mass demonstrated diffuse infiltration of medium and large neoplastic cells with round or lobulated hyperchromatic pleomorphic nuclei. A subset of Reed-Sternberg-like cells was also identified. Immunohistochemically, the neoplastic cells were strongly positive for CD4 and CD30, but negative for CD3, CD8, anaplastic lymphoma kinase (ALK), CD20, CD79α, CD21 and CD23. Based on the histological examination, this patient was diagnosed to have ALK-negative ALCL of the skeletal muscle. Further studies are needed to clarify the biological behavior of primary skeletal muscle ALCL.