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1.
J Nanobiotechnology ; 17(1): 87, 2019 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-31387604

RESUMO

BACKGROUND: Adoptive T cell-transfer (ATC) therapy is a highly promising cancer-treatment approach. However, in vivo-administered T cells tend to disperse, with only a small proportion reaching the tumour. To remedy this, magnetic targeting of T cells has been recently explored. Magnetic nanoparticles (MNPs) functionalised with antibodies were attached to effector T cells and magnetically recruited to tumour sites under MRI guidance. In this study, we investigated whether 3-aminopropyl-triethoxysilane (APS)-coated MNPs directly attached to CD8+ T cell membranes could also magnetically target and accumulate tumour-specific CD8+ T cells in solid tumours using an external magnetic field (EMF). As it has been shown that T cells associated with APS-coated MNPs are retained in lymph nodes (LNs), and tumour-draining LNs are the most common sites of solid-tumour metastases, we further evaluated whether magnetic targeting of APS-MNP-loaded CD8+ T cells could cause them to accumulate in tumour-draining LNs. RESULTS: First, we show that antigen-specific CD8+ T cells preserve their antitumor activity in vitro when associated with APS-MNPs. Next, we demonstrate that the application of a magnetic field enhanced the retention of APS-MNP-loaded OT-I CD8+ T cells under flow conditions in vitro. Using a syngeneic mouse model, we found similar numbers of APS-MNP-loaded OT-I CD8+ T cells and OT-I CD8+ T cells infiltrating the tumour 14 days after cell transfer. However, when a magnet was placed near the tumour during the transfer of tumour-specific APS-MNP-loaded CD8+ T cells to improve tumour infiltration, a reduced percentage of tumour-specific T cells was found infiltrating the tumour 14 days after cell transfer, which was reflected in a smaller reduction in tumour size compared to tumour-specific CD8+ T cells transferred with or without MNPs in the absence of a magnetic field. Nonetheless, magnet placement near the tumour site during cell transfer induced infiltration of activated tumour-specific CD8+ T cells in tumour-draining LNs, which remained 14 days after cell transfer. CONCLUSIONS: The use of an EMF to improve targeting of tumour-specific T cells modified with APS-MNPs reduced the percentage of these cells infiltrating the tumour, but promoted the retention and the persistence of these cells in the tumour-draining LNs.


Assuntos
Transferência Adotiva , Linfócitos T CD8-Positivos/transplante , Linfonodos/patologia , Linfócitos do Interstício Tumoral/imunologia , Nanopartículas de Magnetita/química , Neoplasias Experimentais/terapia , Animais , Linfócitos T CD8-Positivos/imunologia , Linhagem Celular Tumoral , Permeabilidade da Membrana Celular , Proliferação de Células , Sobrevivência Celular , Feminino , Linfonodos/imunologia , Ativação Linfocitária , Linfócitos do Interstício Tumoral/patologia , Camundongos Endogâmicos C57BL , Transplante de Neoplasias , Neoplasias Experimentais/imunologia , Neoplasias Experimentais/patologia , Propilaminas/química , Silanos/química
2.
Cancer Immunol Immunother ; 68(7): 1195-1209, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31177329

RESUMO

The anti-tumor efficacy of TCR-engineered T cells in vivo depends largely on less-differentiated subsets such as T cells with naïve-like T cell (TN) phenotypes with greater expansion and long-term persistence. To increase these subsets, we compared the generation of New York esophageal squamous cell carcinoma-1 (NY-ESO-1)-specific T cells under supplementation with either IL-2 or IL-7/IL-15. PBMCs were transduced with MS3II-NY-ESO-1-siTCR retroviral vector. T cell generation was adapted from a CD19-specific CART cell production protocol. Comparable results in viability, expansion and transduction efficiency of T cells under stimulation with either IL-2 or IL-7/IL-15 were observed. IL-7/IL-15 led to an increase of CD4+ T cells and a decrease of CD8+ T cells, enriched the amount of TN among CD4+ T cells but not among CD8+ T cells. In a 51Cr release assay, similar specific lysis of NY-ESO-1-positive SW982 sarcoma cells was achieved. However, intracellular cytokine staining revealed a significantly increased production of IFN-γ and TNF-α in T cells generated by IL-2 stimulation. To validate these unexpected findings, NY-ESO-1-specific T cell production was evaluated in another protocol originally established for TCR-engineered T cells. IL-7/IL-15 increased the proportion of TN. However, the absolute number of TN did not increase due to a significantly slower expansion of T cells with IL-7/IL-15. In conclusion, IL-7/IL-15 does not seem to be superior to IL-2 for the generation of NY-ESO-1-specific T cells. This is in sharp contrast to the observations in CD19-specific CART cells. Changes of cytokine cocktails should be carefully evaluated for individual vector systems.


Assuntos
Antígenos de Neoplasias/metabolismo , Engenharia Celular/métodos , Imunoterapia Adotiva/métodos , Proteínas de Membrana/metabolismo , Neoplasias/terapia , Receptores de Antígenos Quiméricos/imunologia , Antígenos CD19/metabolismo , Antígenos de Neoplasias/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD4-Positivos/transplante , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Linfócitos T CD8-Positivos/transplante , Técnicas de Cultura de Células/métodos , Linhagem Celular Tumoral , Meios de Cultura , Humanos , Interleucina-15/imunologia , Interleucina-2/imunologia , Interleucina-7/imunologia , Proteínas de Membrana/imunologia , Neoplasias/imunologia , Receptores de Antígenos Quiméricos/genética
3.
Nat Commun ; 10(1): 2157, 2019 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-31089138

RESUMO

T cell senescence and exhaustion are major barriers to successful cancer immunotherapy. Here we show that miR-155 increases CD8+ T cell antitumor function by restraining T cell senescence and functional exhaustion through epigenetic silencing of drivers of terminal differentiation. miR-155 enhances Polycomb repressor complex 2 (PRC2) activity indirectly by promoting the expression of the PRC2-associated factor Phf19 through downregulation of the Akt inhibitor, Ship1. Phf19 orchestrates a transcriptional program extensively shared with miR-155 to restrain T cell senescence and sustain CD8+ T cell antitumor responses. These effects rely on Phf19 histone-binding capacity, which is critical for the recruitment of PRC2 to the target chromatin. These findings establish the miR-155-Phf19-PRC2 as a pivotal axis regulating CD8+ T cell differentiation, thereby paving new ways for potentiating cancer immunotherapy through epigenetic reprogramming of CD8+ T cell fate.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Melanoma Experimental/imunologia , MicroRNAs/metabolismo , Neoplasias Cutâneas/imunologia , Fatores de Transcrição/metabolismo , Transferência Adotiva/métodos , Animais , Linfócitos T CD8-Positivos/metabolismo , Linfócitos T CD8-Positivos/transplante , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Senescência Celular/genética , Senescência Celular/imunologia , Epigênese Genética/imunologia , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Melanoma Experimental/genética , Melanoma Experimental/terapia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fosfatidilinositol-3,4,5-Trifosfato 5-Fosfatases/genética , Fosfatidilinositol-3,4,5-Trifosfato 5-Fosfatases/metabolismo , Complexo Repressor Polycomb 2/imunologia , Complexo Repressor Polycomb 2/metabolismo , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/terapia , Fatores de Transcrição/genética , Fatores de Transcrição/imunologia
5.
Proc Natl Acad Sci U S A ; 115(38): E8939-E8947, 2018 09 18.
Artigo em Inglês | MEDLINE | ID: mdl-30126987

RESUMO

Identifying novel pathways that promote robust function and longevity of cytotoxic T cells has promising potential for immunotherapeutic strategies to combat cancer and chronic infections. We show that sprouty 1 and 2 (Spry1/2) molecules regulate the survival and function of memory CD8+ T cells. Spry1/2 double-knockout (DKO) ovalbumin (OVA)-specific CD8+ T cells (OT-I cells) mounted more vigorous autoimmune diabetes than WT OT-I cells when transferred to mice expressing OVA in their pancreatic ß-islets. To determine the consequence of Spry1/2 deletion on effector and memory CD8+ T cell development and function, we used systemic infection with lymphocytic choriomeningitis virus (LCMV) Armstrong. Spry1/2 DKO LCMV gp33-specific P14 CD8+ T cells survive contraction better than WT cells and generate significantly more polyfunctional memory T cells. The larger number of Spry1/2 DKO memory T cells displayed enhanced infiltration into infected tissue, demonstrating that absence of Spry1/2 can result in increased recall capacity. Upon adoptive transfer into naive hosts, Spry1/2 DKO memory T cells controlled Listeria monocytogenes infection better than WT cells. The enhanced formation of more functional Spry1/2 DKO memory T cells was associated with significantly reduced mTORC1 activity and glucose uptake. Reduced p-AKT, p-FoxO1/3a, and T-bet expression was also consistent with enhanced survival and memory accrual. Collectively, loss of Spry1/2 enhances the survival of effector CD8+ T cells and results in the formation of more protective memory cells. Deleting Spry1/2 in antigen-specific CD8+ T cells may have therapeutic potential for enhancing the survival and functionality of effector and memory CD8+ T cells in vivo.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/imunologia , Linfócitos T CD8-Positivos/fisiologia , Memória Imunológica/genética , Peptídeos e Proteínas de Sinalização Intracelular/imunologia , Ativação Linfocitária/genética , Proteínas de Membrana/imunologia , Fosfoproteínas/imunologia , Proteínas Adaptadoras de Transdução de Sinal/genética , Transferência Adotiva/métodos , Animais , Linfócitos T CD8-Positivos/transplante , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Sobrevivência Celular/genética , Sobrevivência Celular/imunologia , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/imunologia , Diabetes Mellitus Tipo 1/urina , Modelos Animais de Doenças , Feminino , Humanos , Memória Imunológica/imunologia , Peptídeos e Proteínas de Sinalização Intracelular/genética , Listeria monocytogenes/imunologia , Listeria monocytogenes/isolamento & purificação , Listeriose/imunologia , Listeriose/microbiologia , Listeriose/terapia , Ativação Linfocitária/imunologia , Masculino , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fosfoproteínas/genética , Quimeras de Transplante
6.
Hematology ; 23(10): 740-746, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29962321

RESUMO

OBJECTIVES: Acute myeloid leukaemia (AML) is a malignant haematological disease that remains difficult to cure. Cytotoxic T cell (CTL) adoptive infusion therapy may be conducive to tumour remission by boosting physical immunity. Furthermore, programmed death receptor-1 (PD-1) blockade immunotherapy has shown tremendous success in many cancer therapies. METHOD: We attempted to combine these two immunotherapy strategies to intervene in AML by generating AML cellspecific cytotoxic T lymphocytes in vitro and in vivo with an AML cell strain expressing specific antigens. RESULTS: First, we observed that peripheral blood mononuclear cells (PBMCs) could be induced to generate large numbers of CD8+ CTL cells through immune stimulation. In addition, these CD8+ cells could effectively recognize a human AML cell line and exert cytotoxicity. In animal tests, PD-1 blockade combined with CTL infusion could induce significantly more AML tumour reduction than either treatment alone. This synergistic effect was thought to be connected to immune modulation enhancement, as regulatory T cells (Tregs) in the peripheral blood (PB) were found to be suppressed. CONCLUSIONS: This finding suggested the potential application of PD-1 blockade in AML. The present work demonstrated an excellent synergistic tumour therapeutic effect of PD-1 blockade and CTL therapy compared with either treatment alone.


Assuntos
Transferência Adotiva , Linfócitos T CD8-Positivos , Leucemia Mieloide Aguda , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Animais , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , Linfócitos T CD8-Positivos/transplante , Linhagem Celular Tumoral , Feminino , Xenoenxertos , Humanos , Leucemia Mieloide Aguda/imunologia , Leucemia Mieloide Aguda/patologia , Leucemia Mieloide Aguda/terapia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Transplante de Neoplasias , Receptor de Morte Celular Programada 1/imunologia , Ensaios Antitumorais Modelo de Xenoenxerto
7.
Cancer Immunol Immunother ; 67(7): 1053-1066, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29605883

RESUMO

Relapsed/refractory B-precursor acute lymphoblastic leukemia (pre-B ALL) remains a major therapeutic challenge. Chimeric antigen receptor (CAR) T cells are promising treatment options. Central memory T cells (Tcm) and stem cell-like memory T cells (Tscm) are known to promote sustained proliferation and persistence after T-cell therapy, constituting essential preconditions for treatment efficacy. Therefore, we set up a protocol for anti-CD19 CAR T-cell generation aiming at high Tcm/Tscm numbers. 100 ml peripheral blood from pediatric pre-B ALL patients was processed including CD4+/CD8+-separation, T-cell activation with modified anti-CD3/-CD28 reagents and transduction with a 4-1BB-based second generation CAR lentiviral vector. The process was performed on a closed, automated device requiring additional manual/open steps under clean room conditions. The clinical situation of these critically ill and refractory patients with leukemia leads to inconsistent cellular compositions at start of the procedure including high blast counts and low T-cell numbers with exhausted phenotype. Nevertheless, a robust T-cell product was achieved (mean CD4+ = 50%, CD8+ = 39%, transduction = 27%, Tcm = 50%, Tscm = 46%). Strong proliferative potential (up to > 100-fold), specific cytotoxicity and low expression of co-inhibitory molecules were documented. CAR T cells significantly released TH1 cytokines IFN-γ, TNF-α and IL-2 upon target-recognition. In conclusion, partly automated GMP-generation of CAR T cells from critically small blood samples was feasible with a new stimulation protocol that leads to high functionality and expansion potential, balanced CD4/CD8 ratios and a conversion to a Tcm/Tscm phenotype.


Assuntos
Antígenos CD19/metabolismo , Linfócitos T CD4-Positivos/transplante , Linfócitos T CD8-Positivos/transplante , Memória Imunológica/imunologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/imunologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Receptores de Antígenos de Linfócitos T/imunologia , Células-Tronco/imunologia , Adolescente , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Citocinas/metabolismo , Citotoxicidade Imunológica , Feminino , Humanos , Imunoterapia Adotiva , Ativação Linfocitária , Fenótipo , Prognóstico
8.
Gastroenterology ; 154(4): 1024-1036.e9, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29408569

RESUMO

BACKGROUND & AIMS: Ceramide, a sphingolipid metabolite, affects T-cell signaling, induces apoptosis of cancer cells, and slows tumor growth in mice. However, it has not been used as a chemotherapeutic agent because of its cell impermeability and precipitation in aqueous solution. We developed a nanoliposome-loaded C6-ceremide (LipC6) to overcome this limitation and investigated its effects in mice with liver tumors. METHODS: Immune competent C57BL/6 mice received intraperitoneal injections of carbon tetrachloride and intra-splenic injections of oncogenic hepatocytes. As a result, tumors resembling human hepatocellular carcinomas developed in a fibrotic liver setting. After tumors formed, mice were given an injection of LipC6 or vehicle via tail vein every other day for 2 weeks. This was followed by administration, also via tail vein, of tumor antigen-specific (TAS) CD8+ T cells isolated from the spleens of line 416 mice, and subsequent immunization by intraperitoneal injection of tumor antigen-expressing B6/WT-19 cells. Tumor growth was monitored with magnetic resonance imaging. Tumor apoptosis, proliferation, and AKT expression were analyzed using immunohistochemistry and immunoblots. Cytokine production, phenotype, and function of TAS CD8+ T cells and tumor-associated macrophages (TAMs) were studied with flow cytometry, real-time polymerase chain reaction (PCR), and ELISA. Reactive oxygen species (ROS) in TAMs and bone marrow-derived macrophages, induced by colony stimulating factor 2 (GMCSF or CSF2) or colony stimulating factor 1 (MCSF or CSF1), were detected using a luminescent assay. RESULTS: Injection of LipC6 slowed tumor growth by reducing tumor cell proliferation and phosphorylation of AKT, and increasing tumor cell apoptosis, compared with vehicle. Tumors grew more slowly in mice given the combination of LipC6 injection and TAS CD8+ T cells followed by immunization compared with mice given vehicle, LipC6, the T cells, or immunization alone. LipC6 injection also reduced numbers of TAMs and their production of ROS. LipC6 induced TAMs to differentiate into an M1 phenotype, which reduced immune suppression and increased activity of CD8+ T cells. These results were validated by experiments with bone marrow-derived macrophages induced by GMCSF or MCSF. CONCLUSIONS: In mice with liver tumors, injection of LipC6 reduces the number of TAMs and the ability of TAMs to suppress the anti-tumor immune response. LipC6 also increases the anti-tumor effects of TAS CD8+ T cells. LipC6 might therefore increase the efficacy of immune therapy in patients with hepatocellular carcinoma.


Assuntos
Antineoplásicos/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Ceramidas/farmacologia , Neoplasias Hepáticas/tratamento farmacológico , Carga Tumoral/efeitos dos fármacos , Animais , Antígenos Transformantes de Poliomavirus/genética , Apoptose/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Linfócitos T CD8-Positivos/transplante , Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Linhagem Celular Transformada , Proliferação de Células/efeitos dos fármacos , Citocinas/metabolismo , Imunoterapia Adotiva/métodos , Lipossomos , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/metabolismo , Imagem por Ressonância Magnética , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Nanopartículas , Regiões Promotoras Genéticas , Proteínas/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fatores de Tempo , Evasão Tumoral/efeitos dos fármacos , Microambiente Tumoral
9.
J Cell Physiol ; 233(3): 2590-2601, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28777458

RESUMO

Alopecia areata (AA) is a common autoimmune disorder affecting millions of people worldwide, which manifests as a sudden, non-scarring hair loss. The expression of a pro-inflammatory cytokine, interferon-gamma (INF-γ), has been well established to be involved in the development of AA. As IFN-γ and other cytokines are also known to up-regulate programmed cell death ligand 1 and 2 (PD-L1 and PD-L2), which both negatively control immune responses, we asked whether or not a high number of infiltrated T cells, seen in AA lesions, can modulate the expression of PD-L1 and PD-L2 in skin cells. From a series of experiments, we showed that a significantly higher number of PD-L1 or PD-L2 positive cells affect the skin in AA mice, compared to the skin of non-AA mice. The number of PD-L1 positive cells was well correlated with the number of infiltrated T cells, especially CD8+ T cells. We also found that the expression of PD-L1 and PD-L2 was co-localized with type 1 pro-collagen, CD90 and vimentin, which are biomarkers for dermal fibroblasts. Further studies revealed that releasable factors from activated, but not inactivated, lymphocytes significantly increase the expressions of both PD-L1 and PD-L2 in cultured dermal fibroblasts. In conclusion, our findings suggest that the expression of PD-L1 and PD-L2 in dermal fibroblasts is up-regulated by activated T cells in AA-affected skin, and as such, these regulatory molecules may not exert a negative control of the immune activation seen in AA lesions.


Assuntos
Alopecia em Áreas/metabolismo , Antígeno B7-H1/metabolismo , Fibroblastos/metabolismo , Proteína 2 Ligante de Morte Celular Programada 1/metabolismo , Pele/metabolismo , Alopecia em Áreas/imunologia , Alopecia em Áreas/patologia , Animais , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Linfócitos T CD8-Positivos/transplante , Células Cultivadas , Técnicas de Cocultura , Modelos Animais de Doenças , Feminino , Fibroblastos/imunologia , Fibroblastos/patologia , Ativação Linfocitária , Camundongos Endogâmicos C3H , Comunicação Parácrina , Pele/imunologia , Pele/patologia , Regulação para Cima
10.
Biol Aujourdhui ; 212(3-4): 69-76, 2018.
Artigo em Francês | MEDLINE | ID: mdl-30973134

RESUMO

Tumor cells can be recognized by the immune system and in particular by cytotoxic CD8+T cells. From this observation was derived the concept that vaccination targeting these tumor-associated molecules was feasible. Preventive cancer vaccines targeting oncogenic papillomavirus or hepatitis B virus do exist and are efficient. They aim at preventing the introduction into the body of viruses that play a role in oncogenesis. To date, in the case of an already grown cancer, the anti-tumor vaccines have had no impact on the care of patients. These vaccines are gaining renewed interest, as new antigenic targets have emerged and have been incorporated into the design of vaccines, such as mutated antigens which appeared to be more immunogenic. Less editing cells than tumor cells in the tumor microenvironment, such as protumor endothelial cells or fibroblasts, could also be eliminated by cancer vaccines. New vaccine efficacy criteria have been identified, such as the need to induce intratumoral resident T lymphocytes thanks to the development of mucosal vaccination to amplify them. Finally, because of the immunosuppression of the tumor microenvironment and the expression of inhibitory receptors on CD8+T cells in the tumor, various therapeutic association strategies between the anti-cancer vaccines and molecules supporting these inhibitions are currently used in clinical development. Especially, the efficacy of antibodies against costimulatory inhibitory molecules (PD-1, PD-L1…) relies on the presence of pre-existing CD8+T cells occurring in 25-30% of cancer patients. For the 70% resistant patients, cancer vaccine may reprogram this tumor environment via the induction of intratumoral CD8+T cells which will very likely counteract this resistance to anti-PD-1/PD-L1 antibodies.


Assuntos
Vacinas Anticâncer/uso terapêutico , Imunoterapia/tendências , Neoplasias/terapia , Animais , Anticorpos Monoclonais/uso terapêutico , Antineoplásicos Imunológicos/administração & dosagem , Antineoplásicos Imunológicos/efeitos adversos , Linfócitos T CD8-Positivos/fisiologia , Linfócitos T CD8-Positivos/transplante , Terapia Combinada , Humanos , Imunoterapia/métodos , Terapia de Alvo Molecular/métodos , Terapia de Alvo Molecular/tendências , Neoplasias/imunologia , Resultado do Tratamento
11.
Hematology Am Soc Hematol Educ Program ; 2017(1): 708-715, 2017 12 08.
Artigo em Inglês | MEDLINE | ID: mdl-29222325

RESUMO

Relapse of cancer remains one of the primary causes of treatment failure and mortality after allogeneic hematopoietic stem cell transplantation (HSCT). A multitude of approaches have been used in the management of posttransplant relapse. This review focuses on recent data with cellular therapies designed to treat or prevent posttransplant relapse of hematologic malignancies, although many of these therapeutic approaches also have applications to solid tumors and in the nontransplant setting. Currently available cell therapies include second transplant, natural killer cells, monocyte-derived dendritic cell vaccines, and lymphocytes via donor lymphocyte infusion, antigen-primed cytotoxic T lymphocytes, cytokine-induced killer cells, marrow-infiltrating lymphocytes, and chimeric antigen receptor T cells. These treatment options offer the prospect for improved relapse-free survival after HSCT.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Imunoterapia/métodos , Recidiva Local de Neoplasia/prevenção & controle , Neoplasias/prevenção & controle , Aloenxertos , Linfócitos T CD8-Positivos/transplante , Vacinas Anticâncer/uso terapêutico , Células Matadoras Induzidas por Citocinas/transplante , Células Dendríticas/transplante , Humanos , Células Matadoras Naturais/transplante , Monócitos/transplante , Neoplasias/imunologia
12.
Nat Commun ; 8(1): 1343, 2017 11 07.
Artigo em Inglês | MEDLINE | ID: mdl-29116089

RESUMO

Transforming growth factor ß (TGFß) is important in maintaining self-tolerance and inhibits T cell reactivity. We show that CD8+ T cells that lack the tyrosine phosphatase Ptpn22, a major predisposing gene for autoimmune disease, are resistant to the suppressive effects of TGFß. Resistance to TGFß suppression, while disadvantageous in autoimmunity, helps Ptpn22 -/- T cells to be intrinsically superior at clearing established tumors that secrete TGFß. Mechanistically, loss of Ptpn22 increases the capacity of T cells to produce IL-2, which overcomes TGFß-mediated suppression. These data suggest that a viable strategy to improve anti-tumor adoptive cell therapy may be to engineer tumor-restricted T cells with mutations identified as risk factors for autoimmunity.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Imunoterapia Adotiva/métodos , Proteína Tirosina Fosfatase não Receptora Tipo 22/genética , Fator de Crescimento Transformador beta/farmacologia , Animais , Autoimunidade/imunologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/transplante , Feminino , Proteínas de Homeodomínio/genética , Interleucina-2/metabolismo , Masculino , Camundongos Mutantes , Camundongos Transgênicos , Ovalbumina/farmacologia , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/terapia , Fragmentos de Peptídeos/farmacologia , Proteína Tirosina Fosfatase não Receptora Tipo 22/metabolismo , Receptores de Fatores de Crescimento Transformadores beta/metabolismo , Fator de Crescimento Transformador beta/metabolismo
13.
Nat Commun ; 8(1): 1459, 2017 11 13.
Artigo em Inglês | MEDLINE | ID: mdl-29129917

RESUMO

Zika virus (ZIKV) and dengue virus (DENV) are antigenically related flaviviruses that share cross-reactivity in antibody and T cell responses, and co-circulate in increasing numbers of countries. Whether pre-existing DENV immunity can cross-protect or enhance ZIKV infection during sequential infection of the same host is unknown. Here, we show that DENV-immune Ifnar1 -/- or wild-type C57BL/6 mice infected with ZIKV have cross-reactive immunity to subsequent ZIKV infection and pathogenesis. Adoptive transfer and cell depletion studies demonstrate that DENV-immune CD8+ T cells predominantly mediate cross-protective responses to ZIKV. In contrast, passive transfer studies suggest that DENV-immune serum does not protect against ZIKV infection. Thus, CD8+ T cell immunity generated during primary DENV infection can confer protection against secondary ZIKV infection in mice. Further optimization of current DENV vaccines for T cell responses might confer cross-protection and prevent antibody-mediated enhancement of ZIKV infection.


Assuntos
Transferência Adotiva , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/transplante , Proteção Cruzada/imunologia , Vírus da Dengue/imunologia , Infecção por Zika virus/prevenção & controle , Zika virus/imunologia , Animais , Epitopos de Linfócito T/imunologia , Soros Imunes/administração & dosagem , Soros Imunes/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptor de Interferon alfa e beta/genética , Infecção por Zika virus/imunologia , Infecção por Zika virus/virologia
14.
Nat Commun ; 8(1): 793, 2017 10 06.
Artigo em Inglês | MEDLINE | ID: mdl-28986561

RESUMO

The presence of T cells in tumors predicts overall survival for cancer patients. However, why most tumors are poorly infiltrated by T cells is barely understood. T-cell recruitment towards the tumor requires a chemokine gradient of the critical IFNγ-induced chemokines CXCL9/10/11. Here, we describe how tumors can abolish IFNγ-induced chemokines, thereby reducing T-cell attraction. This mechanism requires extracellular galectin-3, a lectin secreted by tumors. Galectins bind the glycans of glycoproteins and form lattices by oligomerization. We demonstrate that galectin-3 binds the glycans of the extracellular matrix and those decorating IFNγ. In mice bearing human tumors, galectin-3 reduces IFNγ diffusion through the tumor matrix. Galectin antagonists increase intratumoral IFNγ diffusion, CXCL9 gradient and tumor recruitment of adoptively transferred human CD8+ T cells specific for a tumor antigen. Transfer of T cells reduces tumor growth only if galectin antagonists are injected. Considering that most human cytokines are glycosylated, galectin secretion could be a general strategy for tumor immune evasion.Most tumours are poorly infiltrated by T cells. Here the authors show that galectin-3 secreted by tumours binds both glycosylated IFNγ and glycoproteins of the tumour extracellular matrix, thus avoiding IFNγ diffusion and the formation of an IFNγ-induced chemokine gradient required for T cell infiltration.


Assuntos
Neoplasias da Mama/imunologia , Quimiocinas/imunologia , Galectina 3/metabolismo , Interferon gama/imunologia , Linfócitos do Interstício Tumoral/imunologia , Melanoma/imunologia , Neoplasias Cutâneas/imunologia , Linfócitos T/imunologia , Microambiente Tumoral/imunologia , Transferência Adotiva , Animais , Neoplasias da Mama/metabolismo , Linfócitos T CD8-Positivos/transplante , Linhagem Celular Tumoral , Quimiocina CXCL10/imunologia , Quimiocina CXCL9 , Matriz Extracelular/metabolismo , Glicoproteínas/metabolismo , Humanos , Melanoma/metabolismo , Camundongos , Transplante de Neoplasias , Neoplasias Cutâneas/metabolismo
15.
Immunotherapy ; 9(10): 837-849, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28877635

RESUMO

The recent tremendous successes in clinical trials take cancer immunotherapy into a new era and have attracted major attention from both academia and industry. Among the variety of immunotherapy strategies developed to boost patients' own immune systems to fight against malignant cells, the pathogen-based and adoptive cell transfer therapies have shown the most promise for treating multiple types of cancer. Pathogen-based therapies could either break the immune tolerance to enhance the effectiveness of cancer vaccines or directly infect and kill cancer cells. Adoptive cell transfer can induce a strong durable antitumor response, with recent advances including engineering dual specificity into T cells to recognize multiple antigens and improving the metabolic fitness of transferred cells. In this review, we focus on the recent prospects in these two areas and summarize some ongoing studies that represent potential advancements for anticancer immunotherapy, including testing combinations of these two strategies.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Imunoterapia Adotiva/métodos , Neoplasias/terapia , Vacinas/imunologia , Animais , Antígenos de Neoplasias/imunologia , Linfócitos T CD8-Positivos/transplante , Ensaios Clínicos como Assunto , Terapia Combinada , Engenharia Genética , Interações Hospedeiro-Patógeno , Humanos , Tolerância Imunológica , Camundongos , Neoplasias/imunologia , Receptores de Antígenos de Linfócitos T/genética , Proteínas Recombinantes de Fusão/genética
16.
Med Oncol ; 34(10): 171, 2017 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-28864944

RESUMO

Fibrosarcoma is a locally aggressive malignant tumor with a high recurrence rate, so that wide excisional surgery is necessary for treatment. However, it is often difficult to resect with a sufficient margin of excision at the site of tumor infiltration. Recombinant tumor vaccine therapy is a useful method to induce specific immunity. In this study, we have shown its utility as a candidate for therapy by applying a recombinant Newcastle disease virus (rNDV) tumor vaccine (rNDV-TV). Although the therapeutic effect of similar viruses has been examined in several tumors, the vaccination efficacy against fibrosarcoma has not been demonstrated until now. In this study, we showed the induction of an antitumor response by rNDV-TV against murine fibrosarcoma and investigated the role of lymphocytes in tumor elimination. Intraperitoneal inoculation of murine fibrosarcoma (WEHI164) cells showed increased lethality in C.B.17scid/scid (scid) mice within 2 weeks of inoculation. The survival rate increased to 80% when the mice were transfused with CD3+ cells from BALB/c mice previously immunized with rNDV-TV. However, all mice died from tumor growth after inoculation with non-immunized CD3+ cells. Although the survival rate was around 50% in mice receiving only immunized CD4+ and CD8+ cells, the survival rate was not decreased in mice receiving CD3+CD4-CD8- (natural killer T; NKT) cells together with immunized CD4+ and CD8+ cells. This study showed rNDV-TV induced an antitumor T cell response to WEHI164 cells, and major subsets of cells involved in tumor exclusion were CD4+ and CD8+ cells, together with NKT cells.


Assuntos
Vacinas Anticâncer/farmacologia , Fibrossarcoma/terapia , Imunoterapia/métodos , Vírus da Doença de Newcastle/genética , Animais , Complexo CD3/metabolismo , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/transplante , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/transplante , Vacinas Anticâncer/genética , Linhagem Celular Tumoral , Feminino , Fibrossarcoma/mortalidade , Fibrossarcoma/patologia , Humanos , Integrina alfa1/metabolismo , Interferon gama/genética , Masculino , Camundongos Endogâmicos BALB C , Camundongos SCID , Baço/citologia , Taxa de Sobrevida , Vacinas Sintéticas/genética , Vacinas Sintéticas/farmacologia
17.
Int J Cancer ; 141(12): 2551-2561, 2017 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-28833076

RESUMO

Targeted oncogene inactivation by small molecule inhibitors can be very effective but tumor recurrence is a frequent problem in the clinic. Therapy by inactivation of the cancer-driving oncogene in transplanted tumors was shown to be augmented in the presence of T cells. However, these experiments did not take into account the long-term, usually tolerogenic, interaction of de novo malignancies with the immune system. Here, we employed mice, in which SV40 large T (Tag) and firefly luciferase (Luc) as fusion protein (TagLuc) could be regulated with the Tet-on system and upon activation resulted in tumors after a long latency. TagLuc inactivation induced profound tumor regression, demonstrating sustained oncogene addiction. While tumor relapse after TagLuc inactivation was prevented in immunocompetent mice bearing transplanted tumors, autochthonous tumors relapsed or recurred after therapy discontinuation indicating that the immune system that coevolved with the malignancy over an extended period of time lost the potency to mount an efficient anti-tumor immune response. By contrast, adoptively transferred CD8+ T cells targeting the cancer-driving oncogene eradicated recurrent autochthonous tumors, highlighting a suitable therapy option in a clinically relevant model.


Assuntos
Linfócitos T CD8-Positivos/transplante , Doxiciclina/administração & dosagem , Inativação Gênica , Sistema Imunitário/metabolismo , Neoplasias Experimentais/terapia , Transferência Adotiva , Animais , Antígenos Transformantes de Poliomavirus/genética , Antígenos Transformantes de Poliomavirus/metabolismo , Linfócitos T CD8-Positivos/imunologia , Linhagem Celular Tumoral , Doxiciclina/uso terapêutico , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Transplante de Neoplasias , Neoplasias Experimentais/imunologia , Proteínas Recombinantes de Fusão/genética
18.
J Immunother Cancer ; 5: 51, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28642819

RESUMO

BACKGROUND: Adoptive cellular therapy (ACT) with cancer antigen-reactive T cells following lymphodepletive pre-conditioning has emerged as a potentially curative therapy for patients with advanced cancers. However, identification and enrichment of appropriate T cell subsets for cancer eradication remains a major challenge for hematologic cancers. METHODS: PD-1+ and PD-1- T cell subsets from myeloma-bearing mice were sorted and analyzed for myeloma reactivity in vitro. In addition, the T cells were activated and expanded in culture and given to syngeneic myeloma-bearing mice as ACT. RESULTS: Myeloma-reactive T cells were enriched in the PD-1+ cell subset. Similar results were also observed in a mouse AML model. PD-1+ T cells from myeloma-bearing mice were found to be functional, they could be activated and expanded ex vivo, and they maintained their anti-myeloma reactivity after expansion. Adoptive transfer of ex vivo-expanded PD-1+ T cells together with a PD-L1 blocking antibody eliminated established myeloma in Rag-deficient mice. Both CD8 and CD4 T cell subsets were important for eradicating myeloma. Adoptively transferred PD-1+ T cells persisted in recipient mice and were able to mount an adaptive memory immune response. CONCLUSIONS: These results demonstrate that PD-1 is a biomarker for functional myeloma-specific T cells, and that activated and expanded PD-1+ T cells can be effective as ACT for myeloma. Furthermore, this strategy could be useful for treating other hematologic cancers.


Assuntos
Linfócitos T CD8-Positivos/transplante , Mieloma Múltiplo/terapia , Receptor de Morte Celular Programada 1/sangue , Subpopulações de Linfócitos T/transplante , Animais , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Linhagem Celular Tumoral , Citocinas/biossíntese , Memória Imunológica/imunologia , Imunofenotipagem , Imunoterapia Adotiva/métodos , Ativação Linfocitária/imunologia , Linfócitos do Interstício Tumoral/imunologia , Camundongos Endogâmicos C57BL , Mieloma Múltiplo/imunologia , Subpopulações de Linfócitos T/imunologia , Células Tumorais Cultivadas
20.
PLoS One ; 12(6): e0179239, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28617827

RESUMO

Immunodeficient mice transplanted with human peripheral blood mononuclear cells (PBMCs) are promising tools to evaluate human immune responses to vaccines. However, these mice usually develop severe graft-versus-host disease (GVHD), which makes estimation of antigen-specific IgG production after antigen immunization difficult. To evaluate antigen-specific IgG responses in PBMC-transplanted immunodeficient mice, we developed a novel NOD/Shi-scid-IL2rγnull (NOG) mouse strain that systemically expresses the human IL-4 gene (NOG-hIL-4-Tg). After human PBMC transplantation, GVHD symptoms were significantly suppressed in NOG-hIL-4-Tg compared to conventional NOG mice. In kinetic analyses of human leukocytes, long-term engraftment of human T cells has been observed in peripheral blood of NOG-hIL-4-Tg, followed by dominant CD4+ T rather than CD8+ T cell proliferation. Furthermore, these CD4+ T cells shifted to type 2 helper (Th2) cells, resulting in long-term suppression of GVHD. Most of the human B cells detected in the transplanted mice had a plasmablast phenotype. Vaccination with HER2 multiple antigen peptide (CH401MAP) or keyhole limpet hemocyanin (KLH) successfully induced antigen-specific IgG production in PBMC-transplanted NOG-hIL-4-Tg. The HLA haplotype of donor PBMCs might not be relevant to the antibody secretion ability after immunization. These results suggest that the human PBMC-transplanted NOG-hIL-4-Tg mouse is an effective tool to evaluate the production of antigen-specific IgG antibodies.


Assuntos
Anticorpos Antineoplásicos/imunologia , Formação de Anticorpos , Proteínas de Transporte/imunologia , Imunização , Imunoglobulina G/imunologia , Interleucina-4/imunologia , Peptídeos/farmacologia , Receptor ErbB-2/farmacologia , Animais , Anticorpos Antineoplásicos/genética , Linfócitos B/imunologia , Linfócitos B/transplante , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/transplante , Proteínas de Transporte/genética , Xenoenxertos , Humanos , Imunoglobulina G/genética , Interleucina-4/genética , Camundongos , Camundongos SCID , Camundongos Transgênicos , Peptídeos/imunologia , Receptor ErbB-2/imunologia , Células Th2/imunologia , Células Th2/transplante
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