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1.
Chem Commun (Camb) ; 55(95): 14255-14258, 2019 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-31657388
2.
Chem Commun (Camb) ; 55(87): 13066-13069, 2019 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-31570904

RESUMO

A platinum(ii) complex containing an aminophosphonate ligand preferentially accumulates in the endoplamic reticulum (ER) in association with potent ER stress and reactive oxygen species generation, followed by the activation of damage-associated molecular pattern signals and immune responses. Importantly, the Pt complex exhibits potent anti-tumour activities in two independent mouse models via an immunogenic cell death pathway.


Assuntos
Antineoplásicos Imunológicos/farmacologia , Ésteres/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Organofosfonatos/farmacologia , Compostos Organoplatínicos/farmacologia , Animais , Antineoplásicos Imunológicos/química , Morte Celular/efeitos dos fármacos , Ésteres/química , Humanos , Ligantes , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Endogâmicos C57BL , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/imunologia , Neoplasias Experimentais/patologia , Organofosfonatos/química , Compostos Organoplatínicos/química
3.
Int J Mol Sci ; 20(19)2019 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-31547586

RESUMO

For optimum radioimmunotherapy (RIT), deep penetration and uniform distribution into the tumor core is important. The solid tumor microenvironment, consisting of a highly fibrotic or desmoplastic tumor, abnormal tumor vasculature, high fluid pressure, and the absence of fluid lymphatics, limits the distribution of monoclonal antibodies mAbs to the tumor core. To investigate the optimal rationale for therapeutic mAbs administration and the microdistribution of mAbs, single and serial fractional dosage regimens of Cu-64-trastuzumab (TRZ) with paclitaxel were evaluated. Groups of nude mice were inoculated with gastric cancer cell line NCI-N87 tumor cells. When the tumor size reached 200 ± 20 mm3, the mice were divided into two groups for injection of Alexa-647-TRZ. One group (n = 5) was injected with 15 mg/kg in a single dose (SD), and the other group (n = 5) with two doses of 7.5 mg/kg (fractionated dose (FD)). In both cases, the injections were done intravenously in combination with intraperitoneal paclitaxel either as a SD of 70 mg/kg or fractionated into two doses of 40 and 30 mg/kg. Tumors were harvested, flash frozen, and sectioned (8 µm) five days after Alexa-647-TRZ injection. Rhodamine lectin (rhodamine-labeled Ricinus communis agglutinin I, 1 mg in 0.2 mL of phosphate-buffered saline (PBS)) was intravenously injected to delineate the functional vessel for a wait time of 5 min before animal euthanization. Microscopic images were acquired with an IN Cell Analyzer. The amount of TRZ that penetrated the tumor surface and the tumor vessel was calculated by area under the curve (AUC) analysis. For RIT efficacy (n = 21), Cu-64-TRZ was injected following the same dose schedule to observe tumor volume and survival ratio for 30 days. The SD and FD regimens of Alexa-647-TRZ were observed to have no significant difference in penetration of mAbs from the tumor edge and vessel, nor was the total accumulation across the whole tumor tissue significantly different. Additionally, the SD and FD regimens of Cu-64-TRZ were not proven to be significantly efficacious. Our study reveals that SD and FD in a treatment design with Cu-64-TRZ and paclitaxel shows no significant difference in therapeutic efficacy on tumor growth inhibition in vivo in mice bearing human gastric cancer xenografts overexpressing HER2 antigen.


Assuntos
Radioisótopos de Cobre/farmacologia , Neoplasias Experimentais/tratamento farmacológico , Compostos Radiofarmacêuticos/farmacologia , Neoplasias Gástricas/tratamento farmacológico , Trastuzumab/farmacologia , Animais , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Humanos , Camundongos , Camundongos Nus , Neoplasias Experimentais/imunologia , Neoplasias Experimentais/patologia , Neoplasias Gástricas/imunologia , Neoplasias Gástricas/patologia , Ensaios Antitumorais Modelo de Xenoenxerto
4.
Nat Commun ; 10(1): 3959, 2019 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-31477729

RESUMO

Successful combinations of radiotherapy and immunotherapy depend on the presence of live T cells within the tumor; however, radiotherapy is believed to damage T cells. Here, based on longitudinal in vivo imaging and functional analysis, we report that a large proportion of T cells survive clinically relevant doses of radiation and show increased motility, and higher production of interferon gamma, compared with T cells from unirradiated tumors. Irradiated intratumoral T cells can mediate tumor control without newly-infiltrating T cells. Transcriptomic analysis suggests T cell reprogramming in the tumor microenvironment and similarities with tissue-resident memory T cells, which are more radio-resistant than circulating/lymphoid tissue T cells. TGFß is a key upstream regulator of T cell reprogramming and contributes to intratumoral Tcell radio-resistance. These findings have implications for the design of radio-immunotherapy trials in that local irradiation is not inherently immunosuppressive, and irradiation of multiple tumors might optimize systemic effects of radiotherapy.


Assuntos
Imunoterapia/métodos , Linfócitos do Interstício Tumoral/metabolismo , Neoplasias Experimentais/terapia , Radioterapia/métodos , Animais , Linhagem Celular Tumoral , Movimento Celular/genética , Sobrevivência Celular/genética , Terapia Combinada , Perfilação da Expressão Gênica/métodos , Interferon gama/imunologia , Interferon gama/metabolismo , Linfócitos do Interstício Tumoral/imunologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Neoplasias Experimentais/genética , Neoplasias Experimentais/imunologia , Tolerância a Radiação/genética
5.
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
6.
Med Hypotheses ; 131: 109303, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31443747

RESUMO

The problems of immunoprotection from the environmental chemical carcinogens are discussed. The main experimental argument pro active immunization against carcinogens is a possibility of specific mucosal antibodies (Abs) to inhibit the penetration of carcinogens from environment and to stimulate its excretion with the following decreasing of carcinogen-DNA adducts levels. Hypothesis of cancer immunostimulation after active immunization against carcinogens is based on a high cancer risk in persons with high levels of serum Abs specific to environmental carcinogens coupled with high levels of Abs to endogenous steroids stimulating the proliferation of target cells, for example, Abs to benzo[a]pyrene together with Abs to estradiol. The active immunization could increase the cancer risk much more in those persons. The passive immunization could be an alternative safe approach to avoid this problem.


Assuntos
Carcinógenos Ambientais/toxicidade , Neoplasias/prevenção & controle , Vacinação , Animais , Anticorpos/sangue , Especificidade de Anticorpos , Autoanticorpos/imunologia , Carcinógenos/toxicidade , Carcinógenos Ambientais/farmacocinética , Linhagem Celular Tumoral , Cocarcinogênese , Adutos de DNA/imunologia , Feminino , Haptenos/imunologia , Humanos , Imunização Passiva , Masculino , Camundongos , Camundongos Endogâmicos , Neoplasias Experimentais/induzido quimicamente , Neoplasias Experimentais/imunologia , Neoplasias Experimentais/prevenção & controle , Neoplasias Hormônio-Dependentes/induzido quimicamente , Neoplasias Hormônio-Dependentes/imunologia , Neoplasias Hormônio-Dependentes/prevenção & controle , Ratos , Ratos Endogâmicos , Risco , Esteroides/imunologia , Vacinação/efeitos adversos
7.
ACS Appl Mater Interfaces ; 11(37): 33716-33724, 2019 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-31454227

RESUMO

Immunotherapy has recently garnered significant research interest in the field of clinical cancer management. The potential of tumor immunotherapy has been demonstrated for targeting a variety of tumors, both in vivo and in vitro, yielding some remarkable therapeutic effects. Herein, inspired by the stem cell niche, we developed a scale-up approach to generating porous microspheres with encapsulated natural killer (NK) cells via microfluidic electrospray for in situ tumor immunotherapy. The generated microspheres contained porous microstructures with tunable morphologies because of versatile but precise fluid control in the microfluidic electrospray system. NK-92MI cells encapsulated in porous microspheres were protected from the outer complex environment, allowing for improved proliferation and functionality. As observed, perforin and granzymes were sustainably secreted from the encapsulated NK-92MI cells, which exhibited robust killing effects on tumors both in vitro and in vivo. With continual proliferation, NK-92MI cells budded from the surface of porous microspheres and migrated into the surrounding residual tumor tissues, further destroying tumor cells. More importantly, no side effects owing to the native host immune system were observed by injecting the NK-92MI cell-encapsulated microspheres into tumors in vivo. Therefore, the NK-cell-encapsulated porous microspheres show great potential for tumor immunotherapy, offering a robust and attractive treatment option for cancer patient management.


Assuntos
Células Imobilizadas , Imunidade Celular , Imunoterapia , Células Matadoras Naturais , Microesferas , Neoplasias Experimentais , Animais , Linhagem Celular Tumoral , Células Imobilizadas/imunologia , Células Imobilizadas/patologia , Células Imobilizadas/transplante , Humanos , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/patologia , Células Matadoras Naturais/transplante , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Neoplasias Experimentais/imunologia , Neoplasias Experimentais/terapia , Porosidade
8.
ACS Appl Mater Interfaces ; 11(31): 27536-27547, 2019 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-31294958

RESUMO

Radiotherapy is a traditional method for cancer therapy but may become ineffective likely due to the radiation-induced immunosuppression. Instead of simply increasing the radiation dose, reactivation of immunosuppression in the tumor microenvironment is an alternative strategy for successful cancer treatment. In this work, we synthesized bismuth sulfide nanoparticles (BiNP) and conjugated with immunoactive Ganoderma lucidum polysaccharide (GLP). GLP-BiNP were able to increase the sensitivity of radiotherapy, attributing to the efficient X-ray absorption of bismuth element. BiNP alone can mildly activate dendritic cells (DC) in vitro, while GLP-BiNP further enhanced the level of DC maturation, shown as the increase in phenotypic maturation markers, cytokine release, acid phosphatase activity, and T cell proliferation in DC/T cell co-culture. Compared to BiNP, GLP-BiNP altered the tissue distribution with faster accumulation in the tumor. Meanwhile, mature DC greatly increased in both tumor and spleen by GLP-BiNP within 24 h. GLP-BiNP combination with radiation achieved remarkable inhibition of tumor growth through apoptosis. Alternatively, lung metastasis was largely prohibited by GLP-BiNP, shown as a reduced amount of tumor nodules and cancer cell invasion by pathological findings. Mechanistically, GLP-BiNP altered the tumor immunosuppression microenvironment by preferably increasing the number of intratumor CD8+ T cell proliferation, as well as the improved immunobalance shown as the increased serum interferon-γ/interleukin-4 ratio. Specifically, GLP conjugation seemed to protect the kidney from injury occasionally introduced by bare BiNP. As a result, GLP-BiNP play a dual role in tumor treatment through radiosensitization and immunoactivities.


Assuntos
Bismuto , Células Dendríticas/imunologia , Polissacarídeos Fúngicos , Nanopartículas , Neoplasias Experimentais/imunologia , Neoplasias Experimentais/radioterapia , Radiossensibilizantes , Reishi/química , Sulfetos , Animais , Bismuto/química , Bismuto/farmacologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , Células Dendríticas/patologia , Feminino , Polissacarídeos Fúngicos/química , Polissacarídeos Fúngicos/farmacologia , Imunidade Celular/efeitos dos fármacos , Imunidade Celular/efeitos da radiação , Interferon gama/imunologia , Interleucina-4/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Células NIH 3T3 , Nanopartículas/química , Nanopartículas/uso terapêutico , Neoplasias Experimentais/patologia , Radiossensibilizantes/química , Radiossensibilizantes/farmacologia , Sulfetos/química , Sulfetos/farmacologia
9.
Cancer Immunol Immunother ; 68(8): 1303-1315, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31278476

RESUMO

Our previous work has demonstrated the high efficiency of CD8+ natural killer T (NKT)-like cells in killing antigen-bearing dendritic cells. To evaluate their role in the tumor microenvironment, we performed in vitro and in vivo antitumor experiments to investigate whether CD8+NKT-like cells could kill Yac-1 and B16 cells like NK cells and kill EL4-OVA8 cells in an antigen-specific manner like cytotoxic T lymphocytes (CTLs). Unlike NK1.1-CTLs, CD8+NKT-like cells also exhibit the capability to kill myeloid-derived suppressor cells (MDSCs) in an antigen-specific manner, indicative of their potential role in clearing tumor antigen-bearing MDSCs to improve the antitumor microenvironment. In vitro blocking experiments showed that granzyme B inhibitor efficiently suppressed the cytotoxicity of CD8+NKT-like cells against tumor cells and MDSCs, while Fas ligand (FasL) or tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) inhibition failed to produce similar effects. Transcriptomic and phenotypic analyses of CD8+NKT-like cells, NK cells, and NK1.1-CTLs indicated that CD8+NKT-like cells expressed both T-cell activation markers and NK cell markers, thus bearing features of both the activated T cells and NK cells. Taken together, CD8+NKT-like cells could exert NK- and CTL-like antitumor effects through the elimination of both tumor cells and MDSCs in a granzyme B-dependent manner.


Assuntos
Células Matadoras Naturais/imunologia , Células Supressoras Mieloides/imunologia , Células T Matadoras Naturais/imunologia , Neoplasias Experimentais/terapia , Linfócitos T Citotóxicos/imunologia , Animais , Antígenos CD8/metabolismo , Citotoxicidade Imunológica , Feminino , Granzimas/metabolismo , Humanos , Ativação Linfocitária , Melanoma Experimental , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neoplasias Experimentais/imunologia , Transcriptoma , Microambiente Tumoral
10.
Immunity ; 51(2): 381-397.e6, 2019 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-31350177

RESUMO

Regulatory T (Treg) cells are crucial for immune homeostasis, but they also contribute to tumor immune evasion by promoting a suppressive tumor microenvironment (TME). Mice with Treg cell-restricted Neuropilin-1 deficiency show tumor resistance while maintaining peripheral immune homeostasis, thereby providing a controlled system to interrogate the impact of intratumoral Treg cells on the TME. Using this and other genetic models, we showed that Treg cells shaped the transcriptional landscape across multiple tumor-infiltrating immune cell types. Treg cells suppressed CD8+ T cell secretion of interferon-γ (IFNγ), which would otherwise block the activation of sterol regulatory element-binding protein 1 (SREBP1)-mediated fatty acid synthesis in immunosuppressive (M2-like) tumor-associated macrophages (TAMs). Thus, Treg cells indirectly but selectively sustained M2-like TAM metabolic fitness, mitochondrial integrity, and survival. SREBP1 inhibition augmented the efficacy of immune checkpoint blockade, suggesting that targeting Treg cells or their modulation of lipid metabolism in M2-like TAMs could improve cancer immunotherapy.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Macrófagos/metabolismo , Melanoma/imunologia , Neoplasias Experimentais/imunologia , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Linfócitos T Reguladores/imunologia , Animais , Carcinogênese , Diferenciação Celular , Ácidos Graxos/metabolismo , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Evasão da Resposta Imune , Interferon gama/metabolismo , Macrófagos/imunologia , Melanoma Experimental , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neuropilina-1/genética , Células Th2/imunologia , Microambiente Tumoral
11.
Cancer Immunol Immunother ; 68(8): 1273-1286, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31243491

RESUMO

Therapeutic cancer vaccines have met limited clinical success. In the setting of cancer, the immune system is either tolerized and/or has a limited tumor-specific T cell repertoire. In this study, we explore whether intratumoral (IT) vaccination with an HPV vaccine can elicit quantitative and qualitative differences in immune response as compared to intramuscular (IM) vaccination to overcome immune resistance in established tumors. We report that IT administration of an HPV-16 E7 peptide vaccine formulated with polyinosinic-polycytidylic acid [poly(I:C)] generated an enhanced antitumor effect relative to IM delivery. The elicited anti-tumor effect with IT vaccination was consistent among the vaccinated groups and across various C57BL/6 substrains. IT vaccination resulted in an increased frequency of PD-1hi TILs, which represented both vaccine-targeted and non-vaccine-targeted tumor-specific CD8+ T cells. Overall, the CD8+/Treg ratio was increased within the tumor microenvironment using IT vaccination. We also assessed transcriptional changes in several immune-related genes in the tumor microenvironment of the various treated groups, and our data suggest that IT vaccination leads to upregulation of a broad complement of immunomodulatory genes, including upregulation of interferon gamma (IFNγ) and antigen presentation and processing machine (APM) components. IT vaccine delivery is superior to traditional IM vaccination routes with the potential to improve tumor immunogenicity, which has potential clinical application in the setting of accessible lesions such as head and neck squamous cell carcinomas (HNSCCs).


Assuntos
Linfócitos T CD8-Positivos/imunologia , Carcinoma de Células Escamosas/terapia , Neoplasias de Cabeça e Pescoço/terapia , Linfócitos do Interstício Tumoral/imunologia , Neoplasias Experimentais/imunologia , Proteínas E7 de Papillomavirus/imunologia , Vacinas contra Papillomavirus/imunologia , Linfócitos T Reguladores/imunologia , Animais , Apresentação do Antígeno/genética , Vacinas Anticâncer/imunologia , Carcinoma de Células Escamosas/imunologia , Células Cultivadas , Citotoxicidade Imunológica , Regulação Neoplásica da Expressão Gênica , Neoplasias de Cabeça e Pescoço/imunologia , Humanos , Imunidade Celular/genética , Injeções Intramusculares , Interferon gama/genética , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos C57BL , Poli I-C/imunologia , Receptor de Morte Celular Programada 1/metabolismo , Vacinação
12.
Cancer Immunol Immunother ; 68(7): 1133-1141, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31139925

RESUMO

Advanced oral squamous cell carcinomas (OSCC) have limited therapeutic options. Although immune therapies are emerging as a potentially effective alternative or adjunct to chemotherapies, the therapeutic efficacy of combination immune chemotherapies has yet to be determined. Using a 4-nitroquinolone-N-oxide (4NQO) orthotopic model of OSCC in immunocompetent mice, we evaluated the therapeutic efficacy of single- and combined-agent treatment with a poly-epitope tumor peptide vaccine, cisplatin and/or an A2AR inhibitor, ZM241385. The monotherapies or their combinations resulted in a partial inhibition of tumor growth and, in some cases, a significant but transient upregulation of systemic anti-tumor CD8+ T cell responses. These responses eroded in the face of expanding immunoregulatory cell populations at later stages of tumor progression. Our findings support the need for the further development of combinatorial therapeutic approaches that could more effectively silence dominant immune inhibitory pathways operating in OSCC and provide novel, more beneficial treatment options for this tumor.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Vacinas Anticâncer/uso terapêutico , Imunoterapia/métodos , Neoplasias Bucais/terapia , Neoplasias Experimentais/terapia , Carcinoma de Células Escamosas de Cabeça e Pescoço/terapia , 4-Nitroquinolina-1-Óxido/toxicidade , Animais , Cisplatino/uso terapêutico , Terapia Combinada/métodos , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Neoplasias Bucais/induzido quimicamente , Neoplasias Bucais/imunologia , Neoplasias Bucais/patologia , Neoplasias Experimentais/induzido quimicamente , Neoplasias Experimentais/imunologia , Neoplasias Experimentais/patologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/induzido quimicamente , Carcinoma de Células Escamosas de Cabeça e Pescoço/imunologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Resultado do Tratamento , Triazinas/uso terapêutico , Triazóis/uso terapêutico , Vacinas de Subunidades/uso terapêutico
13.
J Immunol ; 202(10): 3087-3102, 2019 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-30971441

RESUMO

Inflammatory monocytes have been shown to play key roles in cancer metastasis through promotion of tumor cell extravasation, growth, and angiogenesis. Monocyte recruitment to metastases is mediated primarily via the CCL2-CCR2 chemotactic axis. Thus, disruption of this axis represents an attractive therapeutic target for the treatment of metastatic disease. Losartan, a type I angiotensin II receptor (AT1R) antagonist, has been previously shown to have immunomodulatory actions involving monocyte and macrophage activity. However, the exact mechanisms accounting for these effects have not been fully elucidated. Therefore, we investigated the effects of losartan and its primary metabolite on CCL2-mediated monocyte recruitment and CCR2 receptor function using mouse tumor models and in vitro human monocyte cultures. We show, in this study, that losartan and its metabolite potently inhibit monocyte recruitment through the noncompetitive inhibition of CCL2-induced ERK1/2 activation, independent of AT1R activity. Studies in experimental metastasis models demonstrated that losartan treatment significantly reduced the metastatic burden in mice, an effect associated with a significant decrease in CD11b+/Ly6C+-recruited monocytes in the lungs. Collectively, these results indicate that losartan can exert antimetastatic activity by inhibiting CCR2 signaling and suppressing monocyte recruitment and therefore suggest that losartan (and potentially other AT1R blocker drugs) could be repurposed for use in cancer immunotherapy.


Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Losartan/farmacologia , Neoplasias Pulmonares , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Monócitos/imunologia , Proteínas de Neoplasias/imunologia , Neoplasias Experimentais , Receptor Tipo 1 de Angiotensina/imunologia , Receptores CCR2/imunologia , Animais , Linhagem Celular Tumoral , Feminino , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/secundário , Sistema de Sinalização das MAP Quinases/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos ICR , Camundongos Knockout , Monócitos/patologia , Metástase Neoplásica , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/imunologia , Neoplasias Experimentais/patologia
14.
Immunity ; 50(4): 851-870, 2019 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-30995503

RESUMO

The discovery of interleukin (IL)-6 and its receptor subunits provided a foundation to understand the biology of a group of related cytokines: IL-12, IL-23, and IL-27. These family members utilize shared receptors and cytokine subunits and influence the outcome of cancer, infection, and inflammatory diseases. Consequently, many facets of their biology are being therapeutically targeted. Here, we review the landmark discoveries in this field, the combinatorial biology inherent to this family, and how patient datasets have underscored the critical role of these pathways in human disease. We present significant knowledge gaps, including how similar signals from these cytokines can mediate distinct outcomes, and discuss how a better understanding of the biology of the IL-12 family provides new therapeutic opportunities.


Assuntos
Citocinas/imunologia , Interleucina-12/imunologia , Família Multigênica/imunologia , Animais , Doenças Autoimunes/imunologia , Doenças Autoimunes/terapia , Citocinas/antagonistas & inibidores , Citocinas/genética , Humanos , Imunidade Celular , Inflamação/imunologia , Interleucina-12/antagonistas & inibidores , Interleucina-12/genética , Interleucina-27/uso terapêutico , Subpopulações de Linfócitos/imunologia , Linfopoese , Camundongos , Camundongos Knockout , Família Multigênica/genética , Neoplasias Experimentais/imunologia , Neoplasias Experimentais/terapia , Subunidades Proteicas , Relação Estrutura-Atividade
15.
MAbs ; 11(4): 681-690, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30892132

RESUMO

Monoclonal antibody (mAb)-based blockade of programmed cell death 1 (PD-1) or its ligand to enable antitumor T-cell immunity has been successful in treating multiple tumors. However, the structural basis of the binding mechanisms of the mAbs and PD-1 and the effects of glycosylation of PD-1 on mAb interaction are not well understood. Here, we report the complex structure of PD-1 with toripalimab, a mAb that is approved by China National Medical Products Administration as a second-line treatment for melanoma and is under multiple Phase 1-Phase 3 clinical trials in both China and the US. Our analysis reveals that toripalimab mainly binds to the FG loop of PD-1 with an unconventionally long complementarity-determining region 3 loop of the heavy chain, which is distinct from the known binding epitopes of anti-PD-1 mAbs with structural evidences. The glycan modifications of PD-1 could be observed in three potential N-linked glycosylation sites, while no substantial influences were detected to the binding of toripalimab. These findings benefit our understanding of the binding mechanisms of toripalimab to PD-1 and shed light for future development of biologics targeting PD-1. Atomic coordinates have been deposited in the Protein Data Bank under accession code 6JBT.


Assuntos
Anticorpos Monoclonais Humanizados/metabolismo , Anticorpos Monoclonais/metabolismo , Epitopos/metabolismo , Imunoterapia/métodos , Melanoma/terapia , Neoplasias Experimentais/terapia , Receptor de Morte Celular Programada 1/metabolismo , Animais , Anticorpos Monoclonais/genética , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados/genética , Anticorpos Monoclonais Humanizados/uso terapêutico , Antígeno B7-H1/metabolismo , Linhagem Celular Tumoral , Regiões Determinantes de Complementaridade/genética , Epitopos/genética , Glicosilação , Humanos , Melanoma/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Neoplasias Experimentais/imunologia , Receptor de Morte Celular Programada 1/imunologia , Ligação Proteica
16.
Int Immunopharmacol ; 71: 224-232, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30925323

RESUMO

Immune escape is the final phase of the cancer immunoediting process. Researchers have found that cancer induces immune escape by inhibiting the expression of CD40L. The purpose of the present study was to select a high affinity CD40 single chain variable fragment (ScFv) and to evaluate its effect on tumor-specific immune activation. One Wistar rat was immunized with mouse CD40 antigen. CD40 ScFv with high affinity was constructed by overlap extension-polymerase chain reaction (SOE-PCR) and screened by three rounds of phage display. CD40 ScFv protein was expressed by the pET28a (+)-Rosetta prokaryotic expression system and purified using a nickel-nitrilotriacetic acid (Ni-NTA) column. CD40 ScFv significantly upregulated CD80, CD86, and MHC-II in vitro expression in dendritic cells (DCs) and upregulated the expression of IL-12 (p70) based on ELISA results. Cell counting kit-8 (CCK-8) results indicated that T lymphocytes were stimulated by DCs in an Ag + CD40 ScFv group, which also inhibited the proliferation of immortalized T6-17 cells. In an in vivo assay, 1 × 106 T6-17 cells were subcutaneously injected into BALB/c mice in the hind flank. Tumor volume curves showed that CD40 ScFv exhibited a remarkable inhibition of tumor proliferation after 15 days of treatment. Hematoxylin-eosin (H&E) staining of tumor tissues indicated that CD40 ScFv enhanced lymphocyte infiltration, which remarkably inhibited the proliferation of T6-17 cells. Furthermore, immunohistochemistry (IHC) staining revealed that caspase-3 was abundantly expressed in the T6-17 cytoplasm after CD40 ScFv treatment. In conclusion, this study revealed that high affinity CD40 ScFv could be screened by phage display and had a significant stimulating effect on DCs and inhibited the proliferation of T6-17 cells in vivo and in vitro.


Assuntos
Antígenos CD40/imunologia , Técnicas de Visualização da Superfície Celular/métodos , Células Dendríticas/imunologia , Imunoterapia/métodos , Neoplasias Experimentais/terapia , Anticorpos de Cadeia Única/metabolismo , Linfócitos T/imunologia , Animais , Antígenos CD40/metabolismo , Diferenciação Celular , Linhagem Celular Tumoral , Proliferação de Células , Feminino , Humanos , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos BALB C , Neoplasias Experimentais/imunologia , Ratos , Ratos Wistar , Anticorpos de Cadeia Única/genética , Carga Tumoral , Evasão Tumoral
17.
PLoS One ; 14(3): e0212670, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30913212

RESUMO

Immunotherapy has fundamentally changed the landscape of cancer treatment. Despite the encouraging results with the checkpoint modulators, response rates vary widely across tumor types, with a majority of patients exhibiting either primary resistance without a significant initial response to treatment or acquired resistance with subsequent disease progression. Hematopoietic progenitor kinase 1 (HPK1) is predominantly expressed in hematopoietic cell linages and serves as a negative regulator in T cells and dendritic cells (DC). While HPK1 gene knockout (KO) studies suggest its role in anti-tumor immune responses, the involvement of kinase activity and thereof its therapeutic potential remain unknown. To investigate the potential of pharmacological intervention using inhibitors of HPK1, we generated HPK1 kinase dead (KD) mice which carry a single loss-of-function point mutation in the kinase domain and interrogated the role of kinase activity in immune cells in the context of suppressive factors or the tumor microenvironment (TME). Our data provide novel findings that HKP1 kinase activity is critical in conferring suppressive functions of HPK1 in a wide range of immune cells including CD4+, CD8+, DC, NK to Tregs, and inactivation of kinase domain was sufficient to elicit robust anti-tumor immune responses. These data support the concept that an HPK1 small molecule kinase inhibitor could serve as a novel agent to provide additional benefit in combination with existing immunotherapies, particularly to overcome resistance to current treatment regimens.


Assuntos
Imunidade Celular , Vigilância Imunológica , Linfócitos/imunologia , Neoplasias Experimentais/imunologia , Proteínas Serina-Treonina Quinases/imunologia , Microambiente Tumoral/imunologia , Animais , Linhagem Celular Tumoral , Linfócitos/patologia , Camundongos , Camundongos Mutantes , Neoplasias Experimentais/genética , Mutação Puntual , Proteínas Serina-Treonina Quinases/genética , Microambiente Tumoral/genética
18.
Immunity ; 50(2): 493-504.e7, 2019 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-30737144

RESUMO

Non-lymphoid tissues (NLTs) harbor a pool of adaptive immune cells with largely unexplored phenotype and development. We used single-cell RNA-seq to characterize 35,000 CD4+ regulatory (Treg) and memory (Tmem) T cells in mouse skin and colon, their respective draining lymph nodes (LNs) and spleen. In these tissues, we identified Treg cell subpopulations with distinct degrees of NLT phenotype. Subpopulation pseudotime ordering and gene kinetics were consistent in recruitment to skin and colon, yet the initial NLT-priming in LNs and the final stages of NLT functional adaptation reflected tissue-specific differences. Predicted kinetics were recapitulated using an in vivo melanoma-induction model, validating key regulators and receptors. Finally, we profiled human blood and NLT Treg and Tmem cells, and identified cross-mammalian conserved tissue signatures. In summary, we describe the relationship between Treg cell heterogeneity and recruitment to NLTs through the combined use of computational prediction and in vivo validation.


Assuntos
Adaptação Fisiológica/imunologia , Análise de Célula Única/métodos , Linfócitos T Reguladores/imunologia , Transcriptoma/imunologia , Adaptação Fisiológica/genética , Animais , Linhagem Celular Tumoral , Movimento Celular/genética , Movimento Celular/imunologia , Colo/imunologia , Colo/metabolismo , Humanos , Memória Imunológica/genética , Memória Imunológica/imunologia , Tecido Linfoide/imunologia , Tecido Linfoide/metabolismo , Camundongos Transgênicos , Neoplasias Experimentais/genética , Neoplasias Experimentais/imunologia , Neoplasias Experimentais/patologia , Pele/imunologia , Pele/metabolismo , Baço/imunologia , Baço/metabolismo , Linfócitos T Reguladores/metabolismo
19.
Immunity ; 50(2): 477-492.e8, 2019 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-30737146

RESUMO

Resistance to checkpoint-blockade treatments is a challenge in the clinic. We found that although treatment with combined anti-CTLA-4 and anti-PD-1 improved control of established tumors, this combination compromised anti-tumor immunity in the low tumor burden (LTB) state in pre-clinical models as well as in melanoma patients. Activated tumor-specific T cells expressed higher amounts of interferon-γ (IFN-γ) receptor and were more susceptible to apoptosis than naive T cells. Combination treatment induced deletion of tumor-specific T cells and altered the T cell repertoire landscape, skewing the distribution of T cells toward lower-frequency clonotypes. Additionally, combination therapy induced higher IFN-γ production in the LTB state than in the high tumor burden (HTB) state on a per-cell basis, reflecting a less exhausted immune status in the LTB state. Thus, elevated IFN-γ secretion in the LTB state contributes to the development of an immune-intrinsic mechanism of resistance to combination checkpoint blockade, highlighting the importance of achieving the optimal magnitude of immune stimulation for successful combination immunotherapy strategies.


Assuntos
Anticorpos Monoclonais/farmacologia , Antígeno CTLA-4/antagonistas & inibidores , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Interferon gama/farmacologia , Neoplasias Experimentais/tratamento farmacológico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Linfócitos T/efeitos dos fármacos , Animais , Anticorpos Monoclonais/imunologia , Antígeno CTLA-4/imunologia , Antígeno CTLA-4/metabolismo , Linhagem Celular Tumoral , Deleção Clonal/efeitos dos fármacos , Deleção Clonal/imunologia , Resistencia a Medicamentos Antineoplásicos/imunologia , Humanos , Interferon gama/imunologia , Interferon gama/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neoplasias Experimentais/imunologia , Neoplasias Experimentais/metabolismo , Receptor de Morte Celular Programada 1/imunologia , Receptor de Morte Celular Programada 1/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo , Carga Tumoral/efeitos dos fármacos , Carga Tumoral/imunologia
20.
Nat Immunol ; 20(3): 257-264, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30778250

RESUMO

Post-translational modification of chemokines mediated by the dipeptidyl peptidase DPP4 (CD26) has been shown to negatively regulate lymphocyte trafficking, and its inhibition enhances T cell migration and tumor immunity by preserving functional chemokine CXCL10. By extending those initial findings to pre-clinical models of hepatocellular carcinoma and breast cancer, we discovered a distinct mechanism by which inhibition of DPP4 improves anti-tumor responses. Administration of the DPP4 inhibitor sitagliptin resulted in higher concentrations of the chemokine CCL11 and increased migration of eosinophils into solid tumors. Enhanced tumor control was preserved in mice lacking lymphocytes and was ablated after depletion of eosinophils or treatment with degranulation inhibitors. We further demonstrated that tumor-cell expression of the alarmin IL-33 was necessary and sufficient for eosinophil-mediated anti-tumor responses and that this mechanism contributed to the efficacy of checkpoint-inhibitor therapy. These findings provide insight into IL-33- and eosinophil-mediated tumor control, revealed when endogenous mechanisms of DPP4 immunoregulation are inhibited.


Assuntos
Dipeptidil Peptidase 4/imunologia , Eosinófilos/imunologia , Interleucina-33/imunologia , Neoplasias Experimentais/imunologia , Animais , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Movimento Celular/imunologia , Quimiocina CCL11/imunologia , Quimiocina CCL11/metabolismo , Dipeptidil Peptidase 4/metabolismo , Inibidores da Dipeptidil Peptidase IV/farmacologia , Modelos Animais de Doenças , Eosinófilos/efeitos dos fármacos , Eosinófilos/metabolismo , Humanos , Interleucina-33/metabolismo , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/prevenção & controle , Fosfato de Sitagliptina/farmacologia
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