RESUMO
OBJECTIVE: Gut microbiota is a key player in dictating immunotherapy response. We aimed to explore the immunomodulatory effect of probiotic Lactobacillus gallinarum and its role in improving anti-programmed cell death protein 1 (PD1) efficacy against colorectal cancer (CRC). DESIGN: The effects of L. gallinarum in anti-PD1 response were assessed in syngeneic mouse models and azoxymethane/dextran sulfate sodium-induced CRC model. The change of immune landscape was identified by multicolour flow cytometry and validated by immunohistochemistry staining and in vitro functional assays. Liquid chromatography-mass spectrometry was performed to identify the functional metabolites. RESULTS: L. gallinarum significantly improved anti-PD1 efficacy in two syngeneic mouse models with different microsatellite instability (MSI) statuses (MSI-high for MC38, MSI-low for CT26). Such effect was confirmed in CRC tumourigenesis model. L. gallinarum synergised with anti-PD1 therapy by reducing Foxp3+ CD25+ regulatory T cell (Treg) intratumoural infiltration, and enhancing effector function of CD8+ T cells. L. gallinarum-derived indole-3-carboxylic acid (ICA) was identified as the functional metabolite. Mechanistically, ICA inhibited indoleamine 2,3-dioxygenase (IDO1) expression, therefore suppressing kynurenine (Kyn) production in tumours. ICA also competed with Kyn for binding site on aryl hydrocarbon receptor (AHR) and antagonised Kyn binding on CD4+ T cells, thereby inhibiting Treg differentiation in vitro. ICA phenocopied L. gallinarum effect and significantly improved anti-PD1 efficacy in vivo, which could be reversed by Kyn supplementation. CONCLUSION: L. gallinarum-derived ICA improved anti-PD1 efficacy in CRC through suppressing CD4+Treg differentiation and enhancing CD8+T cell function by modulating the IDO1/Kyn/AHR axis. L. gallinarum is a potential adjuvant to augment anti-PD1 efficacy against CRC.
Assuntos
Neoplasias Colorretais , Inibidores de Checkpoint Imunológico , Cinurenina , Lactobacillus , Animais , Camundongos , Linfócitos T CD8-Positivos , Neoplasias Colorretais/tratamento farmacológico , Cinurenina/metabolismo , Receptores de Hidrocarboneto Arílico/efeitos dos fármacos , Receptores de Hidrocarboneto Arílico/metabolismo , Linfócitos T Reguladores , Lactobacillus/química , Receptor de Morte Celular Programada 1/efeitos dos fármacos , Receptor de Morte Celular Programada 1/imunologia , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Lisados Bacterianos/farmacologia , Lisados Bacterianos/uso terapêuticoRESUMO
BACKGROUND: Neoadjuvant chemotherapy and radiation followed by surgical resection of the rectum is a standard treatment for locally advanced rectal cancer. A subset of rectal cancer is caused by a deficiency in mismatch repair. Because mismatch repair-deficient colorectal cancer is responsive to programmed death 1 (PD-1) blockade in the context of metastatic disease, it was hypothesized that checkpoint blockade could be effective in patients with mismatch repair-deficient, locally advanced rectal cancer. METHODS: We initiated a prospective phase 2 study in which single-agent dostarlimab, an anti-PD-1 monoclonal antibody, was administered every 3 weeks for 6 months in patients with mismatch repair-deficient stage II or III rectal adenocarcinoma. This treatment was to be followed by standard chemoradiotherapy and surgery. Patients who had a clinical complete response after completion of dostarlimab therapy would proceed without chemoradiotherapy and surgery. The primary end points are sustained clinical complete response 12 months after completion of dostarlimab therapy or pathological complete response after completion of dostarlimab therapy with or without chemoradiotherapy and overall response to neoadjuvant dostarlimab therapy with or without chemoradiotherapy. RESULTS: A total of 12 patients have completed treatment with dostarlimab and have undergone at least 6 months of follow-up. All 12 patients (100%; 95% confidence interval, 74 to 100) had a clinical complete response, with no evidence of tumor on magnetic resonance imaging, 18F-fluorodeoxyglucose-positron-emission tomography, endoscopic evaluation, digital rectal examination, or biopsy. At the time of this report, no patients had received chemoradiotherapy or undergone surgery, and no cases of progression or recurrence had been reported during follow-up (range, 6 to 25 months). No adverse events of grade 3 or higher have been reported. CONCLUSIONS: Mismatch repair-deficient, locally advanced rectal cancer was highly sensitive to single-agent PD-1 blockade. Longer follow-up is needed to assess the duration of response. (Funded by the Simon and Eve Colin Foundation and others; ClinicalTrials.gov number, NCT04165772.).
Assuntos
Antineoplásicos , Segunda Neoplasia Primária , Neoplasias Retais , Anticorpos Monoclonais Humanizados , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Quimiorradioterapia/efeitos adversos , Reparo de Erro de Pareamento de DNA , Humanos , Terapia Neoadjuvante/métodos , Estadiamento de Neoplasias , Segunda Neoplasia Primária/patologia , Receptor de Morte Celular Programada 1/efeitos dos fármacos , Estudos Prospectivos , Neoplasias Retais/genética , Neoplasias Retais/terapia , Reto/patologia , Resultado do TratamentoRESUMO
Pulmonary fibrosis induced by silica particles is defined as silicosis, which is an incurable disease. The pathogenesis of silicosis is not completely clear, but it's certain that immune system dysfunction is closely related to it. Immune checkpoint inhibitors (ICIs) are emerging immunotherapeutic agents that mainly target adaptive immune cells, and there is abundant evidence that ICIs are of great value in cancer treatment. However, whether these attractive agents can be implemented in silicosis treatment is unclear. In this study, we explored the efficacy of small molecule inhibitors targeted PD-1/PD-L1 and CTLA-4 on silica-induced pulmonary fibrosis in mice. ICIs were injected intraperitoneally into mice that received silica instillation twice a week. The mice were sacrificed 7 and 28 days after the injection. The lungs, spleen, hilar lymph nodes, thymus, and peripheral blood of mice were collected and subjected to histological examination, flow cytometry analysis, and mRNA and protein quantification. Our results demonstrated that silica exposure caused damage to multiple immune organs in mice, leading to an imbalance in systemic immune homeostasis. Specifically, proportions and subtypes of T and B cells were significantly altered, and the expressions of PD-1, PD-L1 and CTLA-4 were abnormal on these cells. Both PD-1/PD-L1 and CTLA-4 inhibitor administration modulated silica-induced immune system disruption, however, only PD-1/PD-L1 signaling inhibition showed significant amelioration of silicosis. Our findings confirmed for the first time the potential value of ICIs for the treatment of silica-induced pulmonary fibrosis, and this may provide new ideas for the treatment of other fibrosis-related diseases.
Assuntos
Inibidores de Checkpoint Imunológico/farmacologia , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/patologia , Dióxido de Silício/efeitos adversos , Animais , Subpopulações de Linfócitos B/efeitos dos fármacos , Antígeno B7-H1/efeitos dos fármacos , Antígeno CTLA-4/efeitos dos fármacos , Homeostase/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Insuficiência de Múltiplos Órgãos/induzido quimicamente , Insuficiência de Múltiplos Órgãos/patologia , Receptor de Morte Celular Programada 1/efeitos dos fármacos , RNA Mensageiro , Subpopulações de Linfócitos T/efeitos dos fármacosRESUMO
BACKGROUND: Immune checkpoint inhibitors prolong the survival of non-small cell lung cancer (NSCLC) patients. Although it has been acknowledged that there is some correlation between the efficacy of anti-programmed cell death-1 (PD-1) antibody therapy and immunohistochemical analysis, this technique is not yet considered foolproof for predicting a favorable outcome of PD-1 antibody therapy. We aimed to predict the efficacy of nivolumab based on a comprehensive analysis of RNA expression at the gene level in advanced NSCLC. METHODS: This was a retrospective study on patients with NSCLC who were administered nivolumab at the Kansai Medical University Hospital. To identify genes associated with response to anti-PD-1 antibodies, we grouped patients into responders (complete and partial response) and non-responders (stable and progressive disease) to nivolumab therapy. Significant genes were then identified for these groups using Welch's t-test. RESULTS: Among 42 analyzed cases (20 adenocarcinomas and 22 squamous cell carcinomas), enhanced expression of MAGE-A4, BBC3, and OTOA genes was observed in responders with adenocarcinoma, and enhanced expression of DAB2, HLA-DPB,1 and CDH2 genes was observed in responders with squamous cell carcinoma. CONCLUSIONS: This study predicted the efficacy of nivolumab based on a comprehensive analysis of mRNA expression at the gene level in advanced NSCLC. We also revealed different gene expression patterns as predictors of the effectiveness of anti PD-1 antibody therapy in adenocarcinoma and squamous cell carcinoma.
Assuntos
Adenocarcinoma/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma de Células Escamosas/tratamento farmacológico , Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Nivolumabe/uso terapêutico , Proteínas Adaptadoras de Transdução de Sinal/imunologia , Adenocarcinoma/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos CD/imunologia , Antígenos de Neoplasias/imunologia , Proteínas Reguladoras de Apoptose/imunologia , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/imunologia , Caderinas/imunologia , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma de Células Escamosas/imunologia , Resistencia a Medicamentos Antineoplásicos/genética , Resistencia a Medicamentos Antineoplásicos/imunologia , Feminino , Proteínas Ligadas por GPI/imunologia , Expressão Gênica/efeitos dos fármacos , Expressão Gênica/imunologia , Cadeias beta de HLA-DP/imunologia , Humanos , Neoplasias Pulmonares/imunologia , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/imunologia , Valor Preditivo dos Testes , Receptor de Morte Celular Programada 1/efeitos dos fármacos , Receptor de Morte Celular Programada 1/imunologia , Proteínas Proto-Oncogênicas/imunologia , RNA Mensageiro/efeitos dos fármacos , RNA Mensageiro/imunologia , Estudos Retrospectivos , Resultado do TratamentoRESUMO
In recent years, immune-based therapies have emerged as novel pillars for hepatocellular carcinoma (HCC). The rationale of immune-checkpoint inhibitors (ICIs) trial in HCC originated from the fact that the tumor cells and the infiltrating stromal and immune cells promote an immunosuppressive tumor microenvironment, including the up-regulation of immune checkpoint molecules on their surface. Antibody-based blockage targeting inhibitory checkpoint molecules on cytotoxic T cells, including programmed cell death-1 (PD-1) or its counterpart on antigen-presenting cells has shown strong anti-tumor activity in a subset of HCC patients. Single nucleotide polymorphisms (SNP) of PD-1 gene may affect the PD-1 expression or function, which eventually can cause dysfunctionality of immune balance. Based on the inhibitory role of PD-1 in anti-tumor responses, it has been investigated in several studies as a candidate to test for genetic susceptibility of individuals to HCC. The present paper highlights the knowledge on cross-talks for liver immunology and HCC course, recent studies investigating the role of functional SNPs of PD-1 gene in Turkish HCC population, and the data on already investigated PD-1 inhibitor molecules in clinical trials.
Assuntos
Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/genética , Inibidores de Checkpoint Imunológico/farmacologia , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genética , Receptor de Morte Celular Programada 1/genética , Apoptose , Carcinoma Hepatocelular/patologia , Humanos , Imunoterapia , Neoplasias Hepáticas/patologia , Polimorfismo de Nucleotídeo Único , Receptor de Morte Celular Programada 1/efeitos dos fármacos , TurquiaRESUMO
Importance: Microsatellite stable (MSS) metastatic colorectal cancer has been historically characterized as resistant to immunotherapy. Recent studies have demonstrated limited clinical activity of programmed cell death receptor 1/programmed death ligand 1 (PD-1/PD-L1) targeting in MSS metastatic colorectal cancer. The association of metastatic disease in the liver with treatment response has not been fully investigated. Objective: To investigate the association of liver metastases with response to PD-1/PD-L1-targeting therapy in MSS metastatic colorectal cancer. Design, Setting, and Participants: This single-center retrospective cohort study evaluated clinical responses to PD-1- or PD-L1-targeting therapy, with or without other investigational agents, in patients with MSS metastatic colorectal cancer and disease progression after standard of care therapy from January 1, 2014, to December 31, 2020. Main Outcomes and Measures: Objective response rate (ORR) and progression-free survival (PFS), measured from initiation of PD-1/PD-L1-targeting therapy. Results: Ninety-five patients with MSS metastatic colorectal cancer were identified (54 men [56.8%]; median age, 55 [interquartile range (IQR), 49-64] years). The overall ORR was 8.4% (8 of 95 patients). Eight of 41 patients without liver metastases achieved an ORR of 19.5%, and no response was observed in 54 patients with liver metastases. The disease control rate was 58.5% (24 of 41) in patients without liver metastasis and 1.9% (1 of 54) in patients with liver metastasis. Patients without liver metastases at the time of PD-1/PD-L1-targeting treatment had a superior median PFS compared with patients with liver metastases (4.0 [IQR, 2.0-7.5] vs 1.5 [IQR, 1.0-2.0] months; P < .001). In addition, median PFS was 5.5 (IQR, 2.0-11.5) months for patients without any prior or current liver involvement at the time of PD-1/PD-L1-targeting treatment initiation. Using a multivariate Cox regression model correcting for Eastern Cooperative Oncology Group status, primary tumor location, RAS and BRAF status, tumor mutation burden, and metastatic sites, liver metastases was the variable with the most significant association with faster progression after PD-1/PD-L1 treatment inhibition (hazard ratio, 7.00; 95% CI, 3.18-15.42; P < .001). Conclusions and Relevance: Findings of this cohort study suggest that patients with MSS metastatic colorectal cancer and without liver metastases may derive clinical benefits from checkpoint inhibitors, whereas the presence of liver metastases was associated with resistance. Further prospective studies are needed to investigate PD-1/PD-L1 inhibitors in patients with MSS metastatic colorectal cancer without liver metastases.
Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Antígeno B7-H1/efeitos dos fármacos , Neoplasias Colorretais/tratamento farmacológico , Imunoterapia/métodos , Neoplasias Hepáticas/tratamento farmacológico , Receptor de Morte Celular Programada 1/efeitos dos fármacos , Idoso , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Resistencia a Medicamentos Antineoplásicos/imunologia , Feminino , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/secundário , Masculino , Repetições de Microssatélites/efeitos dos fármacos , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Resultado do Tratamento , Carga Tumoral/imunologiaRESUMO
Immunotherapy with checkpoint inhibitors - monoclonal antibodies targeting cytotoxic T lymphocyte-associated antigen 4 (CTLA4) or the programmed death-1 receptor (PD-1) and its ligand PD-L1 - is now standard of care in the treatment of patients with various tumor types. Therefore, the management of immune-related adverse events (irAEs) has become part of clinical routine.Immune-related adverse events can involve any organ or tissue. They can occur very early within days or weeks after initiation of treatment but can also occur months into treatment and after termination of treatment. Newest data suggest that irAEs can occur until 2 years after stopping therapy.Immune-related adverse events are graded according to Common Terminology Criteria for Adverse Events (CTCAE). Treatment ranges from local or symptomatic treatment, systemic application of corticosteroids to other immunosuppressive agents according to severity.The following article seeks to give a general approach to the management of patients receiving immunotherapy and experiencing irAEs including prevention, diagnostics and treatment.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Antineoplásicos Imunológicos/efeitos adversos , Antígeno CTLA-4/efeitos dos fármacos , Imunoterapia/efeitos adversos , Neoplasias/terapia , Receptor de Morte Celular Programada 1/efeitos dos fármacos , Humanos , Padrão de CuidadoRESUMO
Carbon nanotubes (CNTs), as advanced nanotechnology with specific properties and structures, have presented practical drug delivery properties. Ginsenoside Rg3 is a component of puffed ginseng and demonstrates anti-cancer activities. To explore the effect of CNTs-loaded Rg3 (Rg3-CNT) on the PD-1/PD-L1 signaling and the development of triple-negative breast cancer (TNBC). Our data revealed that Rg3 inhibited the cell viability of TNBC cells, in which Rg3-CNT further enhanced this effect in the system. Similarly, the colony formation of TNBC cells was decreased by Rg3, while Rg3-CNT could reinforce its effect in the cells. Besides, the treatment of Rg3 induced apoptosis of TNBC cells, in which Rg3-CNT treatment further increased the phenotype in the cells. Remarkably, Rg3-CNT, but not Rg3, attenuated PD-L1 expression in TNBC cells. Rg3-CNT decreased the PD-L1 upregulation induced by interferon-γ (IFN-γ) in breast cancer cells. Importantly, Rg3-CNT was able to reduce PD-1 expression in activated T cells. Specifically, Rg3-CNT reduced the PD-1/PD-L1 axis in a T cell/triple-negative TNBC cell co-culture system. Moreover, the levels of IFN-γ, interleukins-2 (IL-2), interleukins-9 (IL-9), interleukins-10 (IL-10), interleukins-22 (IL-22), and interleukins-23 (IL-23) were significantly stimulated in the activated T cells, while the treatment of Rg3-CNT could reverse these phenotypes in the cells. Rg3-CNT attenuated the TNBC cell growth in vivo. The Rg3-CNT improved the anti-cancer effect of Rg3 toward TNBC by inhibiting the PD-1/PD-L1 axis. Our finding provides new insights into the mechanism by which Rg3-CNT attenuates the development of TNBC. Rg3-CNT may be applied as the potential therapeutic strategy for immunotherapy of TNBC.
Assuntos
Antineoplásicos Fitogênicos/administração & dosagem , Antineoplásicos Fitogênicos/farmacologia , Antígeno B7-H1/efeitos dos fármacos , Neoplasias da Mama/tratamento farmacológico , Ginsenosídeos/administração & dosagem , Ginsenosídeos/farmacologia , Nanotubos de Carbono , Receptor de Morte Celular Programada 1/efeitos dos fármacos , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Técnicas de Cocultura , Citocinas/metabolismo , Feminino , Humanos , Transdução de Sinais/efeitos dos fármacos , Linfócitos T/efeitos dos fármacos , Ensaio Tumoral de Célula-TroncoRESUMO
PURPOSE: This pilot study aimed on generating insight on alterations in circulating immune cells during the use of FOLFIRINOX and gemcitabine/nab-paclitaxel in pancreatic ductal adenocarcinoma (PDAC). PATIENTS AND METHODS: Peripheral blood mononuclear cells were isolated before and 30 days after initiation of chemotherapy from 20 patients with advanced PDAC. Regulatory T cells (FoxP3+) and immune checkpoints (PD-1 and TIM-3) were analyzed by flow cytometry and immunological changes were correlated with clinical outcome. RESULTS: Heterogeneous changes during chemotherapy were observed in circulating T-cell subpopulations with a pronounced effect on PD-1+ CD4+/CD8+ T cells. An increase in FoxP3+ or PD-1+ T cells had no significant effect on survival. An increase in TIM3+/CD8+ (but not TIM3+/CD4+) T cells was associated with a significant inferior outcome: median progression-free survival in the subgroup with an increase of TIM-3+/CD8+ T cells was 6.0 compared to 14.0 months in patients with a decrease/no change (p = 0.026); corresponding median overall survival was 13.0 and 20.0 months (p = 0.011), respectively. CONCLUSIONS: Chemotherapy with FOLFIRNOX or gemcitabine/nab-paclitaxel induces variable changes in circulating T-cell populations that may provide prognostic information in PDAC.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Ductal Pancreático/tratamento farmacológico , Proteínas de Checkpoint Imunológico/efeitos dos fármacos , Neoplasias Pancreáticas/tratamento farmacológico , Linfócitos T Reguladores/efeitos dos fármacos , Idoso , Albuminas/uso terapêutico , Linfócitos T CD4-Positivos/química , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/química , Linfócitos T CD8-Positivos/efeitos dos fármacos , Carcinoma Ductal Pancreático/imunologia , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapêutico , Feminino , Fluoruracila/uso terapêutico , Fatores de Transcrição Forkhead , Receptor Celular 2 do Vírus da Hepatite A/análise , Humanos , Proteínas de Checkpoint Imunológico/análise , Irinotecano/uso terapêutico , Leucovorina/uso terapêutico , Masculino , Pessoa de Meia-Idade , Oxaliplatina/uso terapêutico , Paclitaxel/uso terapêutico , Neoplasias Pancreáticas/imunologia , Projetos Piloto , Receptor de Morte Celular Programada 1/análise , Receptor de Morte Celular Programada 1/efeitos dos fármacos , Intervalo Livre de Progressão , Estudos Prospectivos , Linfócitos T Reguladores/química , GencitabinaRESUMO
Immune check point inhibition (ICI) is a paradigm shift in oncology, but most patients treated with ICI will not respond to treatment. Thus, the need for predictive biomarkers for ICI is high. Dubuisson and colleagues have now reported on a new functional assay that might accurately inform on ICI response.
Assuntos
Inibidores de Checkpoint Imunológico/uso terapêutico , Oncologia/tendências , Receptor de Morte Celular Programada 1 , Antineoplásicos/uso terapêutico , Antígeno B7-H1/análise , Biomarcadores Tumorais/análise , Antígeno CTLA-4/análise , Resistência a Medicamentos , Humanos , Imunoterapia/efeitos adversos , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Receptor de Morte Celular Programada 1/efeitos dos fármacos , Receptor de Morte Celular Programada 1/metabolismoRESUMO
Blockade of PD-1/PD-L1 interactions is proving an exciting, durable therapeutic modality in a range of cancers whereby T cells are released from checkpoint inhibition to revive their inherent anti-tumour activity. Here we have studied various ways to model ex vivo T cell function in order to compare the impact of the clinically utilised anti-PD-1 antibody, pembrolizumab (Keytruda) on the activation of human T cells: focussing on the release of pro-inflammatory IFNγ and anti-inflammatory IL-10 to assess functionality. Firstly, we investigated the actions of pembrolizumab in an acute model of T-cell activation with either immature or mature allogeneic dendritic cells (DCs); pembrolizumab enhanced IFNγ and IL-10 release from purified CD4+ T-cells in the majority of donors with a bias towards pro-inflammatory cytokine release. Next, we modelled the impact of pembrolizumab in settings of more chronic T-cell activation. In a 7-day antigen-specific response to EBV peptides, the presence of pembrolizumab resulted in a relatively modest increase in both IFNγ and IL-10 release. Where pembrolizumab was assessed against long-term stimulated CD4+ cells that had up-regulated the exhaustion markers TIM-3 and PD-1, there was a highly effective enhancement of the otherwise exhausted response to allogeneic DCs with respect to IFNγ production. By contrast, the restoration of IL-10 production was considerably more limited. Finally, to assess a direct clinical relevance we investigated the consequence of PD-1/PD-L1 blockade in the disease setting of dissociated cells from lung and colon carcinomas responding to allogeneic DCs: here, pembrolizumab once more enhanced IFNγ production from the majority of tumour preparations whereas, again, the increase in IL-10 release was modest at best. In conclusion, we have shown that the contribution of PD-1-revealed by using a canonical blocking antibody to interrupt its interaction with PD-L1-to the production of an exemplar pro- and anti-inflammatory cytokine, respectively, depends in magnitude and ratio on the particular stimulation setting and activation status of the target T cell. We have identified a number of in vitro assays with response profiles that mimic features of dissociated cell populations from primary tumours thereby indicating these represent disease-relevant functional assays for the screening of immune checkpoint inhibitors in current and future development. Such in vitro assays may also support patient stratification of those likely to respond to immuno-oncology therapies in the wider population.
Assuntos
Anticorpos Monoclonais Humanizados/farmacologia , Ativação Linfocitária/efeitos dos fármacos , Linfócitos T/metabolismo , Anticorpos Monoclonais Humanizados/metabolismo , Antígeno B7-H1/efeitos dos fármacos , Antígeno B7-H1/imunologia , Antígeno B7-H1/metabolismo , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Citocinas/imunologia , Receptor Celular 2 do Vírus da Hepatite A/imunologia , Humanos , Inibidores de Checkpoint Imunológico/farmacologia , Imunoterapia/métodos , Ativação Linfocitária/genética , Neoplasias/imunologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/efeitos dos fármacos , Receptor de Morte Celular Programada 1/metabolismo , Linfócitos T/efeitos dos fármacosRESUMO
Exosomes, as the main group of extracellular vesicles, are biologically active lipid-bilayer vesicles that are naturally released from different types of normal or tumor cells. These vesicles play an important role in intercellular communication and influence the extracellular environment and the immune system. Emerging evidence demonstrates that cancer-derived exosomes are enriched in immunosuppressive proteins, such as the programmed death-ligand 1 (PD-L1). PD-L1 and its receptor programmed cell death protein 1 (PD-1) are the key immune checkpoint molecules that promote tumor progression via negative regulation of immune responses. PDL-1 is highly expressed on the surface of tumor cells and binds to PD-1 on the surface of activated T cells, leading to suppression of T cells, which consequently enables cancer cells to escape antitumor immunity. Currently, there are several Food and Drug Administration-approved monoclonal antibodies blocking PD-1/PD-L1 interaction, which are clinically used for cancer treatment. However, despite impressive treatment outcomes, some patients show poor response to PD-1/PD-L1 blockade. Of note, tumor-derived exosomes containing PD-L1 can recapitulate the effect of cell-surface PD-L1. There is evidence that reveals a significant association between levels of circulating exosomal PD-L1 and rate of response to anti-PD-1/PD-L1 antibody therapy. The present article reviews the role of exosomal PDL-1 in the therapeutic resistance to anti-PD-1/PD-L1 treatment. Importantly, it is suggested that the removal of exosomal PDL-1 could serve as a therapeutic adjuvant for enhancing the efficacy of anti-PD-1/PD-L1 therapy in patients with cancer.
Assuntos
Antígeno B7-H1/metabolismo , Resistencia a Medicamentos Antineoplásicos , Exossomos/metabolismo , Neoplasias/imunologia , Antígeno B7-H1/efeitos dos fármacos , Progressão da Doença , Exossomos/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias/tratamento farmacológico , Receptor de Morte Celular Programada 1/efeitos dos fármacos , Receptor de Morte Celular Programada 1/metabolismo , Regulação para Cima/efeitos dos fármacosRESUMO
Upregulation of programmed death ligand 1 (PD-L1) helps tumor cells escape from immune surveillance, and therapeutic antibodies targeting PD-1/PD-L1 have shown better patient outcomes only in several types of malignancies. Recent studies suggest that the clinical efficacy of anti-PD-1/PD-L1 treatments is associated with PD-L1 levels; however, the underlying mechanism of high PD-L1 protein levels in cancers is not well defined. Here, we report that the deubiquitinase OTUB1 positively regulates PD-L1 stability and mediates cancer immune responses through the PD-1/PD-L1 axis. Mechanistically, we demonstrate that OTUB1 interacts with and removes K48-linked ubiquitin chains from the PD-L1 intracellular domain in a manner dependent on its deubiquitinase activity to hinder the degradation of PD-L1 through the ERAD pathway. Functionally, depletion of OTUB1 markedly decreases PD-L1 abundance, reduces PD-1 protein binding to the tumor cell surface, and causes increased tumor cell sensitivity to human peripheral blood mononuclear cells (PBMCs)-mediated cytotoxicity. Meanwhile, OTUB1 ablation-induced PD-L1 destabilization facilitates more CD8+ T cells infiltration and increases the level of IFN-γ in serum to enhance antitumor immunity in mice, and the tumor growth suppression by OTUB1 silencing could be reversed by PD-L1 overexpression. Furthermore, we observe a significant correlation between PD-L1 abundance and OTUB1 expression in human breast carcinoma. Our study reveals OTUB1 as a deubiquitinating enzyme that influences cancer immunosuppression via regulation of PD-L1 stability and may be a potential therapeutic target for cancer immunotherapy.
Assuntos
Cisteína Endopeptidases/metabolismo , Enzimas Desubiquitinantes/metabolismo , Terapia de Imunossupressão/métodos , Imunoterapia/métodos , Receptor de Morte Celular Programada 1/efeitos dos fármacos , Adulto , Animais , Linhagem Celular Tumoral , Modelos Animais de Doenças , Voluntários Saudáveis , Humanos , Camundongos , Transfecção , Regulação para Cima , Adulto JovemRESUMO
Purpose Programmed cell death 1 (PD-1), which is upregulated under the continuous induction of the tumor microenvironment, causes chimeric antigen receptor (CAR)-T cell hypofunction via interaction with programmed death ligand 1 (PD-L1). This study aimed to construct CAR-T cells that are resistant to PD-1 inhibition to improve the effect of CAR-T cells in solid tumors. Methods We constructed a type of dual-function CAR-T cell that targets tumor-associated antigen c-Met and blocks the binding of PD-1 with PD-L1. The expression of c-Met, PD-L1, and inhibitory receptors was measured using flow cytometry. The cytotoxicity, cytokine release, and differentiation level of CAR-T cells were determined using lactate dehydrogenase release assay, enzyme-linked immunosorbent assay, and flow cytometry, respectively. The levels of p-Akt, p-MAPK, caspase-3, and Bcl2 were detected by western blot. The in vivo anti-tumor effect was evaluated using tumor xenograft models. Results Dual-function CAR-T cells could mediate enhanced active signals upon encountering target antigens and had targeted cytotoxicity to target cells. However, the cytotoxicity of c-Met-CAR-PD-1+ T cells was impaired due to the interaction of PD-1 with PD-L1. By blocking the binding of PD-1 and PD-L1, the novel dual-function CAR-PD-1+ T cells could maintain cytotoxicity to PD-L1+ tumor cells. In tumor tissue, the dual-function CAR-T cells showed lower inhibitory receptor expression and lower differentiation characteristics, which resulted in potent anti-tumor effects and prolonged survival in PD-L1+ tumor xenograft models compared to single-target CAR-T cells. Conclusion These results confirm that the novel dual-function CAR-T cells exhibit stronger anti-tumor activity against solid tumors than traditional single-target CAR-T cells and present a new approach that enhance the activity of CAR-T cells in solid tumors.
Assuntos
Imunoterapia Adotiva/métodos , Neoplasias/patologia , Receptor de Morte Celular Programada 1/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-met/efeitos dos fármacos , Receptores de Antígenos Quiméricos/administração & dosagem , Animais , Antígeno B7-H1/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Citocinas/efeitos dos fármacos , Ensaio de Imunoadsorção Enzimática , Humanos , Camundongos , Camundongos Endogâmicos NOD , Microambiente Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND: Toll-like receptor (TLR) signals play vital roles during the blood-stage of malaria infections. However, the roles of TLR agonists in the regulation of immune responses and the development of protective immunity to malaria remain poorly understood. METHOD: BALB/c mice were pre-treated with TLR4, TLR7 and TLR9 agonists, followed by infection with Plasmodium chabaudi. After infection, splenic dendritic cells (DCs), Th1 cells and programmed death-1 (PD-1) expressed on Th1 cells, as well as regulatory T cells (Tregs) were analyzed by flow cytometry. The levels of IFN-γ, TNF-α, TGF-ß and IL-10 in splenocytes and IgG1 and IgG2a in serum were measured by ELISA. RESULT: Administration of TLR4, TLR7 and TLR9 agonists prior to infection improved disease outcomes. All TLR agonists promoted DC activation, and the proportions of Th1 cells increased. In TLR4, TLR7 and TLR9 agonist treated groups the levels of pro-inflammatory cytokines IFN-γ and TNF-α were elevated, and IgG1 and IgG2a serum levels were also significantly increased. TLR4, TLR7 and TLR9 agonists diminished the activation of Tregs and down-regulated the anti-inflammatory cytokines TGF-ß and IL-10. Finally, PD-1 expressed on Th1 cells were decreased in TLR4, TLR7 and TLR9 agonist treated groups compared with control groups. CONCLUSION: TLR4, TLR7 and TLR9 agonists activated DC-mediated innate immune responses and adaptive immune response, which against the blood-stage of Plasmodium and might be applied to malaria protection and treatment.
Assuntos
Malária/imunologia , Malária/prevenção & controle , Glicoproteínas de Membrana/agonistas , Plasmodium chabaudi/efeitos dos fármacos , Plasmodium chabaudi/imunologia , Receptor 4 Toll-Like/agonistas , Receptor 7 Toll-Like/agonistas , Receptor Toll-Like 9/agonistas , Imunidade Adaptativa/efeitos dos fármacos , Animais , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/metabolismo , Feminino , Imunidade Inata/efeitos dos fármacos , Imunoglobulina G/sangue , Imunoglobulina G/efeitos dos fármacos , Interferon gama/metabolismo , Interleucina-10/metabolismo , Estágios do Ciclo de Vida , Camundongos Endogâmicos BALB C , Parasitemia/prevenção & controle , Receptor de Morte Celular Programada 1/efeitos dos fármacos , Baço/efeitos dos fármacos , Baço/metabolismo , Linfócitos T Reguladores/efeitos dos fármacos , Células Th1/efeitos dos fármacos , Células Th1/metabolismo , Fator de Crescimento Transformador beta/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Immunotherapies revolutionized cancer treatment by harnessing the immune system to target cancer cells. However, most patients are resistant to immunotherapies and the mechanisms underlying this resistant is still poorly understood. Here, we report that overexpression of BMP7, a member of the TGFB superfamily, represents a mechanism for resistance to anti-PD1 therapy in preclinical models and in patients with disease progression while on immunotherapies. BMP7 secreted by tumor cells acts on macrophages and CD4+ T cells in the tumor microenvironment, inhibiting MAPK14 expression and impairing pro-inflammatory responses. Knockdown of BMP7 or its neutralization via follistatin in combination with anti-PD1 re-sensitizes resistant tumors to immunotherapies. Thus, we identify the BMP7 signaling pathway as a potential immunotherapeutic target in cancer.
Assuntos
Proteína Morfogenética Óssea 7/genética , Proteína Morfogenética Óssea 7/metabolismo , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Imunoterapia/métodos , Neoplasias/metabolismo , Animais , Anticorpos Monoclonais Humanizados/farmacologia , Linfócitos T CD4-Positivos , Linhagem Celular Tumoral , Feminino , Folistatina/metabolismo , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Camundongos , Proteína Quinase 14 Ativada por Mitógeno/genética , Proteína Quinase 14 Ativada por Mitógeno/metabolismo , Receptor de Morte Celular Programada 1/efeitos dos fármacos , Células RAW 264.7 , Proteína Smad1/metabolismo , Transcriptoma , Microambiente Tumoral/efeitos dos fármacosRESUMO
The human immune system has structures called checkpoints controlling the intensity and the duration of immune responses. In the last years, studies and research have been concentrating on creating new drugs recognized as Immune Checkpoint Inhibitors that have been launched in clinical practice to treat patients with several types of cancer, including multiple myeloma. Multiple myeloma is characterized by dysfunctions in humoral and cellular immunity altering immune surveillance and support tumor advancement to escape: in particular, the disease causes the inactivation of T-cells because of their bond with antigens shown in cancer cells. It can be stated that checkpoint inhibitors "inhibit the inhibition" of cell-mediated immunity and induce tumor cells apoptosis. In this review we have focused our attention on summarizing current information about Immune Checkpoint Inhibitors which have been developed in the last years to treat multiple myeloma; particular consideration will be dedicated to describing their mechanism of action and their potential use in therapy. Further investigations are necessary in this field to define the possibility of an effective and safe inclusion of these drugs in clinical practice.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Inibidores de Checkpoint Imunológico/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/imunologia , Humanos , Imunoterapia/métodos , Terapia de Alvo Molecular/métodos , Receptor de Morte Celular Programada 1/efeitos dos fármacos , Receptor de Morte Celular Programada 1/imunologiaRESUMO
BACKGROUND: The clinical significance of adoptive tumor-infiltrating lymphocyte (TIL) therapy has been demonstrated in many clinical trials. We analyzed the in vitro reactivity of cultured TILs against autologous breast cancer cells. METHODS: TILs and cancer cells were cultured from 31 breast tumor tissues. Reactivity of TILs against cancer cells was determined by measuring secreted interferon-gamma. Expression levels of epithelial markers, major histocompatibility complex molecules, and programmed death-ligand 1 (PD-L1) in cancer cells, and T cell markers (memory, T cell activation and exhaustion, and regulatory T cell markers) in expanded TILs were analyzed and compared between the reactive and non-reactive groups. RESULTS: In seven cases, TILs showed reactivity to autologous cancer cells. Six of these cases were associated with triple-negative breast cancer (TNBC). All reactive TNBCs were derived from surgical specimens after neoadjuvant chemotherapy (NAC). Higher expression of Ki67 in tumor tissues and lower expression of PD-L1 in cultured cancer cells were associated with reactivity. Proliferation of reactive TILs was high. High proportions of T cells and PD-1+CD4+ and PD1+CD8+ T cells were associated with reactivity in TNBC cases, while other activation or exhaustion markers were not. CONCLUSION: TILs from approximately half the TNBC cases with NAC showed reactivity against autologous cancer cells. The proportion of PD-1+ T cells was higher in the reactive group. Adoptive TIL therapy combined with PD-1 inhibitors might be promising for TNBC patients with residual tumors after NAC.
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Linfócitos do Interstício Tumoral/imunologia , Neoplasias de Mama Triplo Negativas/imunologia , Neoplasias de Mama Triplo Negativas/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/uso terapêutico , Quimioterapia Adjuvante/métodos , Feminino , Humanos , Pessoa de Meia-Idade , Terapia Neoadjuvante/métodos , Receptor de Morte Celular Programada 1/efeitos dos fármacos , Receptor de Morte Celular Programada 1/metabolismo , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Células Tumorais CultivadasRESUMO
BACKGROUNDPD-1 and PD-L1 have been studied interchangeably in the clinic as checkpoints to reinvigorate T cells in diverse tumor types. Data for biologic effects of checkpoint blockade in human premalignancy are limited.METHODSWe analyzed the immunologic effects of PD-L1 blockade in a clinical trial of atezolizumab in patients with asymptomatic multiple myeloma (AMM), a precursor to clinical malignancy. Genomic signatures of PD-L1 blockade in purified monocytes and T cells in vivo were also compared with those following PD-1 blockade in lung cancer patients. Effects of PD-L1 blockade on monocyte-derived DCs were analyzed to better understand its effects on myeloid antigen-presenting cells.RESULTSIn contrast to anti-PD-1 therapy, anti-PD-L1 therapy led to a distinct inflammatory signature in CD14+ monocytes and increase in myeloid-derived cytokines (e.g., IL-18) in vivo. Treatment of AMM patients with atezolizumab led to rapid activation and expansion of circulating myeloid cells, which persisted in the BM. Blockade of PD-L1 on purified monocyte-derived DCs led to rapid inflammasome activation and synergized with CD40L-driven DC maturation, leading to greater antigen-specific T cell expansion.CONCLUSIONThese data show that PD-L1 blockade leads to distinct systemic immunologic effects compared with PD-1 blockade in vivo in humans, particularly manifest as rapid myeloid activation. These findings also suggest an additional role for PD-L1 as a checkpoint for regulating inflammatory phenotype of myeloid cells and antigen presentation in DCs, which may be harnessed to improve PD-L1-based combination therapies.TRIAL REGISTRATIONNCT02784483.FUNDINGThis work is supported, in part, by funds from NIH/NCI (NCI CA197603, CA238471, and CA208328).
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Anticorpos Monoclonais Humanizados/uso terapêutico , Antígeno B7-H1/imunologia , Mieloma Múltiplo/tratamento farmacológico , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/uso terapêutico , Células Apresentadoras de Antígenos/imunologia , Humanos , Imunoterapia/métodos , Inflamação/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/imunologia , Mieloma Múltiplo/imunologia , Receptor de Morte Celular Programada 1/efeitos dos fármacosRESUMO
HTLV-1, the first human oncogenic retrovirus, is a type C retrovirus that belongs to the Deltaretrovirus genus. The HTLV-1 genome has 8.5 kbp length, and consists of major genes such as gag, pol, pro, env, and pX region. This retrovirus is considered as one of the most deadly infectious agent for peripheral-blood mononuclear cells (PBMC). The infection of HTLV-1 can lead to dangerous complications, such as infective dermatitis (ID), uveitis, arthritis, lymphadenitis, arthropathies, Sjögren's Syndrome (SS), and particularly HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) or Adult T-Cell Leukemia Lymphoma (ATLL). At the moment, Zidovudine (AZT) plus IFN-α is the only treatment available for HTLV-1 infections. Based on scientific studies, alongside the therapeutic regimens, intrinsic mechanisms also play a determinant role in reducing the signs of disease. Programmed cell death-1 (PD-1) signaling pathway, one of the most important checkpoints, has recently received interest, such as the development of a novel generation of anti-tumors. In the present study, we discuss the role of PD-1 signaling pathway in HTLV-1 infection as well as its application as a novel approach for treatment of HTLV-1 infections.