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1.
Adv Exp Med Biol ; 1248: 651-653, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32185727

RESUMO

The regulation of immune checkpoint is a pivotal mechanism mediating both self-tolerance physiologically and tumor immune evasion pathologically. Along with an increasing number of identified checkpoint ligand-receptor pairs, the complexity of regulation at genetic, epigenetic, transcriptional, translational, and post-translational levels makes it highly challenging to assemble a comprehensive regulatory network. Advanced animal models are required for determining the exact regulatory effects, given the differences in human and mouse immune systems. Our further understanding on checkpoint regulation may energize translational studies aimed to improve cancer immunotherapy, and collaborations between researchers with different expertise would help to tackle existing challenges in this field.


Assuntos
Imunoterapia , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Animais , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/imunologia , Humanos , Camundongos , Neoplasias/genética , Neoplasias/patologia , Receptores Imunológicos/antagonistas & inibidores , Receptores Imunológicos/imunologia , Evasão Tumoral/efeitos dos fármacos , Evasão Tumoral/imunologia
2.
Nat Commun ; 11(1): 790, 2020 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-32034147

RESUMO

APOBEC3B, an anti-viral cytidine deaminase which induces DNA mutations, has been implicated as a mediator of cancer evolution and therapeutic resistance. Mutational plasticity also drives generation of neoepitopes, which prime anti-tumor T cells. Here, we show that overexpression of APOBEC3B in tumors increases resistance to chemotherapy, but simultaneously heightens sensitivity to immune checkpoint blockade in a murine model of melanoma. However, in the vaccine setting, APOBEC3B-mediated mutations reproducibly generate heteroclitic neoepitopes in vaccine cells which activate de novo T cell responses. These cross react against parental, unmodified tumors and lead to a high rate of cures in both subcutaneous and intra-cranial tumor models. Heteroclitic Epitope Activated Therapy (HEAT) dispenses with the need to identify patient specific neoepitopes and tumor reactive T cells ex vivo. Thus, actively driving a high mutational load in tumor cell vaccines increases their immunogenicity to drive anti-tumor therapy in combination with immune checkpoint blockade.


Assuntos
Vacinas Anticâncer/farmacologia , Citidina Desaminase/imunologia , Imunoterapia/métodos , Antígenos de Histocompatibilidade Menor/imunologia , Linfócitos T/imunologia , Animais , Linhagem Celular Tumoral , Citidina Desaminase/genética , Citidina Desaminase/metabolismo , Resistencia a Medicamentos Antineoplásicos , Epitopos/imunologia , Feminino , Humanos , Células Matadoras Naturais/imunologia , Melanoma/imunologia , Melanoma/terapia , Melanoma Experimental/imunologia , Melanoma Experimental/terapia , Camundongos Endogâmicos C57BL , Antígenos de Histocompatibilidade Menor/genética , Antígenos de Histocompatibilidade Menor/metabolismo , Mutação , Evasão Tumoral/efeitos dos fármacos
3.
Life Sci ; 247: 117437, 2020 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-32070710

RESUMO

Although both the incidence and the mortality rate of breast cancer is rising, there is no potent and practical option for the treatment of these patients, particularly in advanced stages. One of the most critical challenges for treatment is the presence of complicated and extensive tumor escape mechanisms in the tumor microenvironment. Immune checkpoint molecules are of the main immunosuppressive mechanisms used by cancerous cells to block anti-cancer immune responses. Among these molecules, PD-1 (Programmed cell death) and PD-L1 (programmed cell death-ligand 1) have been considered as worthy therapeutic targets for breast cancer therapy. In this review, we intend to discuss the immunobiology and signaling of the PD-1/PD-L1 axis and highlight its importance as a worthy therapeutic target in breast cancer. We believe that the prognostic value of PD-L1 depends on the breast cancer subtype. Moreover, the combination of PD-1/PD-L1 targeting with immune-stimulating vaccines can be considered as an effective therapeutic strategy in breast cancer.


Assuntos
Antineoplásicos/química , Antígeno B7-H1/metabolismo , Neoplasias da Mama/tratamento farmacológico , Terapia de Alvo Molecular/métodos , Receptor de Morte Celular Programada 1/metabolismo , Animais , Antineoplásicos/uso terapêutico , Antígeno B7-H1/química , Antígeno B7-H1/genética , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Imunoterapia , Receptor de Morte Celular Programada 1/química , Receptor de Morte Celular Programada 1/genética , Ligação Proteica/efeitos dos fármacos , Conformação Proteica , Transdução de Sinais , Linfócitos T/efeitos dos fármacos , Evasão Tumoral/efeitos dos fármacos , Microambiente Tumoral/efeitos dos fármacos
4.
Nat Commun ; 11(1): 437, 2020 01 23.
Artigo em Inglês | MEDLINE | ID: mdl-31974367

RESUMO

Immune checkpoint inhibitors (ICIs) have dramatically modified the prognosis of several advanced cancers, however many patients still do not respond to treatment. Optimal results might be obtained by targeting cancer cell metabolism to modulate the immunosuppressive tumor microenvironment. Here, we identify sphingosine kinase-1 (SK1) as a key regulator of anti-tumor immunity. Increased expression of SK1 in tumor cells is significantly associated with shorter survival in metastatic melanoma patients treated with anti-PD-1. Targeting SK1 markedly enhances the responses to ICI in murine models of melanoma, breast and colon cancer. Mechanistically, SK1 silencing decreases the expression of various immunosuppressive factors in the tumor microenvironment to limit regulatory T cell (Treg) infiltration. Accordingly, a SK1-dependent immunosuppressive signature is also observed in human melanoma biopsies. Altogether, this study identifies SK1 as a checkpoint lipid kinase that could be targeted to enhance immunotherapy.


Assuntos
Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Melanoma/tratamento farmacológico , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Neoplasias Cutâneas/tratamento farmacológico , Idoso , Animais , Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Linfócitos T CD8-Positivos/patologia , Feminino , Regulação Enzimológica da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Melanoma/imunologia , Melanoma/mortalidade , Melanoma/patologia , Melanoma Experimental/tratamento farmacológico , Melanoma Experimental/patologia , Camundongos Endogâmicos BALB C , Pessoa de Meia-Idade , Terapia de Alvo Molecular , Nivolumabe/uso terapêutico , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/mortalidade , Neoplasias Cutâneas/patologia , Taxa de Sobrevida , Linfócitos T Reguladores/patologia , Evasão Tumoral/efeitos dos fármacos , Evasão Tumoral/fisiologia
5.
Cancer Immunol Immunother ; 69(5): 867-877, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-31970440

RESUMO

Acute lymphoblastic leukaemia (ALL) in adults is a rare and difficult-to-treat cancer that is characterised by excess lymphoblasts in the bone marrow. Although many patients achieve remission with chemotherapy, relapse rates are high and the associated impact on survival devastating. Most patients receive chemotherapy and for those whose overall fitness supports it, the most effective treatment to date is allogeneic stem cell transplant that can improve overall survival rates in part due to a 'graft-versus-leukaemia' effect. However, due to the rarity of this disease, and the availability of mature B-cell antigens on the cell surface, few new cancer antigens have been identified in adult B-ALL that could act as targets to remove residual disease in first remission or provide alternative targets for escape variants if and when current immunotherapy strategies fail. We have used RT-PCR analysis, literature searches, antibody-specific profiling and gene expression microarray analysis to identify and prioritise antigens as novel targets for the treatment of adult B-ALL.


Assuntos
Antígenos de Neoplasias/imunologia , Antineoplásicos Imunológicos/farmacologia , Imunoterapia/métodos , Leucemia-Linfoma Linfoblástico de Células Precursoras B/terapia , Evasão Tumoral/efeitos dos fármacos , Adulto , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/isolamento & purificação , Antígenos de Neoplasias/metabolismo , Antineoplásicos Imunológicos/uso terapêutico , Linfócitos B/efeitos dos fármacos , Linfócitos B/imunologia , Linfócitos B/metabolismo , Conjuntos de Dados como Assunto , Perfilação da Expressão Gênica , Humanos , Terapia de Alvo Molecular/métodos , Análise de Sequência com Séries de Oligonucleotídeos , Leucemia-Linfoma Linfoblástico de Células Precursoras B/imunologia , Indução de Remissão/métodos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Resultado do Tratamento , Evasão Tumoral/imunologia
6.
Cancer Immunol Immunother ; 69(1): 3-14, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31811337

RESUMO

With the introduction of multiple new agents, the role of immunotherapy is rapidly expanding across all malignancies. Bladder cancer is known to be immunogenic and is responsive to immunotherapy including intravesical BCG and immune checkpoint inhibitors. Multiple trials have addressed the role of checkpoint inhibitors in advanced bladder cancer, including atezolizumab, avelumab, durvalumab, nivolumab and pembrolizumab (all targeting the PD1/PD-L1 pathway). While these trials have demonstrated promising results and improvements over existing therapies, less than half of patients with advanced disease demonstrate clinical benefit from checkpoint inhibitor therapy. Recent breakthroughs in cancer biology and immunology have led to an improved understanding of the influence of the tumor microenvironment on the host's immune system. It appears that tumors promote the formation of highly immunosuppressive microenvironments preventing generation of effective anti-tumor immune response through multiple mechanisms. Therefore, reconditioning of the tumor microenvironment and restoration of the competent immune response is essential for achieving optimal efficacy of cancer immunotherapy. In this review, we aim to discuss the major mechanisms of immune evasion in bladder cancer and highlight novel pathways and molecular targets that may help to attenuate tumor-induced immune tolerance, overcome resistance to immunotherapy and improve clinical outcomes.


Assuntos
Antineoplásicos Imunológicos/farmacologia , Antígeno B7-H1/imunologia , Receptor de Morte Celular Programada 1/imunologia , Evasão Tumoral/imunologia , Neoplasias da Bexiga Urinária/imunologia , Antineoplásicos Imunológicos/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Humanos , Terapia de Alvo Molecular/métodos , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Resultado do Tratamento , Evasão Tumoral/efeitos dos fármacos , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia , Neoplasias da Bexiga Urinária/tratamento farmacológico
7.
Immunology ; 159(2): 167-177, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31646612

RESUMO

Immune checkpoint inhibition with monoclonal antibodies is becoming increasingly commonplace in cancer medicine, having contributed to a widening of therapeutic options across oncological indications. Disruption of immune tolerance is the key mechanism of action of checkpoint inhibitors and although immune-related adverse events are a typical class effect of these compounds, the relationship between toxicity and response is not fully understood. Awareness and vigilance are paramount in recognizing potentially life-threatening toxicities and managing them in a timely manner. In this review article, we provide an overview of the clinical features, pathological findings and management principles of common immune-related toxicities, attempting to provide mechanistic insight into an increasingly common complication of cancer therapy.


Assuntos
Antineoplásicos Imunológicos/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Doenças do Sistema Endócrino/induzido quimicamente , Gastroenteropatias/induzido quimicamente , Tolerância Imunológica/efeitos dos fármacos , Imunoterapia/efeitos adversos , Pneumopatias/induzido quimicamente , Terapia de Alvo Molecular/efeitos adversos , Neoplasias/tratamento farmacológico , Animais , Doença Hepática Induzida por Substâncias e Drogas/imunologia , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/terapia , Doenças do Sistema Endócrino/imunologia , Doenças do Sistema Endócrino/metabolismo , Doenças do Sistema Endócrino/terapia , Gastroenteropatias/imunologia , Gastroenteropatias/metabolismo , Gastroenteropatias/terapia , Humanos , Pneumopatias/imunologia , Pneumopatias/metabolismo , Pneumopatias/terapia , Neoplasias/imunologia , Neoplasias/metabolismo , Fatores de Risco , Evasão Tumoral/efeitos dos fármacos
8.
Cancer Immunol Immunother ; 69(1): 23-32, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31768581

RESUMO

BACKGROUND: Several articles have recently reported that certain colon microbiota can improve the efficacy of cancer immunotherapy. To develop new treatment strategies, including immunotherapy for colorectal cancer (CRC), we evaluated the correlations between subpopulations of tumor-infiltrating immune cells (TIICs) and intestinal microbiota in CRC. METHODS: Fresh surgically resected specimens, formalin-fixed paraffin-embedded whole tissue samples, and stool samples were collected. TIICs including Tregs, Th17 cells and tumor-associated macrophages (TAMs) in the surgically resected specimens were analyzed using flow cytometry. FOXp3, CD8, CD163, and phosphorylated-STAT1-positive TIICs in the whole tissue samples were analyzed using IHC, and intestinal microbiota in the stool samples was analyzed using 16S metagenome sequencing. TIICs subpopulations in the normal mucosa and tumor samples were evaluated, and the correlations between the TIIC subpopulations and intestinal microbiota were analyzed. RESULTS: FOXp3lowCD45RA+ Tregs were significantly reduced (p = 0.02), FOXp3lowCD45RA- Tregs were significantly increased (p = 0.006), and M1 TAMs were significantly reduced in the tumor samples (p = 0.03). Bacteroides (phylum Bacteroidetes) and Faecalibacterium (phylum Firmicutes) were increased in the patients with high numbers of Tregs and clearly high distribution of FOXp3highCD45RA- Tregs, which are the effector Tregs. Faecalibacterium, Ruminococcaceae, Eubacterium (phylum Firmicutes), and Bacteroides were increased in patients with a high distribution of M1 TAMs. CONCLUSIONS: The findings of the present study indicate that immune responses to tumors are suppressed in the tumor microenvironment of CRC depending on the increment of Tregs and the reduction of M1 TAMs and that intestinal microbiota might be involved in immunosuppression.


Assuntos
Neoplasias Colorretais/imunologia , Microbioma Gastrointestinal/imunologia , Linfócitos do Interstício Tumoral/imunologia , Macrófagos/imunologia , Evasão Tumoral/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Imunológicos/farmacologia , Antineoplásicos Imunológicos/uso terapêutico , Bactérias/imunologia , Bactérias/isolamento & purificação , Estudos de Coortes , Colectomia , Colo/imunologia , Colo/microbiologia , Colo/patologia , Neoplasias Colorretais/microbiologia , Neoplasias Colorretais/terapia , Fezes/microbiologia , Feminino , Humanos , Mucosa Intestinal/imunologia , Mucosa Intestinal/microbiologia , Mucosa Intestinal/patologia , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Linfócitos do Interstício Tumoral/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Pessoa de Meia-Idade , Evasão Tumoral/efeitos dos fármacos , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia
9.
Int J Cancer ; 146(2): 542-552, 2020 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-31584197

RESUMO

Our previous researches have identified immunoevasive subtype muscle-invasive bladder cancer (MIBC) characterized with immune cells infiltration patterns. Our study explored the clinical significance, immunoregulatory role and therapeutic value of intratumoral IL22-producing cells in MIBC. Two hundred and fifty-nine formalin-fixed paraffin-embedded MIBC samples and 83 freshly resected MIBC tissues and 391 TCGA MIBC samples were retrospectively evaluated. Immunohistochemistry and flow cytometry were applied to identify immune cell infiltration and functional status. In vitro intervention studies were to test the therapeutic and predictive potential of IL22+ cells. Our data revealed patients with high IL22+ cells infiltration suffered poor overall survival and recurrence-free survival in both training and validation cohorts. Only pT2 patients of combined cohort with low IL22+ cells infiltration gained survival benefits from adjuvant chemotherapy (ACT) significantly. Besides, immune contexture featured with increased pro-tumor cells and immunosuppressive cytokines was identified in patients with high IL22+ cells density. The expression pattern of exhausted and effector markers in CD8+ T cells from high IL22+ cells subgroup indicated their dysfunctional status. Importantly, nivolumab showed tumor-killing efficacy in tumors with high IL22+ cells infiltration, and immunosuppressive contexture with CD8+ T cells exhaustion was abrogated in tumors treated with anti-IL22 antibody. In summary, IL22+ cells infiltration determined immunosuppressive contexture with CD8+ T cell dysfunction. Tumor-infiltrating IL22+ cells could be used as an independent marker to predict prognosis and ACT responses. IL22+ cells infiltration possessed the potential to be a favorable predictor for nivolumab application and IL22 blockade could be a novel therapeutic strategy in MIBC.


Assuntos
Antineoplásicos Imunológicos/farmacologia , Interleucinas/metabolismo , Nivolumabe/farmacologia , Evasão Tumoral/efeitos dos fármacos , Neoplasias da Bexiga Urinária/terapia , Idoso , Antineoplásicos Imunológicos/uso terapêutico , Linfócitos T CD8-Positivos/imunologia , Quimioterapia Adjuvante/métodos , Cistectomia , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Interleucinas/imunologia , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica/imunologia , Invasividade Neoplásica/patologia , Nivolumabe/uso terapêutico , Prognóstico , Estudos Retrospectivos , Evasão Tumoral/imunologia , Bexiga Urinária/citologia , Bexiga Urinária/imunologia , Bexiga Urinária/patologia , Neoplasias da Bexiga Urinária/imunologia , Neoplasias da Bexiga Urinária/patologia
10.
Immunol Rev ; 290(1): 6-23, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31355494

RESUMO

Immune checkpoint inhibitors (ICIs) have revolutionized our approach to cancer treatment in the past decade. While monoclonal antibodies to CTLA-4 and PD-1/PD-L1 have produced remarkable and durable responses in a subset of patients, the majority of patients will still develop primary or adaptive resistance. With complex mechanisms of resistance limiting the efficacy of checkpoint inhibitor monotherapy, it is critical to develop combination approaches to allow more patients to benefit from immunotherapy. In this review, I approach the current landscape of ICI research from the perspective of sarcomas, a rare group of bone and soft tissue cancers that have had limited benefit from checkpoint inhibitor monotherapy, and little investigation of biomarkers to predict responses. By surveying the various mechanisms of resistance and treatment modalities being explored in other solid tumors, I outline how ICIs will undoubtedly serve as the critical foundation for future directions in modern immunotherapy.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Biomarcadores Tumorais/antagonistas & inibidores , Imunomodulação/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Animais , Antineoplásicos Imunológicos/administração & dosagem , Antineoplásicos Imunológicos/efeitos adversos , Vacinas Anticâncer/administração & dosagem , Vacinas Anticâncer/imunologia , Terapia Combinada , Citotoxicidade Imunológica , Humanos , Imunoterapia , Neoplasias/diagnóstico , Neoplasias/metabolismo , Subpopulações de Linfócitos T/efeitos dos fármacos , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Resultado do Tratamento , Evasão Tumoral/efeitos dos fármacos , Evasão Tumoral/imunologia , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia
11.
Int J Mol Sci ; 20(10)2019 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-31096713

RESUMO

Classic Hodgkin lymphoma (cHL) is characterized by a few tumor cells surrounded by a protective, immunosuppressive tumor microenvironment composed of normal cells that are an active part of the disease. Hodgkin and Reed-Sternberg (HRS) cells evade the immune system through a variety of different mechanisms. They evade antitumor effector T cells and natural killer cells and promote T cell exhaustion. Using cytokines and extracellular vesicles, they recruit normal cells, induce their proliferation and "educate" (i.e. reprogram) them to become immunosuppressive and protumorigenic. Therefore, alternative treatment strategies are being developed to target not only tumor cells but also the tumor microenvironment. Here we summarize current knowledge on the ability of HRS cells to build their microenvironment and to educate normal cells to become immunosuppressive. We also describe therapeutic strategies to counteract formation of the tumor microenvironment and related processes leading to T cell exhaustion and repolarization of immunosuppressive tumor-associated macrophages.


Assuntos
Doença de Hodgkin/tratamento farmacológico , Doença de Hodgkin/imunologia , Imunossupressores/farmacologia , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia , Anticorpos Monoclonais Humanizados/farmacologia , Quimiocinas/metabolismo , Citocinas/metabolismo , Imunossupressores/uso terapêutico , Células Matadoras Naturais , Maraviroc/farmacologia , Nivolumabe/farmacologia , Prognóstico , Receptores CCR5/efeitos dos fármacos , Células de Reed-Sternberg/efeitos dos fármacos , Células de Reed-Sternberg/imunologia , Linfócitos T , Trabectedina/farmacologia , Triptofano/análogos & derivados , Triptofano/farmacologia , Evasão Tumoral/efeitos dos fármacos , Ácido Zoledrônico/farmacologia
12.
Int J Mol Sci ; 20(6)2019 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-30884772

RESUMO

In tumor microenvironment, the programmed death 1 (PD-1) immune checkpoint has a crucial role of mechanism of T cell exhaustion leading to tumor evasion. Ligands of PD-1, programmed death ligand 1/2 (PD-L1/L2) are over-expressed in tumor cells and participate in prolonged tumor progression and survivals. Recently, clinical trials for patients who failed to obtain an optimal response prior to standardized chemotherapy in several solid cancers have been focused on targeting therapy against PD-1 to reduce disease progression rates and prolonged survivals. Since various inhibitors targeting the immune checkpoint in PD-1/PD-L1 pathway in solid cancers have been introduced, promising approach using anti-PD-1 antibodies were attempted in several types of hematologic malignances. In diffuse large B cell lymphoma (DLBCL) as the most common and aggressive B cell type of non-Hodgkin's lymphoma, anti-PD-1 and anti-PD-L1 antibodies were studies in various clinical trials. In this review, we summarized the results of several studies associated with PD-1/PD-L1 pathway as an immune evasion mechanism and described clinical trials about targeting therapy against PD-1/PD-L1 pathway in DLBCL.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Antígeno B7-H1/imunologia , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/imunologia , Receptor de Morte Celular Programada 1/imunologia , Evasão Tumoral/efeitos dos fármacos , Animais , Antineoplásicos Imunológicos/farmacologia , Antígeno B7-H1/análise , Antígeno B7-H1/antagonistas & inibidores , Humanos , Imunoterapia/métodos , Linfoma Difuso de Grandes Células B/patologia , Linfoma Difuso de Grandes Células B/terapia , Terapia de Alvo Molecular/métodos , Receptor de Morte Celular Programada 1/análise , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Linfócitos T/patologia
13.
Am J Clin Dermatol ; 20(3): 391-407, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30784027

RESUMO

Merkel cell carcinoma (MCC) is an aggressive skin cancer. Until 2017, patients with advanced disease were typically treated with conventional chemotherapies, with a median response duration of 3 months. Increased evidence of the role of the immune system in controlling this cancer has paved the way for immune-based therapies, with programmed cell death protein 1 (PD-1)/programmed cell death protein ligand 1 (PD-L1) inhibitors at the frontline. Avelumab, an anti-PD-L1 antibody, was the first-ever drug approved in advanced MCC after showing meaningful efficacy in a second-line setting. Objective responses were observed in one-third of patients and, most importantly, were durable with half of patients and one-third of patients still alive at 1 and 2 years, respectively. When used in a first-line setting, PD-1/PD-L1 inhibitors (avelumab, pembrolizumab, nivolumab) are even more promising as objective responses are observed in approximately 50-70% of patients within the first 4-8 weeks of treatment. Safety profiles are acceptable with 10-20% of patients experiencing adverse events grade ≥ 3. PD-1/PD-L1 inhibitors are considered the standard of care in advanced MCC and are currently being investigated in the adjuvant and neoadjuvant settings. However, innovative treatments are still needed in the metastatic setting, as approximately 50% of these patients will not persistently respond to currently available immunotherapies, and no predictors of response are available yet. Therefore, other immunotherapeutic strategies are now being investigated-ideally in combinations-to enhance the various aspects of the immune response against tumoral cells.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Carcinoma de Célula de Merkel/terapia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Neoplasias Cutâneas/terapia , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados/farmacologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/farmacologia , Antígeno B7-H1/imunologia , Carcinoma de Célula de Merkel/imunologia , Carcinoma de Célula de Merkel/patologia , Quimiorradioterapia Adjuvante/métodos , Quimioterapia Adjuvante/métodos , Ensaios Clínicos como Assunto , Procedimentos Cirúrgicos Dermatológicos , Humanos , Terapia Neoadjuvante/métodos , Nivolumabe/farmacologia , Nivolumabe/uso terapêutico , Receptor de Morte Celular Programada 1/imunologia , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/patologia , Padrão de Cuidado , Resultado do Tratamento , Evasão Tumoral/efeitos dos fármacos , Evasão Tumoral/imunologia
14.
Br J Cancer ; 120(5): 527-536, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30723303

RESUMO

BACKGROUND: Interferon-induced expression of programmed cell death ligands (PD-L1/PD-L2) may sustain tumour immune-evasion. Patients featuring MET amplification, a genetic lesion driving transformation, may benefit from anti-MET treatment. We explored if MET-targeted therapy interferes with Interferon-γ modulation of PD-L1/PD-L2 in MET-amplified tumours. METHODS: PD-L1/PD-L2 expression and signalling pathways downstream of MET or Interferon-γ were analysed in MET-amplified tumour cell lines and in patient-derived tumour organoids, in basal condition, upon Interferon-γ stimulation, and after anti-MET therapy. RESULTS: PD-L1 and PD-L2 were upregulated in MET-amplified tumour cells upon Interferon-γ treatment. This induction was impaired by JNJ-605, a selective inhibitor of MET kinase activity, and MvDN30, an antibody inducing MET proteolytic cleavage. We found that activation of JAKs/ STAT1, signal transducers downstream of the Interferon-γ receptor, was neutralised by MET inhibitors. Moreover, JAK2 and MET associated in the same signalling complex depending on MET phosphorylation. Results were confirmed in MET-amplified organoids derived from human colorectal tumours, where JNJ-605 treatment revoked Interferon-γ induced PD-L1 expression. CONCLUSIONS: These data show that in MET-amplified cancers, treatment with MET inhibitors counteracts the induction of PD-1 ligands by Interferon-γ. Thus, therapeutic use of anti-MET drugs may provide additional clinical benefit over and above the intended inhibition of the target oncogene.


Assuntos
Antígeno B7-H1/efeitos dos fármacos , Interferon gama/farmacologia , Neoplasias/genética , Proteína 2 Ligante de Morte Celular Programada 1/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Evasão Tumoral/efeitos dos fármacos , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Linhagem Celular Tumoral , Neoplasias Colorretais/patologia , Humanos , Janus Quinases/efeitos dos fármacos , Janus Quinases/metabolismo , Neoplasias Hepáticas/secundário , Terapia de Alvo Molecular , Neoplasias/metabolismo , Organoides , Proteína 2 Ligante de Morte Celular Programada 1/genética , Proteína 2 Ligante de Morte Celular Programada 1/metabolismo , Proteínas Proto-Oncogênicas c-met/genética , Receptores de Interferon , Fator de Transcrição STAT1/efeitos dos fármacos , Fator de Transcrição STAT1/metabolismo , Transdução de Sinais , Evasão Tumoral/genética
15.
Gastroenterology ; 156(6): 1849-1861.e13, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30711629

RESUMO

BACKGROUND & AIMS: Inhibitors of MET have not produced satisfactory outcomes in trials of patients with liver cancer. We investigated the mechanisms of liver tumor resistance to MET inhibitors in mice. METHODS: We tested the effects of MET inhibitors tivantinib and capmatinib in the mouse hepatocellular carcinoma (HCC) cell line HCA-1 and in immune-competent and immunodeficient mice with subcutaneous tumors grown from this cell line. Tumors were collected from mice and tumor cells were analyzed by time-of-flight mass cytometry. We used short hairpin RNAs to weaken expression of MET in Hep3B, SK-HEP-1, HA59T, and HA22T liver cancer cell lines and analyzed cells by immunoblot, immunofluorescence, and immunoprecipitation assays. Mass spectrometry was used to assess interactions between MET and glycogen synthase kinase 3ß (GSK3B), and GSK3B phosphorylation, in liver cancer cell lines. C57/BL6 mice with orthotopic tumors grown from Hep1-6 cells were given combinations of capmatinib or tivantinib and antibodies against programmed cell death 1 (PDCD1; also called PD1); tumors were collected and analyzed by immunofluorescence. We analyzed 268 HCCsamples in a tissue microarray by immunohistochemistry. RESULTS: Exposure of liver cancer cell lines to MET inhibitors increased their expression of PD ligand 1 (PDL1) and inactivated cocultured T cells. MET phosphorylated and activated GSK3B at tyrosine 56, which decreased the expression of PDL1 by liver cancer cells. In orthotopic tumors grown in immune-competent mice, MET inhibitors decreased the antitumor activity of T cells. However, addition of anti-PD1 decreased orthotopic tumor growth and prolonged survival of mice compared with anti-PD1 or MET inhibitors alone. Tissue microarray analysis of HCC samples showed an inverse correlation between levels of MET and PDL1 and a positive correlation between levels of MET and phosphorylated GSK3B. CONCLUSIONS: In studies of liver cancer cell lines and mice with orthotopic tumors, MET mediated phosphorylation and activated GSK3B, leading to decreased expression of PDL1. Combined with a MET inhibitor, anti-PD1 and anti-PDL1 produced additive effect to slow growth of HCCs in mice.


Assuntos
Antígeno B7-H1/metabolismo , Carcinoma Hepatocelular/enzimologia , Glicogênio Sintase Quinase 3 beta/metabolismo , Neoplasias Hepáticas/enzimologia , Proteínas Proto-Oncogênicas c-met/metabolismo , Fator 6 Associado a Receptor de TNF/metabolismo , Evasão Tumoral/efeitos dos fármacos , Animais , Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/imunologia , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/imunologia , Linhagem Celular Tumoral , Regulação para Baixo , Granzimas/metabolismo , Imidazóis/farmacologia , Imidazóis/uso terapêutico , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/imunologia , Masculino , Camundongos , Fosforilação , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Pirrolidinonas/farmacologia , Pirrolidinonas/uso terapêutico , Quinolinas/farmacologia , Quinolinas/uso terapêutico , Fator 6 Associado a Receptor de TNF/imunologia , Triazinas/farmacologia , Triazinas/uso terapêutico , Ubiquitinação
16.
Oncogene ; 38(3): 390-405, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30111819

RESUMO

Immunotherapy strategies have been emerging as powerful weapons against cancer. Early clinical trials reveal that overall response to immunotherapy is low in breast cancer patients, suggesting that effective strategies to overcome resistance to immunotherapy are urgently needed. In this study, we investigated whether epigenetic reprograming by modulating histone methylation could enhance effector T lymphocyte trafficking and improve therapeutic efficacy of immune checkpoint blockade in breast cancer with focus on triple-negative breast cancer (TNBC) subtype. In silico analysis of The Cancer Genome Atlas (TCGA) data shows that expression of histone lysine-specific demethylase 1 (LSD1) is inversely associated with the levels of cytotoxic T cell-attracting chemokines (C-C motif chemokine ligand 5 (CCL5), C-X-C motif chemokine ligand 9 and 10 (CXCL9, CXCL10)) and programmed death-ligand 1 (PD-L1) in clinical TNBC specimens. Tiling chromatin immunoprecipitation study showed that re-expression of chemokines by LSD1 inhibition is associated with increased H3K4me2 levels at proximal promoter regions. Rescue experiments using concurrent treatment with small interfering RNA or inhibitor of chemokine receptors blocked LSD1 inhibitor-enhanced CD8+ T cell migration, indicating a critical role of key T cell chemokines in LSD1-mediated CD8+ lymphocyte trafficking to the tumor microenvironment. In mice bearing TNBC xenograft tumors, anti-PD-1 antibody alone failed to elicit obvious therapeutic effect. However, combining LSD1 inhibitors with PD-1 antibody significantly suppressed tumor growth and pulmonary metastasis, which was associated with reduced Ki-67 level and augmented CD8+ T cell infiltration in xenograft tumors. Overall, these results suggest that LSD1 inhibition may be an effective adjuvant treatment with immunotherapy as a novel management strategy for poorly immunogenic breast tumors.


Assuntos
Antineoplásicos/uso terapêutico , Código das Histonas/efeitos dos fármacos , Inibidores de Histona Desacetilases/farmacologia , Histona Desmetilases/antagonistas & inibidores , Imunoterapia/métodos , Proteínas de Neoplasias/antagonistas & inibidores , Neoplasias de Mama Triplo Negativas/imunologia , Evasão Tumoral/efeitos dos fármacos , Animais , Antineoplásicos Imunológicos/uso terapêutico , Antígeno B7-H1/metabolismo , Linfócitos T CD8-Positivos/imunologia , Linhagem Celular Tumoral , Quimiocinas/metabolismo , Feminino , Inibidores de Histona Desacetilases/uso terapêutico , Humanos , Metilação , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Regiões Promotoras Genéticas/efeitos dos fármacos , Interferência de RNA , RNA Interferente Pequeno/genética , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/enzimologia , Microambiente Tumoral/imunologia , Ensaios Antitumorais Modelo de Xenoenxerto
17.
Cancer Lett ; 442: 279-286, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30419350

RESUMO

Gastric adenocarcinoma and esophageal adenocarcinoma are aggressive cancers with a poor prognosis. Therefore, new therapeutic strategies are needed, especially for patients refractory to conventional treatment. Cancer immunotherapy (CIT), is a promising new treatment option and is effective in a proportion of patients with gastroesophageal malignancies. Biomarkers for selecting patients likely to benefit from CIT in gastroesophageal malignancies remain unproven. Programmed cell death ligand-1 (PD-L1), which is a validated biomarker in non-small cell lung cancer (NSCLC), is often also used to select patients for CIT in the context of gastroesophageal cancer, although this marker has not been validated for this purpose. We question the use of PD-L1 as a biomarker in gastroesophageal cancers, as there are fundamental differences in PD-L1 expression between NSCLC and gastroesophageal cancers. This review discusses the value of PD-L1 in selecting patients for CIT in esophageal and gastric cancer. Potential alternatives, especially microsatellite instability and Epstein-Barr virus positivity, are discussed.


Assuntos
Adenocarcinoma/tratamento farmacológico , Antineoplásicos Imunológicos/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Biomarcadores Tumorais/antagonistas & inibidores , Neoplasias Esofágicas/tratamento farmacológico , Imunoterapia/métodos , Neoplasias Gástricas/tratamento farmacológico , Adenocarcinoma/genética , Adenocarcinoma/imunologia , Adenocarcinoma/virologia , Animais , Antineoplásicos Imunológicos/efeitos adversos , Antígeno B7-H1/imunologia , Antígeno B7-H1/metabolismo , Biomarcadores Tumorais/imunologia , Biomarcadores Tumorais/metabolismo , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/imunologia , Neoplasias Esofágicas/virologia , Herpesvirus Humano 4/isolamento & purificação , Humanos , Imunoterapia/efeitos adversos , Instabilidade de Microssatélites , Terapia de Alvo Molecular , Transdução de Sinais/efeitos dos fármacos , Neoplasias Gástricas/genética , Neoplasias Gástricas/imunologia , Neoplasias Gástricas/virologia , Resultado do Tratamento , Evasão Tumoral/efeitos dos fármacos
18.
Eur Urol ; 75(3): 435-444, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30274701

RESUMO

CONTEXT: The abysmal outlook of urothelial cancer (UC) has changed with the introduction of immunotherapy. Still, many patients do not respond and distinctive biomarkers are currently lacking. The rise of this novel armamentarium of immunotherapy treatments, in combination with the complex biology of an immunological tumor response, warrants the development of a comprehensive framework that can provide an overview of important immunological processes at play in individual patients. OBJECTIVE: To develop a comprehensive framework based on tumor- and host-specific parameters to understand immunotherapy response in UC. This framework can inform rational, biology-driven clinical trials and ultimately guide us toward individualized patient treatment. EVIDENCE ACQUISITION: A literature review was conducted on UC immunotherapy, clinical trial data, and biomarkers of response to checkpoint inhibition. EVIDENCE SYNTHESIS: Here, we propose a UC immunogram, based on currently available clinical and translational data. The UC immunogram describes several tumor- and host-specific parameters that are required for successful immunotherapy treatment. These seven parameters are tumor foreignness, immune cell infiltration, absence of inhibitory checkpoints, general performance and immune status, absence of soluble inhibitors, absence of inhibitory tumor metabolism, and tumor sensitivity to immune effectors. CONCLUSIONS: Longitudinal integration of individual patient parameters may ultimately lead to personalized and dynamic immunotherapy, to adjust to the Darwinian forces that drive tumor evolution. Incorporating multiparameter biomarkers into quantitative predictive models will be a key challenge to integrate the immunogram into daily clinical practice. PATIENT SUMMARY: Here, we propose the urothelial cancer immunogram, a novel way of describing important immunological characteristics of urothelial cancer patients and their tumors. Seven characteristics determine the chance of having an immunological tumor response. Using this immunogram, we aim to better understand why some patients respond to immunotherapy and some do not, to ultimately improve anticancer therapy.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Biomarcadores Tumorais/antagonistas & inibidores , Imunoterapia/métodos , Medicina de Precisão/métodos , Neoplasias da Bexiga Urinária/tratamento farmacológico , Urotélio/efeitos dos fármacos , Animais , Antineoplásicos Imunológicos/efeitos adversos , Biomarcadores Tumorais/imunologia , Tomada de Decisão Clínica , Humanos , Imunoterapia/efeitos adversos , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/patologia , Seleção de Pacientes , Valor Preditivo dos Testes , Transdução de Sinais/efeitos dos fármacos , Resultado do Tratamento , Evasão Tumoral/efeitos dos fármacos , Microambiente Tumoral , Neoplasias da Bexiga Urinária/imunologia , Neoplasias da Bexiga Urinária/patologia , Urotélio/imunologia , Urotélio/patologia
19.
Oncol Rep ; 41(1): 3-14, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30365127

RESUMO

Cancer cells can escape antitumor immune responses by exploiting inhibitory immune checkpoints. Immune checkpoint therapy, mainly including anti­CTLA­4 therapy and anti­PD­1/PD­L1 therapy, can enhance antitumor immune responses by blocking the inhibitory signals of the immune system. This therapy has produced clinical advances in a fraction of patients. Deeper insight into the tumor microenvironment and immune checkpoint inhibitors will improve this therapy. Here, we review immune checkpoint inhibitors that prevent tumor immune escape and recent clinical studies of immune checkpoint therapy. We also compare the efficacy of different combination immunotherapies, describe how the relationship between the gut microbiome and immune system can determine the therapeutic outcomes for immune checkpoint inhibitors and introduce several novel immune checkpoints that are potential targets for antitumor immunotherapy in the future.


Assuntos
Anticorpos Monoclonais/farmacologia , Neoplasias/tratamento farmacológico , Evasão Tumoral/efeitos dos fármacos , Anticorpos Monoclonais/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Antígeno CTLA-4/antagonistas & inibidores , Humanos , Neoplasias/imunologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores
20.
Am J Clin Dermatol ; 20(1): 41-54, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30259383

RESUMO

The recent development of effective immune checkpoint inhibition (ICI), first demonstrated in melanoma, has revolutionized cancer treatment. Monoclonal antibodies blocking the immune checkpoints cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and programmed death 1 receptor (PD-1) have shown substantial clinical benefit in a subset of patients across tumor types and in both the metastatic and adjuvant settings. In this article, we review the interaction between the immune system and solid tumors, and describe modes of immune response failure and the physiologic role of immune checkpoints. We also review the known mechanisms of immune checkpoint inhibitors, focusing on US FDA-approved agents targeting CTLA-4 and PD-1. Within this framework, we classify hypothesized tumor intrinsic and extrinsic predictive markers for response and resistance to ICI, and map them to their putative underlying biological mechanism. Finally, we outline future directions in ICI, including the development of new therapeutic targets, rational combination therapies, integrated predictive models for individual patients to optimize therapy, and expansion into different disease types.


Assuntos
Antineoplásicos Imunológicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Resistencia a Medicamentos Antineoplásicos/genética , Melanoma/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológico , Antineoplásicos Imunológicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/imunologia , Antígeno CTLA-4/antagonistas & inibidores , Antígeno CTLA-4/genética , Antígeno CTLA-4/imunologia , Resistencia a Medicamentos Antineoplásicos/imunologia , Humanos , Imunoterapia/métodos , Melanoma/imunologia , Mutação , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/imunologia , Neoplasias Cutâneas/imunologia , Resultado do Tratamento , Evasão Tumoral/efeitos dos fármacos , Evasão Tumoral/genética
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