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1.
Anticancer Res ; 40(10): 5445-5456, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32988866

RESUMO

BACKGROUND/AIM: Dietary interventions like time-restricted feeding (TRF) show promising anti-cancer properties. We examined whether therapeutic TRF alone or combined with immunotherapy would diminish renal tumor growth in mice of varying body weights. MATERIALS AND METHODS: Young (7 week) chow-fed or older (27 week) high-fat diet (HFD)-fed BALB/c mice were orthotopically injected with renal tumor cells expressing luciferase. After tumor establishment, mice were randomized to ad libitum feeding or TRF +/- anti-CTLA-4. Body composition, tumor viability and growth, and immune responses were quantified. RESULTS: TRF alone reduced renal tumor bioluminescence in older HFD-fed, but not young chow-fed mice. In the latter, TRF mitigated tumor-induced loss of lean- and fat-mass. However, TRF did not alter excised renal tumor weights or intratumoral immune responses and failed to improve anti-CTLA-4 outcomes in any mice. CONCLUSION: Therapeutic TRF exhibits modest anti-cancer properties but fails to improve anti-CTLA-4 immune checkpoint blockade in murine renal cancer.


Assuntos
Jejum , Neoplasias Renais/tratamento farmacológico , Obesidade/tratamento farmacológico , Animais , Antígeno CTLA-4/antagonistas & inibidores , Antígeno CTLA-4/imunologia , Modelos Animais de Doenças , Ingestão de Alimentos/fisiologia , Humanos , Imunoterapia/efeitos adversos , Neoplasias Renais/complicações , Neoplasias Renais/genética , Neoplasias Renais/patologia , Camundongos , Obesidade/complicações , Obesidade/genética
2.
PLoS Pathog ; 16(8): e1008696, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32760139

RESUMO

HLA-B*35Px is associated with HIV-1 disease rapid progression to AIDS. However, the mechanism(s) underlying this deleterious effect of this HLA allele on HIV-1 infection outcome has not fully understood. CD8+ T cells play a crucial role to control the viral replication but impaired CD8+ T cells represent a major hallmark of HIV-1 infection. Here, we examined the effector functions of CD8+ T cells restricted by HLA-B*35Px (HLA-B*35:03 and HLA-B*35:02), HLA-B*27/B57 and non-HLA-B*27/B57 (e.g. HLA-A*01, A*02, A*03, A*11, A*24, A*26, B*40, B*08, B*38, B*44). CD8+ T cells restricted by HLA-B*35Px exhibited an impaired phenotype compared with those restricted by HLA-B*27/B57 and even non-HLA-B*27/B57. CD8+ T cells restricted by non-HLA-B*27/B57 when encountered their cognate epitopes upregulated TIM-3 and thus became suppressed by regulatory T cells (Tregs) via TIM-3: Galectin-9 (Gal-9). Strikingly, CD8+ T cells restricted by HLA-B*35Px expressed fewer TIM-3 and therefore did not get suppressed by Tregs, which was similar to CD8+ T cells restricted by HLA-B*27/B57. Instead, CD8+ T cells restricted by HLA-B*35Px upon recognition of their cognate epitopes upregulated CTLA-4. The transcriptional and impaired phenotype (e.g. poor effector functions) of HIV-specific CD8+ T cells restricted by HLA-B*35 was related to persistent CTLA-4, elevated Eomes and blimp-1 but poor T-bet expression. As such, anti-CTLA-4 antibody, Ipilimumab, reversed the impaired proliferative capacity of antigen-specific CD8+ T cells restricted by HLA-B*35Px but not others. This study supports the concept that CD8+ T resistance to Tregs-mediated suppression is related to allele restriction rather than the epitope specificity. Our results aid to explain a novel mechanism for the inability of HIV-specific CD8+ T cells restricted by HLA-B*35Px to control viral replication.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Antígeno CTLA-4/metabolismo , Epitopos de Linfócito T/imunologia , Infecções por HIV/imunologia , HIV-1/imunologia , Antígeno HLA-B35/imunologia , Replicação Viral , Antígeno CTLA-4/imunologia , Citocinas/metabolismo , Infecções por HIV/metabolismo , Infecções por HIV/virologia , HIV-1/metabolismo , Humanos , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/metabolismo , Ativação Linfocitária/imunologia , Fenótipo , Linfócitos T Reguladores/imunologia
3.
Int J Nanomedicine ; 15: 5279-5288, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32801691

RESUMO

Introduction: Today, a new paradigm has emerged for cancer treatment introducing combination therapies. Doxil, a liposomal doxorubicin serving as a chemotherapeutic agent, is an effective immunogenic killer of cancer cells. Anti-CTLA-4 has been approved for the treatment of some cancers, including melanoma, but side effects have limited its therapeutic potential. Methods: In this study, two approaches were utilized to increase treatment efficiency and decrease the side effects of anti-CTLA-4, combining it with chemotherapy and encapsulation in a PEGylated liposome. A different sequence of anti-CTLA-4 and Doxil was assessed in combination therapy using non-liposomal and liposomal anti-CTLA-4. Results: Our results showed that liposomal anti-CTLA-4 reduced the size of established tumors and increased survival in comparison with non-liposomal anti-CTLA-4 in a well-established B16 mouse melanoma model. In combination therapy with Doxil, only the administration of anti-CTLA-4 before Doxil showed synergism in both non-liposomal and liposomal form and increased the CD8+/regulatory T cell ratio. Discussion: In summary, our results demonstrate the potential of utilizing a nanocarrier system for the delivery of checkpoint blockers, such as anti-CTLA-4 which further showed potential in a combination therapy, especially when administered before chemotherapy.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Antígeno CTLA-4/antagonistas & inibidores , Melanoma Experimental/tratamento farmacológico , Animais , Antineoplásicos Imunológicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Antígeno CTLA-4/imunologia , Doxorrubicina/administração & dosagem , Doxorrubicina/análogos & derivados , Feminino , Lipossomos/química , Camundongos Endogâmicos C57BL , Polietilenoglicóis/administração & dosagem , Polietilenoglicóis/química , Linfócitos T Reguladores/efeitos dos fármacos
5.
Arch Virol ; 165(10): 2249-2258, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32696270

RESUMO

While infectious bursal disease virus (IBDV) mainly targets immature B cells and causes T cell infiltration in the bursa of Fabricius (BF) of chickens, the effect of IBDV infection on the properties of T cells and relevant cytokine production in avian gut-associated lymphoid tissues (GALTs) remains unknown. Here, we show that while the CD8+ T cell subset is not affected, IBDV infection decreases the percentage of CD4+ T cells in the cecal tonsil (CT), but not in esophagus tonsil, pylorus tonsil, and Meckel's diverticulum of GALTs, in contrast to BF and spleen, in which the proportion of CD4+ cells increases upon IBDV infection. Further, IBDV infection upregulates IFN-γ, IL-10, and the T cell checkpoint receptor LAG-3 mRNA expression in BF. In contrast, in CTs, IBDV infection significantly increases the production of IFN-ß and CTLA-4 mRNA, while no significant effect is seen in the case of IFN-γ, IL-10 and LAG-3. Together, our data reveal differential modulation of T cell subsets and proinflammatory cytokine production in different lymphoid tissues during the course of IBDV infection.


Assuntos
Subpopulações de Linfócitos B/imunologia , Infecções por Birnaviridae/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Regulação da Expressão Gênica/imunologia , Doenças das Aves Domésticas/imunologia , Animais , Antígenos CD/genética , Antígenos CD/imunologia , Subpopulações de Linfócitos B/virologia , Infecções por Birnaviridae/genética , Infecções por Birnaviridae/patologia , Infecções por Birnaviridae/virologia , Bolsa de Fabricius/imunologia , Bolsa de Fabricius/virologia , Linfócitos T CD4-Positivos/virologia , Linfócitos T CD8-Positivos/virologia , Antígeno CTLA-4/genética , Antígeno CTLA-4/imunologia , Galinhas/virologia , Vírus da Doença Infecciosa da Bursa/crescimento & desenvolvimento , Vírus da Doença Infecciosa da Bursa/imunologia , Vírus da Doença Infecciosa da Bursa/patogenicidade , Interferon beta/genética , Interferon beta/imunologia , Interferon gama/genética , Interferon gama/imunologia , Interleucina-10/genética , Interleucina-10/imunologia , Mucosa Intestinal/imunologia , Mucosa Intestinal/virologia , Tonsila Palatina/imunologia , Tonsila Palatina/virologia , Doenças das Aves Domésticas/genética , Doenças das Aves Domésticas/patologia , Doenças das Aves Domésticas/virologia
6.
Cancer Treat Rev ; 88: 102057, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32574991

RESUMO

Despite advances in metastatic prostate cancer therapy, expected survival for patients in the castration-resistant phase of disease is poor. Immune-checkpoints inhibitors significantly prolonged life expectancy in some solid tumors and have been evaluated also in advanced stage prostate cancer. The majority of data available derive from preliminary phase I and II trials evaluating CTLA-4 and PD-1 as monotherapy or in combination with each other, vaccines, radiotherapy or targeted/hormonal therapy, achieving only limited benefits in terms of biochemical and radiologic responses. There are many reasons that may explain why prostate cancer responds poorly to modern immunotherapies, such as its characteristic low tumor mutational burden or immune-suppressive tumor microenvironment. The present review summarizes the results obtained treating advanced prostate cancer patients with immune-checkpoints inhibitors and analyzes potential mechanisms of both resistance and sensitivity, in order to hypothesize possible avenues of special interest for future research.


Assuntos
Imunoterapia/métodos , Neoplasias de Próstata Resistentes à Castração/terapia , Antineoplásicos Imunológicos/administração & dosagem , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/imunologia , Antígeno CTLA-4/antagonistas & inibidores , Antígeno CTLA-4/imunologia , Vacinas Anticâncer/administração & dosagem , Ensaios Clínicos Fase II como Assunto , Ensaios Clínicos Fase III como Assunto , Humanos , Masculino , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Neoplasias de Próstata Resistentes à Castração/genética , Neoplasias de Próstata Resistentes à Castração/imunologia , Ensaios Clínicos Controlados Aleatórios como Assunto
7.
Gene ; 754: 144888, 2020 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-32544493

RESUMO

The development and progression of different pathologies including, cancer, are associated with suppressed immune responses. This restrained immune activity could be associated with the activation of different immune checkpoint pathways that mediate immunosuppressive functions. Therapeutic Protocols based on abolishing the activity of immune check points provided a promising potential for treating cancer. Among the distinct known immune checkpoints, PD-1/PD-L1 and CTLA-4, are the most studied and have been the focus for development of different blocking agents. Monoclonal antibodies that can block PD-1, PD-L1 or CTLA4 have been approved for treatment of different cancers. MicroRNAs (miRNAs), short non-coding regulatory RNA molecules, could repress mRNA expression at a post-transcriptional level. Many miRNAs have been reported to modulate the expression of CTLA-4 and PD-1/PD-L1, either directly or indirectly, in multiple pathological cases, mainly cancer. In this review, after a brief introduction about T cell activation and immune checkpoints, the miRNAs regulating the expression of CTLA-4 and PD-1/PD-L1 are discussed with highlights on their role in cancer. Many of these miRNAs could serve as novel treatments in different types of cancer as detailed throughout the review.


Assuntos
Antígeno B7-H1/antagonistas & inibidores , Antígeno CTLA-4/antagonistas & inibidores , Imunoterapia/métodos , Ativação Linfocitária , MicroRNAs/farmacologia , Neoplasias/terapia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Antígeno B7-H1/imunologia , Antígeno CTLA-4/imunologia , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias/genética , Neoplasias/imunologia , Neoplasias/patologia , Receptor de Morte Celular Programada 1/imunologia
8.
Clin Cancer Res ; 26(16): 4201-4205, 2020 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-32540850

RESUMO

The potential immune intersection between COVID-19 disease and cancer therapy raises important practical clinical questions and highlights multiple scientific gaps to be filled. Among available therapeutic approaches to be considered, immune checkpoint inhibitors (ICI) seem to require major attention as they may act at the crossroads between cancer treatment and COVID-19 disease, due to their profound immunomodulatory activity. On the basis of available literature evidence, we suggest guidance to consider for treating physicians, and propose areas of clinical and preclinical investigation. Comprehensively, although with the necessary caution, ICI therapy seems to remain a suitable therapeutic option for patients with cancer during the COVID-19 pandemic.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Betacoronavirus/imunologia , Infecções por Coronavirus/imunologia , Neoplasias/tratamento farmacológico , Pneumonia Viral/imunologia , Antineoplásicos Imunológicos/farmacologia , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/imunologia , Antígeno CTLA-4/antagonistas & inibidores , Antígeno CTLA-4/imunologia , Tomada de Decisão Clínica , Ensaios Clínicos como Assunto , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/prevenção & controle , Infecções por Coronavirus/virologia , Humanos , Neoplasias/imunologia , Pandemias/prevenção & controle , Pneumonia Viral/epidemiologia , Pneumonia Viral/prevenção & controle , Pneumonia Viral/virologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Resultado do Tratamento
9.
Am Surg ; 86(4): 284-292, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-32391751

RESUMO

Progress in the arena of cancer immunotherapy has been immense in recent years. The fact remains that most of the cancer resections in the United States are performed by general surgeons and not oncologic specialists. A busy practice in general surgery will invariably make it difficult to keep pace with such rapid advancement. This review offers a concise summary of the major concepts and trials that have driven the immunotherapy revolution and their implications for surgeons who deliver cancer care.


Assuntos
Imunoterapia , Melanoma/tratamento farmacológico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Neoplasias Cutâneas/tratamento farmacológico , Antígeno CTLA-4/antagonistas & inibidores , Antígeno CTLA-4/imunologia , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Quimioterapia Adjuvante , Neoplasias Gastrointestinais/tratamento farmacológico , Humanos , Imunoterapia/efeitos adversos , Neoplasias Hepáticas/tratamento farmacológico , Receptor de Morte Celular Programada 1/imunologia
10.
Nat Med ; 26(4): 519-528, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32284611

RESUMO

The primary human immunodeficiency virus (HIV) reservoir is composed of resting memory CD4+ T cells, which often express the immune checkpoint receptors programmed cell death protein 1 (PD-1) and cytotoxic T lymphocyte-associated protein 4 (CTLA-4), which limit T cell activation via synergistic mechanisms. Using simian immunodeficiency virus (SIV)-infected, long-term antiretroviral therapy (ART)-treated rhesus macaques, we demonstrate that PD-1, CTLA-4 and dual CTLA-4/PD-1 immune checkpoint blockade using monoclonal antibodies is well tolerated, with evidence of bioactivity in blood and lymph nodes. Dual blockade was remarkably more effective than PD-1 blockade alone in enhancing T cell cycling and differentiation, expanding effector-memory T cells and inducing robust viral reactivation in plasma and peripheral blood mononuclear cells. In lymph nodes, dual CTLA-4/PD-1 blockade, but not PD-1 alone, decreased the total and intact SIV-DNA in CD4+ T cells, and SIV-DNA and SIV-RNA in B cell follicles, a major site of viral persistence during ART. None of the tested interventions enhanced SIV-specific CD8+ T cell responses during ART or viral control after ART interruption. Thus, despite CTLA-4/PD-1 blockade inducing robust latency reversal and reducing total levels of integrated virus, the degree of reservoir clearance was still insufficient to achieve viral control. These results suggest that immune checkpoint blockade regimens targeting PD-1 and/or CTLA-4, if performed in people living with HIV with sustained aviremia, are unlikely to induce HIV remission in the absence of additional interventions.


Assuntos
Antirretrovirais/uso terapêutico , Anticorpos Monoclonais/farmacologia , Antígeno CTLA-4/imunologia , Receptor de Morte Celular Programada 1/imunologia , Síndrome de Imunodeficiência Adquirida dos Símios/tratamento farmacológico , Vírus da Imunodeficiência Símia/efeitos dos fármacos , Ativação Viral/efeitos dos fármacos , Animais , Antirretrovirais/imunologia , Anticorpos Monoclonais/sangue , Anticorpos Monoclonais/farmacocinética , Antígeno CTLA-4/antagonistas & inibidores , Macaca mulatta , Masculino , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Síndrome de Imunodeficiência Adquirida dos Símios/sangue , Síndrome de Imunodeficiência Adquirida dos Símios/imunologia , Síndrome de Imunodeficiência Adquirida dos Símios/virologia , Vírus da Imunodeficiência Símia/fisiologia , Carga Viral/efeitos dos fármacos , Viremia/induzido quimicamente , Replicação Viral/efeitos dos fármacos , Suspensão de Tratamento
11.
Cancer Immunol Immunother ; 69(9): 1737-1749, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32333082

RESUMO

Combination immunotherapy targeting the PD-1 and CTLA-4 checkpoint inhibitor pathways provides substantial clinical benefit in patients with advanced-stage cancer but at the risk of dose-limiting inflammatory and autoimmune toxicity. The delicate balance that exists between unleashing tumor killing and promoting systemic autoimmune toxicity represents a major clinical challenge. We hypothesized that targeting anti-CTLA-4 so that it perfuses tumor-draining lymph nodes would provide a significant therapeutic advantage and developed an injectable hydrogel with controlled antibody release characteristics for this purpose. Injection of hydrogel-encapsulated anti-CTLA-4 at a peri-tumor location (MC-38 tumor model) produced dose-dependent antitumor responses and survival that exceeded those by anti-CTLA-4 alone (p < 0.05). Responses to 100 µg of targeted anti-CTLA-4 also equaled or exceeded those observed with a series of systemic injections delivering 600 µg (p < 0.05). While preserving antitumor activity, this approach resulted in serum anti-CTLA-4 exposure (area under the curve) that averaged only 1/16th of that measured with systemic therapy. Consistent with the marked differences in systemic exposure, systemic anti-CTLA-4 stimulated the onset of autoimmune thyroiditis in iodide-exposed NOD.H-2h4 mice, as measured by anti-thyroglobulin antibody titer, while hydrogel-encapsulated anti-CTLA-4 had a minimal effect (p ≤ 0.01). At the same time, this targeted low-dose anti-CTLA-4 approach synergized well with systemic anti-PD-1 to control tumor growth and resulted in a high frequency of complete responders that were immune to tumor re-challenge at a distant site. We conclude that targeted and controlled delivery of low-dose anti-CTLA-4 has the potential to improve the benefit-risk ratio associated with combination checkpoint inhibitor therapy.


Assuntos
Antineoplásicos/farmacologia , Antígeno CTLA-4/imunologia , Preparações de Ação Retardada/farmacologia , Imunidade/efeitos dos fármacos , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Animais , Autoimunidade/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Terapia Combinada/métodos , Sinergismo Farmacológico , Feminino , Imunoterapia/métodos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD
12.
PLoS One ; 15(4): e0231003, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32240238

RESUMO

Systematic interrogation of tumor-infiltrating immune cells (TIICs) is key to the prediction of clinical outcome and development of immunotherapies. However, little is known about the TIICs of hepatocellular carcinoma (HCC) and its impact on the prognosis of patients and potential for immunotherapy. We applied CIBERSORT of 1090 tumors to infer the infiltration of 22 subsets of TIICs using gene expression data. Unsupervised clustering analysis by 22 TIICs revealed 4 clusters of tumors, mainly defined by macrophages and T cells, with distinct prognosis and associations with immune checkpoint molecules, including PD-1, CD274, CTLA-4, LAG-3 and IFNG. We found tumors with decreased number of M1 macrophages or increased regulatory T cells were associated with poor prognosis. Based on the multivariate Cox analysis, a nomogram was also established for clinical application. In conclusion, composition of the TIICs in HCC was quite different, which is an important determinant of prognosis with great potential to identify candidates for immunotherapy.


Assuntos
Carcinoma Hepatocelular/imunologia , Neoplasias Hepáticas/imunologia , Linfócitos do Interstício Tumoral/imunologia , Linfócitos T Reguladores/imunologia , Antígeno B7-H1/imunologia , Antígeno CTLA-4/imunologia , Feminino , Expressão Gênica/imunologia , Humanos , Imunoterapia/métodos , Macrófagos/imunologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Receptor de Morte Celular Programada 1/imunologia
13.
Nat Med ; 26(5): 781-791, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32284588

RESUMO

Although immunotherapy has revolutionized cancer treatment, only a subset of patients demonstrate durable clinical benefit. Definitive predictive biomarkers and targets to overcome resistance remain unidentified, underscoring the urgency to develop reliable immunocompetent models for mechanistic assessment. Here we characterize a panel of syngeneic mouse models, representing a variety of molecular and phenotypic subtypes of human melanomas and exhibiting their diverse range of responses to immune checkpoint blockade (ICB). Comparative analysis of genomic, transcriptomic and tumor-infiltrating immune cell profiles demonstrated alignment with clinical observations and validated the correlation of T cell dysfunction and exclusion programs with resistance. Notably, genome-wide expression analysis uncovered a melanocytic plasticity signature predictive of patient outcome in response to ICB, suggesting that the multipotency and differentiation status of melanoma can determine ICB benefit. Our comparative preclinical platform recapitulates melanoma clinical behavior and can be employed to identify mechanisms and treatment strategies to improve patient care.


Assuntos
Ensaios de Seleção de Medicamentos Antitumorais , Imunoterapia , Melanoma/patologia , Melanoma/terapia , Animais , Antineoplásicos Imunológicos/uso terapêutico , Antígeno CTLA-4/imunologia , Células Cultivadas , Modelos Animais de Doenças , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Heterogeneidade Genética , Humanos , Imunoterapia/efeitos adversos , Imunoterapia/métodos , Ipilimumab/uso terapêutico , Melanoma/diagnóstico , Melanoma/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Prognóstico , Receptor de Morte Celular Programada 1/imunologia , RNA-Seq , Resultado do Tratamento , Sequenciamento Completo do Genoma
15.
Adv Exp Med Biol ; 1248: 7-32, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32185705

RESUMO

Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) is an inhibitory receptor belonging to the CD28 immunoglobulin subfamily, expressed primarily by T-cells. Its ligands, CD80 and CD86, are typically found on the surface of antigen-presenting cells and can either bind CD28 or CTLA-4, resulting in a costimulatory or a co-inhibitory response, respectively. Because of its dampening effect, CTLA-4 is a crucial regulator of T-cell homeostasis and self-tolerance. The mechanisms by which CTLA-4 exerts its inhibitory function can be categorized as either cell-intrinsic (affects the CTLA-4 expressing T-cell) or cell-extrinsic (affects secondary cells). Research from the last decade has shown that CTLA-4 mainly acts in a cell-extrinsic manner via its competition with CD28, CTLA-4-mediated trans-endocytosis of CD80 and CD86, and its direct tolerogenic effects on the interacting cell. Nonetheless, intrinsic CTLA-4 signaling has been implicated in T-cell motility and the regulation of CTLA-4 its subcellular localization amongst others. CTLA-4 is well recognized as a key immune checkpoint and has gained significant momentum as a therapeutic target in the field of autoimmunity and cancer. In this chapter, we describe the role of costimulation in immune response induction as well as the main mechanisms by which CTLA-4 can inhibit this process.


Assuntos
Antígeno CTLA-4/imunologia , Antígeno CTLA-4/metabolismo , Animais , Antígeno B7-1/metabolismo , Antígeno B7-2/metabolismo , Antígenos CD28/metabolismo , Humanos , Ativação Linfocitária
16.
Clin Dermatol ; 38(1): 94-104, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32197753

RESUMO

Immune checkpoint inhibitors (ICPi) have emerged as a new frontier of cancer therapy. Although monoclonal antibodies to cytotoxic T-lymphocyte associated protein 4 (CTLA-4), programmed cell death 1 (PD-1), and programmed cell death ligand 1 (PD-L1) have revolutionized oncologic management, these agents may result in a spectrum of immune-related adverse events (irAE) of which dermatologic toxicities are among the most frequent. Prompt recognition and management of irAE is essential for dermatologists caring for the expanding population of cancer patients exposed to these drugs. Cutaneous toxicities range from mild cases to severe and life-threatening presentations that may cause significant morbidity and mortality. This review provides an overview of severe cutaneous adverse reactions (SCARs) that may develop during ICPi therapy, including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP). In addition, immunobullous disorders, erythroderma, neutrophilic dermatoses, and cutaneous eruptions associated with systemic manifestations are discussed.


Assuntos
Anticorpos Monoclonais/efeitos adversos , Antineoplásicos/efeitos adversos , Erupção por Droga/etiologia , Erupção por Droga/patologia , Pustulose Exantematosa Aguda Generalizada/etiologia , Pustulose Exantematosa Aguda Generalizada/patologia , Antígeno B7-H1/imunologia , Antígeno CTLA-4/imunologia , Humanos , Receptor de Morte Celular Programada 1 , Síndrome de Stevens-Johnson/etiologia , Síndrome de Stevens-Johnson/patologia
17.
Support Care Cancer ; 28(6): 2499-2502, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32147760

RESUMO

We present the first detailed report of acneiform eruptions in patients on CTLA-4 inhibitor therapy. Acneiform eruptions commonly occur (up to 75-100%) as a cutaneous adverse event associated with EGFR inhibition; however, acneiform eruptions have not been highly reported as a cutaneous adverse event associated with CTLA-4 inhibitor therapy. We conducted a retrospective chart review of our institution's database to assess cutaneous adverse events associated with ipilimumab and tremelimumab, identifying 12 patients with acneiform eruptions (2 on tremelimumab and 10 on ipilimumab). The median time to onset of rash was 3 weeks after starting CTLA-4 inhibitor therapy, ranging from 0.7-45 weeks. Median time to cutaneous resolution was 6 weeks, ranging from 2 to 282 weeks. Treatment included oral and topical antibiotics, antihistamines, and oral or topical corticosteroids with four patients receiving no treatment. Acneiform eruptions are seen less commonly with CTLA-4 inhibitors than other cancer therapies, but awareness that it does occur is important for clinical practice. Better description is a necessary help to aid in early diagnosis and intervention. While EGFR inhibitor-associated acneiform eruptions are associated with clinical benefit, our sample size is too small to determine whether CTLA-4 inhibitor associated acneiform eruptions display the same correlation.


Assuntos
Erupções Acneiformes/induzido quimicamente , Antígeno CTLA-4/antagonistas & inibidores , Erupções Acneiformes/imunologia , Idoso , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Antineoplásicos Hormonais/efeitos adversos , Antígeno CTLA-4/imunologia , Estudos de Coortes , Feminino , Humanos , Ipilimumab/administração & dosagem , Ipilimumab/efeitos adversos , Masculino , Pessoa de Meia-Idade , Neoplasias/tratamento farmacológico , Estudos Retrospectivos
18.
Proc Natl Acad Sci U S A ; 117(14): 8022-8031, 2020 04 07.
Artigo em Inglês | MEDLINE | ID: mdl-32213589

RESUMO

Innate immune receptors such as toll-like receptors (TLRs) provide critical molecular links between innate cells and adaptive immune responses. Here, we studied the CD40 pathway as an alternative bridge between dendritic cells (DCs) and adaptive immunity in cancer. Using an experimental design free of chemo- or radiotherapy, we found CD40 activation with agonistic antibodies (⍺CD40) produced complete tumor regressions in a therapy-resistant pancreas cancer model, but only when combined with immune checkpoint blockade (ICB). This effect, unachievable with ICB alone, was independent of TLR, STING, or IFNAR pathways. Mechanistically, αCD40/ICB primed durable T cell responses, and efficacy required DCs and host expression of CD40. Moreover, ICB drove optimal generation of polyfunctional T cells in this "cold" tumor model, instead of rescuing T cell exhaustion. Thus, immunostimulation via αCD40 is sufficient to synergize with ICB for priming. Clinically, combination αCD40/ICB may extend efficacy in patients with "cold" and checkpoint-refractory tumors.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Antígenos CD40/agonistas , Carcinoma Ductal Pancreático/tratamento farmacológico , Neoplasias/tratamento farmacológico , Neoplasias Pancreáticas/tratamento farmacológico , Animais , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Antígenos CD40/imunologia , Antígenos CD40/metabolismo , Antígeno CTLA-4/antagonistas & inibidores , Antígeno CTLA-4/imunologia , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/imunologia , Carcinoma Ductal Pancreático/patologia , Linhagem Celular Tumoral , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Modelos Animais de Doenças , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/imunologia , Ensaios de Seleção de Medicamentos Antitumorais , Sinergismo Farmacológico , Feminino , Humanos , Ativação Linfocitária/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neoplasias/imunologia , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/imunologia , Neoplasias Pancreáticas/patologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia
19.
Nat Rev Urol ; 17(3): 137-150, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32020040

RESUMO

Kidney cancer has unique features that make this malignancy attractive for therapeutic approaches that target components of the immune system. Immune checkpoint inhibition is a well-established part of kidney cancer treatment, and rapid advances continue to be made in this field. Initial preclinical studies that elucidated the biology of the programmed cell death 1 (PD-1), programmed cell death 1 ligand 1 (PD-L1) and cytotoxic T lymphocyte antigen 4 (CTLA-4) immune checkpoints led to a series of clinical trials that resulted in regulatory approval of nivolumab and the combination of ipilimumab plus nivolumab for the treatment of advanced renal cell carcinoma. Subsequent data led to approvals of combination strategies of immune checkpoint inhibition plus agents that target the vascular endothelial growth factor receptor and a shift in the current standard of renal cell carcinoma care. However, controversies remain regarding the optimal therapy selection and treatment strategy for individual patients, which might be eventually overcome by current intensive efforts in biomarker research. That work includes evaluation of tumour cell PD-L1 expression, gene expression signatures, CD8+ T cell density and others. In the future, further advances in the understanding of immune checkpoint biology might reveal new therapeutic targets beyond PD-1, PD-L1 and CTLA-4, as well as new combination approaches.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Antígeno CTLA-4/antagonistas & inibidores , Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/tratamento farmacológico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Antineoplásicos Imunológicos/imunologia , Antineoplásicos Imunológicos/farmacologia , Antígeno B7-H1/imunologia , Antígeno B7-H1/farmacologia , Antígeno CTLA-4/imunologia , Carcinoma de Células Renais/imunologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/imunologia , Quimioterapia Combinada , Humanos , Imunoterapia/métodos , Neoplasias Renais/imunologia , Receptor de Morte Celular Programada 1/imunologia
20.
Nat Med ; 26(2): 171-177, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-32015555

RESUMO

Recent progress in single-cell genomics urges its application in drug development, particularly of cancer immunotherapies. Current immunotherapy pipelines are focused on functional outcome and simple cellular and molecular readouts. A thorough mechanistic understanding of the cells and pathways targeted by immunotherapy agents is lacking, which limits the success rate of clinical trials. A large leap forward can be made if the immunotherapy target cells and pathways are characterized at high resolution before and after treatment, in clinical cohorts and model systems. This will enable rapid development of effective immunotherapies and data-driven design of synergistic drug combinations. In this Perspective, we discuss how emerging single-cell genomic technologies can serve as an engine for target identification and drug development.


Assuntos
Imunoterapia/métodos , Análise de Célula Única/métodos , Animais , Antígeno B7-H1/imunologia , Biomarcadores/metabolismo , Linfócitos T CD8-Positivos/imunologia , Antígeno CTLA-4/imunologia , Ensaios Clínicos como Assunto , Desenho de Fármacos , Indústria Farmacêutica/tendências , Quimioterapia Combinada , Genômica , Humanos , Fatores Imunológicos , Neoplasias/terapia , Fenótipo , Linfócitos T/metabolismo
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