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1.
Cancer Res ; 84(12): 1978-1995, 2024 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-38635895

RESUMO

T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domains (TIGIT) is an inhibitory receptor on immune cells that outcompetes an activating receptor, CD226, for shared ligands. Tumor-infiltrating lymphocytes express TIGIT and CD226 on regulatory T cells (Treg) and on CD8+ T cells with tumor-reactive or exhausted phenotypes, supporting the potential of therapeutically targeting TIGIT to enhance antitumor immunity. To optimize the efficacy of therapeutic antibodies against TIGIT, it is necessary to understand IgG Fc (Fcγ) receptor binding for therapeutic benefit. In this study, we showed that combining Fc-enabled (Fce) or Fc-silent (Fcs) anti-TIGIT with antiprogrammed cell death protein 1 in mice resulted in enhanced control of tumors by differential mechanisms: Fce anti-TIGIT promoted the depletion of intratumoral Treg, whereas Fcs anti-TIGIT did not. Despite leaving Treg numbers intact, Fcs anti-TIGIT potentiated the activation of tumor-specific exhausted CD8+ populations in a lymph node-dependent manner. Fce anti-TIGIT induced antibody-dependent cell-mediated cytotoxicity against human Treg in vitro, and significant decreases in Treg were measured in the peripheral blood of patients with phase I solid tumor cancer treated with Fce anti-TIGIT. In contrast, Fcs anti-TIGIT did not deplete human Treg in vitro and was associated with anecdotal objective clinical responses in two patients with phase I solid tumor cancer whose peripheral Treg frequencies remained stable on treatment. Collectively, these data provide evidence for pharmacologic activity and antitumor efficacy of anti-TIGIT antibodies lacking the ability to engage Fcγ receptor. SIGNIFICANCE: Fcs-silent anti-TIGIT antibodies enhance the activation of tumor-specific pre-exhausted T cells and promote antitumor efficacy without depleting T regulatory cells.


Assuntos
Receptores Imunológicos , Linfócitos T Reguladores , Animais , Linfócitos T Reguladores/imunologia , Camundongos , Receptores Imunológicos/imunologia , Receptores Imunológicos/antagonistas & inibidores , Humanos , Linfócitos do Interstício Tumoral/imunologia , Feminino , Linfócitos T CD8-Positivos/imunologia , Camundongos Endogâmicos C57BL , Linhagem Celular Tumoral , Neoplasias/imunologia , Neoplasias/tratamento farmacológico
2.
Mol Cancer Ther ; 21(6): 948-959, 2022 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-35405741

RESUMO

T cells play a critical role in the control of cancer. The development of immune checkpoint blockers (ICB) aimed at enhancing antitumor T-cell responses has revolutionized cancer treatment. However, durable clinical benefit is observed in only a subset of patients, prompting research efforts to focus on strategies that target multiple inhibitory signals within the tumor microenvironment (TME) to limit tumor evasion and improve patient outcomes. Adenosine has emerged as a potent immune suppressant within the TME, and CD73 is the major enzyme responsible for its extracellular production. CD73 can be co-opted within the TME to impair T-cell-mediated antitumor immunity and promote tumor growth. To target this pathway and block the formation of adenosine, we designed a novel, selective, and potent class of small-molecule inhibitors of CD73, including AB680 (quemliclustat), which is currently being tested in patients with cancer. AB680 effectively restored T-cell proliferation, cytokine secretion, and cytotoxicity that were dampened by the formation of immunosuppressive adenosine by CD73. Furthermore, in an allogeneic mixed lymphocyte reaction where CD73-derived adenosine had a dominant suppressive effect in the presence of PD-1 blockade, AB680 restored T-cell activation and function. Finally, in a preclinical mouse model of melanoma, AB680 inhibited CD73 in the TME and increased the antitumor activity of PD-1 blockade. Collectively, these data provide a rationale for the inhibition of CD73 with AB680 in combination with ICB, such as anti-PD-1, to improve cancer patient outcomes.


Assuntos
Melanoma , Receptor de Morte Celular Programada 1 , Adenosina/metabolismo , Adenosina/farmacologia , Adenosina/uso terapêutico , Animais , Humanos , Inibidores de Checkpoint Imunológico , Melanoma/tratamento farmacológico , Camundongos , Receptor de Morte Celular Programada 1/metabolismo , Microambiente Tumoral
3.
Cell Rep ; 34(11): 108839, 2021 03 16.
Artigo em Inglês | MEDLINE | ID: mdl-33730567

RESUMO

Naive CD8+ T cell activation results in an autonomous program of cellular proliferation and differentiation. However, the mechanisms that underpin this process are unclear. Here, we profile genome-wide changes in chromatin accessibility, gene transcription, and the deposition of a key chromatin modification (H3K27me3) early after naive CD8+ T cell activation. Rapid upregulation of the histone demethylase KDM6B prior to the first cell division is required for initiating H3K27me3 removal at genes essential for subsequent T cell differentiation and proliferation. Inhibition of KDM6B-dependent H3K27me3 demethylation limits the magnitude of an effective primary virus-specific CD8+ T cell response and the formation of memory CD8+ T cell populations. Accordingly, we define the early spatiotemporal events underpinning early lineage-specific chromatin reprogramming that are necessary for autonomous CD8+ T cell proliferation and differentiation.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Diferenciação Celular/imunologia , Montagem e Desmontagem da Cromatina , Histona Desmetilases com o Domínio Jumonji/metabolismo , Vírus/imunologia , Animais , Desmetilação , Feminino , Histonas/metabolismo , Humanos , Memória Imunológica , Ativação Linfocitária , Lisina/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Ligação Proteica , Fatores de Transcrição/metabolismo , Regulação para Cima
4.
Cell Rep ; 19(3): 461-470, 2017 04 18.
Artigo em Inglês | MEDLINE | ID: mdl-28423310

RESUMO

Humoral immune responses are tailored to the invading pathogen through regulation of key transcription factors and their networks. This is critical to establishing effective antibody-mediated responses, yet it is unknown how B cells integrate pathogen-induced signals to drive or suppress transcriptional programs specialized for each class of pathogen. Here, we detail the key role of the transcription factor c-Myb in regulating the T-bet-mediated anti-viral program. Deletion of c-Myb in mature B cells significantly increased serum IgG2c and CXCR3 expression by upregulating T-bet, normally suppressed during Th2-cell-mediated responses. Enhanced expression of T-bet resulted in aberrant plasma cell differentiation within the germinal center, mediated by CXCR3 expression. These findings identify a dual role for c-Myb in limiting inappropriate effector responses while coordinating plasma cell differentiation with germinal center egress. Identifying such intrinsic regulators of specialized antibody responses can assist in vaccine design and therapeutic intervention in B-cell-mediated immune disorders.


Assuntos
Formação de Anticorpos/imunologia , Linfócitos B/citologia , Linfócitos B/imunologia , Diferenciação Celular , Proteínas Proto-Oncogênicas c-myb/metabolismo , Proteínas com Domínio T/metabolismo , Animais , Afinidade de Anticorpos , Feminino , Deleção de Genes , Regulação da Expressão Gênica , Centro Germinativo/citologia , Centro Germinativo/metabolismo , Humanos , Masculino , Camundongos , Plasmócitos/citologia , Plasmócitos/metabolismo , Proteínas Proto-Oncogênicas c-myb/deficiência , Receptores CXCR3/metabolismo , Sindecana-1/metabolismo , Transcrição Gênica
5.
J Pediatr Hematol Oncol ; 38(3): 216-20, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26808370

RESUMO

The complexity of managing children with chronic disease has led to an increase in the use of long-term warfarin therapy. Time in therapeutic range (TTR) is the preferred method for determining efficacy and stability of warfarin management. This study aimed to determine the TTR achievement and incidence of adverse events among pediatric warfarin patients managed by an anticoagulation clinic over 12 months and to compare TTR achievement between patients self-testing (PST) at home and those monitored using routine methods. International normalized ratio (INR) results reported for 2012 for children currently having their warfarin therapy managed by a dedicated pediatric anticoagulation clinic were analyzed. Warfarin-related adverse events were recorded. A total of 164 patients were included. In total, 93 children performed PST and 71 children tested their INR at a hospital or pathology service. TTR achievement for the cohort was 67.1% (95% confidence interval, 64.4-69.7). A total of 69.2% of INR tests conducted at home were within the TTR compared with 64.3% of INR tests conducted at a hospital or pathology service (P=0.07). One major bleeding event occurred and there was 1 thrombotic episode. PST demonstrated noninferior warfarin stability compared with routine methods. Routine outcome evaluation of pediatric anticoagulation management within single institutions is necessary to confirm the success of such programs.


Assuntos
Anticoagulantes/uso terapêutico , Coagulação Sanguínea/efeitos dos fármacos , Monitoramento de Medicamentos/métodos , Autocuidado/métodos , Varfarina/uso terapêutico , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Coeficiente Internacional Normatizado , Masculino , Avaliação de Resultados em Cuidados de Saúde , Ambulatório Hospitalar , Adulto Jovem
6.
Thromb Haemost ; 111(6): 1015-21, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24522152

RESUMO

There has been an extensive body of research focusing on the epidemiology of thrombosis in adult cancer populations; however, there is significantly less knowledge about thrombosis in paediatric cancer populations. Thrombosis is diagnosed with increasing frequency in children being treated for cancer, and there is an urgent need to increase our understanding of the epidemiology of thrombosis in this population. Currently, there are no guidelines for identification of high-risk groups, prophylaxis or management of thrombotic complications in paediatric cancer patients. We reviewed the available literature regarding the epidemiology, mechanisms, risk factors, prophylaxis and outcomes of thrombosis in children with cancer and identified areas that require further research. The reported incidence of symptomatic venous thromboembolism (VTE) in children with cancer ranges between 2.1% and 16%, while the incidence of asymptomatic events is approximately 40%. Approximately 30% of VTE in this population is associated with central venous lines (CVL). The most common location of VTE is upper and lower extremity deep venous thrombosis (43 to 50% of events, respectively), while 50% of events in ALL patients occur in the central nervous system. Key characteristics that increase the risk of thrombosis include the type of cancer, age of the patient, the presence of a CVL, presence of pulmonary/intra thoracic disease, as well as the type of chemotherapy. Outcomes for paediatric cancer patients with VTE include post-thrombotic syndrome, pulmonary embolism, recurrent thromboembolism, destruction of upper venous system and death. Prospective studies aimed at enabling risk stratification of patients are required to facilitate development of paediatric specific recommendations related to thromboprophylaxis in this population.


Assuntos
Neoplasias/complicações , Trombose Venosa/epidemiologia , Trombose Venosa/etiologia , Antineoplásicos/efeitos adversos , Biomarcadores/sangue , Cateterismo Venoso Central/efeitos adversos , Criança , Humanos , Incidência , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicações , Prognóstico , Fatores de Risco , Tromboembolia Venosa/epidemiologia , Tromboembolia Venosa/etiologia , Tromboembolia Venosa/prevenção & controle , Trombose Venosa/prevenção & controle
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