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1.
Immunity ; 55(3): 512-526.e9, 2022 03 08.
Artigo em Inglês | MEDLINE | ID: mdl-35263569

RESUMO

Dual blockade of the PD-1 and TIGIT coinhibitory receptors on T cells shows promising early results in cancer patients. Here, we studied the mechanisms whereby PD-1 and/or TIGIT blockade modulate anti-tumor CD8+ T cells. Although PD-1 and TIGIT are thought to regulate different costimulatory receptors (CD28 and CD226), effectiveness of PD-1 or TIGIT inhibition in preclinical tumor models was reduced in the absence of CD226. CD226 expression associated with clinical benefit in patients with non-small cell lung carcinoma (NSCLC) treated with anti-PD-L1 antibody atezolizumab. CD226 and CD28 were co-expressed on NSCLC infiltrating CD8+ T cells poised for expansion. Mechanistically, PD-1 inhibited phosphorylation of both CD226 and CD28 via its ITIM-containing intracellular domain (ICD); TIGIT's ICD was dispensable, with TIGIT restricting CD226 co-stimulation by blocking interaction with their common ligand PVR (CD155). Thus, full restoration of CD226 signaling, and optimal anti-tumor CD8+ T cell responses, requires blockade of TIGIT and PD-1, providing a mechanistic rationale for combinatorial targeting in the clinic.


Assuntos
Linfócitos T CD8-Positivos , Neoplasias , Antígenos de Diferenciação de Linfócitos T/metabolismo , Antígenos CD28/metabolismo , Humanos , Neoplasias/metabolismo , Receptor de Morte Celular Programada 1/metabolismo , Receptores Imunológicos/metabolismo
2.
Nature ; 554(7693): 544-548, 2018 02 22.
Artigo em Inglês | MEDLINE | ID: mdl-29443960

RESUMO

Therapeutic antibodies that block the programmed death-1 (PD-1)-programmed death-ligand 1 (PD-L1) pathway can induce robust and durable responses in patients with various cancers, including metastatic urothelial cancer. However, these responses only occur in a subset of patients. Elucidating the determinants of response and resistance is key to improving outcomes and developing new treatment strategies. Here we examined tumours from a large cohort of patients with metastatic urothelial cancer who were treated with an anti-PD-L1 agent (atezolizumab) and identified major determinants of clinical outcome. Response to treatment was associated with CD8+ T-effector cell phenotype and, to an even greater extent, high neoantigen or tumour mutation burden. Lack of response was associated with a signature of transforming growth factor ß (TGFß) signalling in fibroblasts. This occurred particularly in patients with tumours, which showed exclusion of CD8+ T cells from the tumour parenchyma that were instead found in the fibroblast- and collagen-rich peritumoural stroma; a common phenotype among patients with metastatic urothelial cancer. Using a mouse model that recapitulates this immune-excluded phenotype, we found that therapeutic co-administration of TGFß-blocking and anti-PD-L1 antibodies reduced TGFß signalling in stromal cells, facilitated T-cell penetration into the centre of tumours, and provoked vigorous anti-tumour immunity and tumour regression. Integration of these three independent biological features provides the best basis for understanding patient outcome in this setting and suggests that TGFß shapes the tumour microenvironment to restrain anti-tumour immunity by restricting T-cell infiltration.


Assuntos
Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Linfócitos T CD8-Positivos/efeitos dos fármacos , Fator de Crescimento Transformador beta/metabolismo , Neoplasias Urológicas/tratamento farmacológico , Neoplasias Urológicas/imunologia , Urotélio/patologia , Animais , Anticorpos/imunologia , Anticorpos/farmacologia , Anticorpos/uso terapêutico , Anticorpos Monoclonais Humanizados , Antígenos de Neoplasias/análise , Antígenos de Neoplasias/imunologia , Antígenos de Neoplasias/metabolismo , Antígeno B7-H1/imunologia , Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/imunologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Estudos de Coortes , Colágeno/metabolismo , Modelos Animais de Doenças , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Fibroblastos/metabolismo , Humanos , Imunoterapia , Camundongos , Mutação , Metástase Neoplásica , Fenótipo , Transdução de Sinais/efeitos dos fármacos , Fator de Crescimento Transformador beta/antagonistas & inibidores , Resultado do Tratamento , Microambiente Tumoral/imunologia , Neoplasias Urológicas/genética , Neoplasias Urológicas/patologia , Urotélio/efeitos dos fármacos , Urotélio/imunologia
3.
PLoS Pathog ; 17(7): e1009732, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34280251

RESUMO

We have recently demonstrated that the function of T follicular helper (Tfh) cells from lymph nodes (LN) of HIV-infected individuals is impaired. We found that these cells were unable to provide proper help to germinal center (GC)-B cells, as observed by altered and inefficient anti-HIV antibody response and premature death of memory B cells. The underlying molecular mechanisms of this dysfunction remain poorly defined. Herein, we have used a unique transcriptional approach to identify these molecular defects. We consequently determined the transcriptional profiles of LN GC-Tfh cells following their interactions with LN GC-B cells from HIV-infected and HIV-uninfected individuals, rather than analyzing resting ex-vivo GC-Tfh cells. We observed that proliferating GC-Tfh cells from HIV-infected subjects were transcriptionally different than their HIV-uninfected counterparts, and displayed a significant downregulation of immune- and GC-Tfh-associated pathways and genes. Our results strongly demonstrated that MAF (coding for the transcription factor c-Maf) and its upstream signaling pathway mediators (IL6R and STAT3) were significantly downregulated in HIV-infected subjects, which could contribute to the impaired GC-Tfh and GC-B cell functions reported during infection. We further showed that c-Maf function was associated with the adenosine pathway and that the signaling upstream c-Maf could be partially restored by adenosine deaminase -1 (ADA-1) supplementation. Overall, we identified a novel mechanism that contributes to GC-Tfh cell impairment during HIV infection. Understanding how GC-Tfh cell function is altered in HIV is crucial and could provide critical information about the mechanisms leading to the development and maintenance of effective anti-HIV antibodies.


Assuntos
Infecções por HIV/imunologia , Proteínas Proto-Oncogênicas c-maf/imunologia , Células T Auxiliares Foliculares/imunologia , Adulto , Doença Crônica , Feminino , Centro Germinativo/imunologia , Humanos , Masculino , Transdução de Sinais/imunologia
4.
Immunity ; 39(4): 758-69, 2013 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-24035365

RESUMO

The vast majority of currently licensed human vaccines work on the basis of long-term protective antibody responses. It is now conceivable that an antibody-dependent HIV vaccine might be possible, given the discovery of HIV broadly neutralizing antibodies (bnAbs) in some HIV-infected individuals. However, these antibodies are difficult to develop and have characteristics indicative of a high degree of affinity maturation in germinal centers (GCs). CD4⁺ T follicular helper (Tfh) cells are specialized for B cell help and necessary for GCs. Therefore, the development of HIV bnAbs might depend on Tfh cells. Here, we identified in normal individuals a subpopulation of circulating memory PD-1⁺CXCR5⁺CD4⁺ T cells that are resting memory cells most related to bona fide GC Tfh cells by gene expression profile, cytokine profile, and functional properties. Importantly, the frequency of these cells correlated with the development of bnAbs against HIV in a large cohort of HIV⁺ individuals.


Assuntos
Anticorpos Neutralizantes/biossíntese , Anticorpos Anti-HIV/biossíntese , Infecções por HIV/imunologia , HIV-1/imunologia , Receptor de Morte Celular Programada 1/imunologia , Receptores CXCR5/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Sequência de Aminoácidos , Linfócitos B/imunologia , Linfócitos B/patologia , Linfócitos B/virologia , Expressão Gênica , Perfilação da Expressão Gênica , Centro Germinativo/imunologia , Centro Germinativo/patologia , Centro Germinativo/virologia , Infecções por HIV/patologia , Infecções por HIV/virologia , Humanos , Imunidade Humoral , Memória Imunológica , Dados de Sequência Molecular , Receptor de Morte Celular Programada 1/genética , Receptores CXCR3/genética , Receptores CXCR3/imunologia , Receptores CXCR5/genética , Transdução de Sinais , Linfócitos T Auxiliares-Indutores/patologia , Linfócitos T Auxiliares-Indutores/virologia
5.
Eur J Immunol ; 50(6): 891-902, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32043568

RESUMO

CD96 is a member of the poliovirus receptor (PVR, CD155)-nectin family that includes T cell Ig and ITIM domain (TIGIT) and CD226. While CD96, TIGIT, and CD226 have important roles in regulating NK cell activity, and TIGIT and CD226 have also been shown to regulate T cell responses, it is unclear whether CD96 has inhibitory or stimulatory function in CD8+ T cells. Here, we demonstrate that CD96 has co-stimulatory function on CD8+ T cells. Crosslinking of CD96 on human or mouse CD8+ T cells induced activation, effector cytokine production, and proliferation. CD96 was found to transduce its activating signal through the MEK-ERK pathway. CD96-mediated signaling led to increased frequencies of NUR77- and T-bet-expressing CD8+ T cells and enhanced cytotoxic effector activity, indicating that CD96 can modulate effector T cell differentiation. Antibody blockade of CD96 or genetic ablation of CD96 expression on CD8+ T cells impaired expression of transcription factors and proinflammatory cytokines associated with CD8+ T cell activation in in vivo models. Taken together, CD96 has a co-stimulatory role in CD8+ T cell activation and effector function.


Assuntos
Antígenos CD/imunologia , Linfócitos T CD8-Positivos/imunologia , Diferenciação Celular/imunologia , Ativação Linfocitária , Sistema de Sinalização das MAP Quinases/imunologia , Modelos Imunológicos , Animais , Antígenos CD/genética , Diferenciação Celular/genética , Linhagem Celular Tumoral , Humanos , Sistema de Sinalização das MAP Quinases/genética , Camundongos , Camundongos Knockout
6.
Proc Natl Acad Sci U S A ; 115(50): E11731-E11740, 2018 12 11.
Artigo em Inglês | MEDLINE | ID: mdl-30504141

RESUMO

Natural killer (NK) cell recognition of tumor cells is mediated through activating receptors such as CD226, with suppression of effector functions often controlled by negative regulatory transcription factors such as FOXO1. Here we show that CD226 regulation of NK cell cytotoxicity is facilitated through inactivation of FOXO1. Gene-expression analysis of NK cells isolated from syngeneic tumors grown in wild-type or CD226-deficient mice revealed dysregulated expression of FOXO1-regulated genes in the absence of CD226. In vitro cytotoxicity and stimulation assays demonstrated that CD226 is required for optimal killing of tumor target cells, with engagement of its ligand CD155 resulting in phosphorylation of FOXO1. CD226 deficiency or anti-CD226 antibody blockade impaired cytotoxicity with concomitant compromised inactivation of FOXO1. Furthermore, inhibitors of FOXO1 phosphorylation abrogated CD226-mediated signaling and effector responses. These results define a pathway by which CD226 exerts control of NK cell responses against tumors.


Assuntos
Antígenos de Diferenciação de Linfócitos T/metabolismo , Proteína Forkhead Box O1/antagonistas & inibidores , Proteína Forkhead Box O1/metabolismo , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Animais , Antígenos de Diferenciação de Linfócitos T/genética , Linhagem Celular Tumoral , Citotoxicidade Imunológica , Regulação Neoplásica da Expressão Gênica , Humanos , Ligantes , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Melanoma Experimental/genética , Melanoma Experimental/imunologia , Melanoma Experimental/metabolismo , Camundongos , Camundongos Knockout , Nectinas/metabolismo , Fosforilação , Receptores Virais/metabolismo , Transdução de Sinais/imunologia
7.
J Immunol ; 201(8): 2273-2286, 2018 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-30209192

RESUMO

Immunotherapy with checkpoint inhibitors has proved to be highly effective, with durable responses in a subset of patients. Given their encouraging clinical activity, checkpoint inhibitors are increasingly being tested in clinical trials in combination with chemotherapy. In many instances, there is little understanding of how chemotherapy might influence the quality of the immune response generated by checkpoint inhibitors. In this study, we evaluated the impact of chemotherapy alone or in combination with anti-PD-L1 in a responsive syngeneic tumor model. Although multiple classes of chemotherapy treatment reduced immune cell numbers and activity in peripheral tissues, chemotherapy did not antagonize but in many cases augmented the antitumor activity mediated by anti-PD-L1. This dichotomy between the detrimental effects in peripheral tissues and enhanced antitumor activity was largely explained by the reduced dependence on incoming cells for antitumor efficacy in already established tumors. The effects of the various chemotherapies were also agent specific, and synergy with anti-PD-L1 was achieved by different mechanisms that ultimately helped establish a new threshold for response. These results rationalize the combination of chemotherapy with immunotherapy and suggest that, despite the negative systemic effects of chemotherapy, effective combinations can be obtained through distinct mechanisms acting within the tumor.


Assuntos
Adenocarcinoma/terapia , Anticorpos Monoclonais/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfócitos T CD8-Positivos/efeitos dos fármacos , Neoplasias do Colo/terapia , Imunoterapia/métodos , Adenocarcinoma/imunologia , Animais , Antígenos de Neoplasias/imunologia , Antígeno B7-H1/imunologia , Linfócitos T CD8-Positivos/imunologia , Linhagem Celular Tumoral , Neoplasias do Colo/imunologia , Feminino , Citometria de Fluxo , Humanos , Imunidade Celular , Camundongos , Camundongos Endogâmicos C57BL , Neoplasias Experimentais , Carga Tumoral/efeitos dos fármacos
8.
J Immunol ; 196(5): 2401-9, 2016 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-26826246

RESUMO

Given the critical role of mucosal surfaces in susceptibility to infection, it is imperative that effective mucosal responses are induced when developing efficacious vaccines and prevention strategies for infection. Modulating the microbiota in the gastrointestinal (GI) tract through the use of probiotics (PBio) is a safe and well-tolerated approach to enhance mucosal and overall health. We assessed the longitudinal impact of daily treatment with the VSL#3 probiotic on cellular and humoral immunity and inflammation in healthy macaques. PBio therapy resulted in significantly increased frequencies of B cells expressing IgA in the colon and lymph node (LN), likely because of significantly increased LN T follicular helper cell frequencies and LN follicles. Increased frequencies of IL-23(+) APCs in the colon were found post-PBio treatment, which correlated with LN T follicular helper cells. Finally, VSL#3 significantly downmodulated the response of TLR2-, TLR3-, TLR4-, and TLR9-expressing HEK293 cells to stimulation with Pam3CSK4, polyinosinic-polycytidylic acid, LPS, and ODN2006, respectively. These data provide a mechanism for the beneficial impact of PBio on mucosal health and implicates the use of PBio therapy in the context of vaccination or preventative approaches to enhance protection from mucosal infection by improving immune defenses at the mucosal portal of entry.


Assuntos
Imunidade , Microbiota , Mucosa/imunologia , Mucosa/microbiologia , Animais , Células Apresentadoras de Antígenos , Linfócitos B/imunologia , Linfócitos B/metabolismo , Linhagem Celular , Colo/imunologia , Colo/microbiologia , Microbioma Gastrointestinal/imunologia , Humanos , Imunidade Inata , Imunidade nas Mucosas , Imunoglobulina A/imunologia , Imunoglobulina G/imunologia , Interleucina-23/biossíntese , Linfonodos/imunologia , Linfonodos/metabolismo , Ativação Linfocitária/imunologia , Macaca , Probióticos/administração & dosagem , Transdução de Sinais , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T Auxiliares-Indutores/metabolismo , Receptores Toll-Like/metabolismo
9.
J Immunol ; 195(12): 5625-36, 2015 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-26546609

RESUMO

Despite the overwhelming benefits of antiretroviral therapy (ART) in curtailing viral load in HIV-infected individuals, ART does not fully restore cellular and humoral immunity. HIV-infected individuals under ART show reduced responses to vaccination and infections and are unable to mount an effective antiviral immune response upon ART cessation. Many factors contribute to these defects, including persistent inflammation, especially in lymphoid tissues, where T follicular helper (Tfh) cells instruct and help B cells launch an effective humoral immune response. In this study we investigated the phenotype and function of circulating memory Tfh cells as a surrogate of Tfh cells in lymph nodes and found significant impairment of this cell population in chronically HIV-infected individuals, leading to reduced B cell responses. We further show that these aberrant memory Tfh cells exhibit an IL-2-responsive gene signature and are more polarized toward a Th1 phenotype. Treatment of functional memory Tfh cells with IL-2 was able to recapitulate the detrimental reprogramming. Importantly, this defect was reversible, as interfering with the IL-2 signaling pathway helped reverse the abnormal differentiation and improved Ab responses. Thus, reversible reprogramming of memory Tfh cells in HIV-infected individuals could be used to enhance Ab responses. Altered microenvironmental conditions in lymphoid tissues leading to altered Tfh cell differentiation could provide one explanation for the poor responsiveness of HIV-infected individuals to new Ags. This explanation has important implications for the development of therapeutic interventions to enhance HIV- and vaccine-mediated Ab responses in patients under ART.


Assuntos
Linfócitos B/imunologia , Infecções por HIV/imunologia , HIV , Interleucina-2/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Adulto , Anticorpos Antivirais/imunologia , Formação de Anticorpos , Linfócitos B/virologia , Diferenciação Celular , Células Cultivadas , Reprogramação Celular , Doença Crônica , Humanos , Memória Imunológica , Pessoa de Meia-Idade , Transdução de Sinais , Linfócitos T Auxiliares-Indutores/virologia , Adulto Jovem
10.
Blood ; 121(15): 2914-22, 2013 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-23422746

RESUMO

The determinants of HIV-1-associated lymphadenopathy are poorly understood. We hypothesized that lymphocytes could be sequestered in the HIV-1+ lymph node (LN) through impairments in sphingosine-1-phosphate (S1P) responsiveness. To test this hypothesis, we developed novel assays for S1P-induced Akt phosphorylation and actin polymerization. In the HIV-1+ LN, naïve CD4 T cells and central memory CD4 and CD8 T cells had impaired Akt phosphorylation in response to S1P, whereas actin polymerization responses to S1P were impaired dramatically in all LN maturation subsets. These defects were improved with antiretroviral therapy. LN T cells expressing CD69 were unable to respond to S1P in either assay, yet impaired S1P responses were also seen in HIV-1+ LN T cells lacking CD69 expression. Microbial elements, HIV-1, and interferon α - putative drivers of HIV-1 associated immune activation all tended to increase CD69 expression and reduce T-cell responses to S1P in vitro. Impairment in T-cell egress from lymph nodes through decreased S1P responsiveness may contribute to HIV-1-associated LN enlargement and to immune dysregulation in a key organ of immune homeostasis.


Assuntos
Linfa/efeitos dos fármacos , Ativação Linfocitária/efeitos dos fármacos , Lisofosfolipídeos/farmacologia , Esfingosina/análogos & derivados , Linfócitos T/efeitos dos fármacos , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Antirretrovirais/uso terapêutico , Antígenos CD/imunologia , Antígenos CD/metabolismo , Antígenos de Diferenciação de Linfócitos T/imunologia , Antígenos de Diferenciação de Linfócitos T/metabolismo , Linhagem Celular Tumoral , Células Cultivadas , Feminino , Citometria de Fluxo , Expressão Gênica/imunologia , Infecções por HIV/tratamento farmacológico , Infecções por HIV/imunologia , Infecções por HIV/metabolismo , HIV-1/efeitos dos fármacos , HIV-1/imunologia , Humanos , Lectinas Tipo C/imunologia , Lectinas Tipo C/metabolismo , Linfa/imunologia , Linfa/metabolismo , Ativação Linfocitária/imunologia , Masculino , Pessoa de Meia-Idade , Fosforilação/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores de Lisoesfingolipídeo/genética , Receptores de Lisoesfingolipídeo/imunologia , Receptores de Lisoesfingolipídeo/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Esfingosina/farmacologia , Receptores de Esfingosina-1-Fosfato , Linfócitos T/imunologia , Linfócitos T/metabolismo
11.
Nat Commun ; 14(1): 4703, 2023 08 05.
Artigo em Inglês | MEDLINE | ID: mdl-37543621

RESUMO

TGFß signaling is associated with non-response to immune checkpoint blockade in patients with advanced cancers, particularly in the immune-excluded phenotype. While previous work demonstrates that converting tumors from excluded to inflamed phenotypes requires attenuation of PD-L1 and TGFß signaling, the underlying cellular mechanisms remain unclear. Here, we show that TGFß and PD-L1 restrain intratumoral stem cell-like CD8 T cell (TSCL) expansion and replacement of progenitor-exhausted and dysfunctional CD8 T cells with non-exhausted T effector cells in the EMT6 tumor model in female mice. Upon combined TGFß/PD-L1 blockade IFNγhi CD8 T effector cells show enhanced motility and accumulate in the tumor. Ensuing IFNγ signaling transforms myeloid, stromal, and tumor niches to yield an immune-supportive ecosystem. Blocking IFNγ abolishes the anti-PD-L1/anti-TGFß therapy efficacy. Our data suggest that TGFß works with PD-L1 to prevent TSCL expansion and replacement of exhausted CD8 T cells, thereby maintaining the T cell compartment in a dysfunctional state.


Assuntos
Antígeno B7-H1 , Neoplasias da Mama , Linfócitos T CD8-Positivos , Inibidores de Checkpoint Imunológico , Fator de Crescimento Transformador beta , Feminino , Animais , Camundongos , Diferenciação Celular , Linfócitos T CD8-Positivos/imunologia , Células-Tronco , Antígeno B7-H1/antagonistas & inibidores , Fator de Crescimento Transformador beta/antagonistas & inibidores , Interferon gama/imunologia , Exaustão das Células T , Inibidores de Checkpoint Imunológico/farmacologia , Camundongos Endogâmicos BALB C , Linhagem Celular Tumoral , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/imunologia , RNA-Seq
12.
Nat Commun ; 12(1): 2965, 2021 05 20.
Artigo em Inglês | MEDLINE | ID: mdl-34017005

RESUMO

Single-cell RNA sequencing (scRNA-seq) has revealed an unprecedented degree of immune cell diversity. However, consistent definition of cell subtypes and cell states across studies and diseases remains a major challenge. Here we generate reference T cell atlases for cancer and viral infection by multi-study integration, and develop ProjecTILs, an algorithm for reference atlas projection. In contrast to other methods, ProjecTILs allows not only accurate embedding of new scRNA-seq data into a reference without altering its structure, but also characterizing previously unknown cell states that "deviate" from the reference. ProjecTILs accurately predicts the effects of cell perturbations and identifies gene programs that are altered in different conditions and tissues. A meta-analysis of tumor-infiltrating T cells from several cohorts reveals a strong conservation of T cell subtypes between human and mouse, providing a consistent basis to describe T cell heterogeneity across studies, diseases, and species.


Assuntos
Neoplasias/imunologia , RNA-Seq/métodos , Análise de Célula Única/métodos , Linfócitos T/imunologia , Viroses/imunologia , Animais , Diferenciação Celular/imunologia , Estudos de Coortes , Modelos Animais de Doenças , Regulação da Expressão Gênica/imunologia , Humanos , Linfócitos do Interstício Tumoral/imunologia , Camundongos , Neoplasias/sangue , Neoplasias/patologia , Valores de Referência , Software , Especificidade da Espécie , Subpopulações de Linfócitos T/imunologia , Microambiente Tumoral/imunologia , Viroses/sangue
13.
Biochim Biophys Acta ; 1796(2): 309-14, 2009 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-19683559

RESUMO

Trop2 is a cell-surface glycoprotein overexpressed in a variety of late stage epithelial carcinomas with low to no expression in normal tissues. Some of the important roles that Trop2 plays in epithelial cancers have recently been revealed. Trop2 overexpression is associated with decreased patient survival as well as increased tumor aggressiveness and metastasis. Its overexpression in metastatic tissue makes it a very attractive and potential therapeutic target for late stage disease. This protein can transduce an intracellular calcium signal and contains a conserved phosphatidylinositol 4,5-bisphosphate (PIP(2)) binding motif as well as a serine phosphorylation site which interacts with protein kinase C. This protein has recently being found to be expressed in cells with stem-like properties which allude to a potential role in progenitor cell biology. Further understanding of the signaling pathways involved with this molecule and its important role in metastasis will shed new light on the mechanism of Trop2 overexpression in late stage disease and could result in the development of new therapies targeting this widely overexpressed oncogene.


Assuntos
Antígenos de Neoplasias/fisiologia , Moléculas de Adesão Celular/fisiologia , Neoplasias/etiologia , Sequência de Aminoácidos , Animais , Antígenos de Neoplasias/análise , Antígenos de Neoplasias/genética , Moléculas de Adesão Celular/análise , Moléculas de Adesão Celular/antagonistas & inibidores , Moléculas de Adesão Celular/genética , Genes bcl-1 , Humanos , Dados de Sequência Molecular , Neoplasias/química , Neoplasias/genética , Neoplasias/terapia , Oncogenes
14.
Mol Cancer ; 9: 253, 2010 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-20858281

RESUMO

BACKGROUND: Trop2 is a cell-surface glycoprotein overexpressed by a variety of epithelial carcinomas with reported low to restricted expression in normal tissues. Expression of Trop2 has been associated with increased tumor aggressiveness, metastasis and decreased patient survival, but the signaling mechanisms mediated by Trop2 are still unknown. Here, we studied the effects murine Trop2 (mTrop2) exerted on tumor cellular functions and some of the signaling mechanisms activated by this oncogene. RESULTS: mTrop2 expression significantly increased tumor cell proliferation at low serum concentration, migration, foci formation and anchorage-independent growth. These in vitro characteristics translated to increased tumor growth in both subcutaneous and orthotopic pancreatic cancer murine models and also led to increased liver metastasis. mTrop2 expression also increased the levels of phosphorylated ERK1/2 mediating cell cycle progression by increasing the levels of cyclin D1 and cyclin E as well as downregulating p27. The activation of ERK was also observed in human pancreatic ductal epithelial cells and colorectal adenocarcinoma cells overexpressing human Trop2. CONCLUSIONS: These findings demonstrate some of the pathogenic effects mediated by mTrop2 expression on cancer cells and the importance of targeting this cell surface glycoprotein. This study also provides the first indication of a molecular signaling pathway activated by Trop2 which has important implications for cancer cell growth and survival.


Assuntos
Antígenos de Neoplasias/metabolismo , Moléculas de Adesão Celular/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Neoplasias/metabolismo , Neoplasias/patologia , Proteínas/metabolismo , Transdução de Sinais/fisiologia , Animais , Antígenos de Neoplasias/genética , Moléculas de Adesão Celular/genética , Ciclo Celular/genética , Ciclo Celular/fisiologia , Linhagem Celular , Linhagem Celular Tumoral , Proliferação de Células , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Ciclina D1/genética , Ciclina D1/metabolismo , Ciclina E/genética , Ciclina E/metabolismo , Feminino , Células HCT116 , Humanos , Imuno-Histoquímica , Camundongos , Camundongos Nus , Neoplasias/genética , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Proteínas/genética , Transdução de Sinais/genética
15.
J Immunother Cancer ; 8(2)2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-33127657

RESUMO

BACKGROUND: Cancer immunotherapy has evolved from interferon-alpha (IFNα) and interleukin-2 in the 1980s to CTLA-4 and PD-1/PD-L1 checkpoint inhibitors (CPIs), the latter highlighting the importance of enhancing T-cell functions. While the search for novel immunomodulatory pathways continues, combination therapies augmenting multiple pathways can also increase efficacy. The association of autoimmune-related adverse events with clinical efficacy following CPI treatment has been inferred and suggests that breaking tolerance thresholds associated with autoimmunity may affect host immune responses for effective cancer immunotherapy. RESULTS: Here, we show that loss of autoimmune associated PTPN22, a key desensitization node for multiple signaling pathways, including IFNα receptor (IFNAR) and T-cell receptor, can augment tumor responses. Implantation of syngeneic tumors in Ptpn22-/- mice led to expansion and activation of peripheral and intratumoral T cells and, in turn, spontaneous tumor regression as well as enhanced responses in combination with anti-PD-L1 treatment. Using genetically modified mice expressing a catalytically inactive PTPN22 or the autoimmunity-associated human single-nucleotide polymorphism variant, augmentation of antitumor immunity was dependent on PTPN22 phosphatase activity and partially on its adaptor functions. Further, antitumor responses were dependent on both CD4+ and CD8+T cells and, in part, IFNAR function. Finally, we demonstrate that the autoimmune susceptibility Ptpn22(C1858T) variant is associated with lower risk of developing non-melanoma skin cancers, improved overall survival and increased risk for development of hyperthyroidism or hypothyroidism following atezolizumab (anti-PD-L1) treatment. CONCLUSIONS: Together, these data suggest that inhibition of PTPN22 phosphatase activity may provide an effective therapeutic option for cancer immunotherapy and that exploring genetic variants that shift immune tolerance thresholds may serve as a paradigm for finding new cancer immunotherapy targets.


Assuntos
Autoimunidade/genética , Imunoterapia/métodos , Neoplasias/terapia , Proteína Tirosina Fosfatase não Receptora Tipo 22/metabolismo , Animais , Humanos , Masculino , Camundongos
16.
J Immunother Cancer ; 8(2)2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32675310

RESUMO

The recent success of multiple immunomodulating drugs in oncology highlights the potential of relieving immunosuppression by directly engaging the immune system in the tumor bed to target cancer cells. Durable responses to immune checkpoint inhibitors experienced by some patients may be indicative of the formation of a T cell memory response. This has prompted the search for preclinical evidence of therapy-induced long-term immunity as part of the evaluation of novel therapeutics. A common preclinical method used to document long-term immunity is the use of tumor rechallenge experiments in which tumor growth is assessed in mice that have previously rejected tumors in response to therapy. Failure of rechallenge engraftment, typically alongside successful engraftment of the same tumor in naive animals as a control, is often presented as evidence of therapy-induced tumor immunity. Here, we present evidence that formation of tumor immunity often develops independent of therapy. We observed elevated rates of rechallenge rejection following surgical resection of primary tumors for four of five commonly used models and that such postexcision immunity could be adoptively transferred to treatment-naïve mice. We also show that tumor-specific cytolytic T cells are induced on primary tumor challenge independent of therapeutic intervention. Taken together these data call into question the utility of tumor rechallenge studies and the use of naïve animals as controls to demonstrate therapy-induced formation of long-term tumor immunity.


Assuntos
Imunização/métodos , Neoplasias/terapia , Animais , Feminino , Humanos , Masculino , Camundongos , Neoplasias/patologia
17.
Nat Cancer ; 1(7): 681-691, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-35122038

RESUMO

Inhibiting the programmed death-1 (PD-1) pathway is one of the most effective approaches to cancer immunotherapy, but its mechanistic basis remains incompletely understood. Binding of PD-1 to its ligand PD-L1 suppresses T-cell function in part by inhibiting CD28 signaling. Tumor cells and infiltrating myeloid cells can express PD-L1, with myeloid cells being of particular interest as they also express B7-1, a ligand for CD28 and PD-L1. Here we demonstrate that dendritic cells (DCs) represent a critical source of PD-L1, despite being vastly outnumbered by PD-L1+ macrophages. Deletion of PD-L1 in DCs, but not macrophages, greatly restricted tumor growth and led to enhanced antitumor CD8+ T-cell responses. Our data identify a unique role for DCs in the PD-L1-PD-1 regulatory axis and have implications for understanding the therapeutic mechanism of checkpoint blockade, which has long been assumed to reflect the reversal of T-cell exhaustion induced by PD-L1+ tumor cells.


Assuntos
Antígeno B7-H1 , Neoplasias , Antígeno B7-H1/genética , Antígenos CD28/metabolismo , Células Dendríticas , Humanos , Ligantes , Neoplasias/genética , Receptor de Morte Celular Programada 1/genética
18.
Nat Commun ; 10(1): 823, 2019 02 18.
Artigo em Inglês | MEDLINE | ID: mdl-30778076

RESUMO

Follicular helper T cells (Tfh) play critical roles instructing, and initiating T-cell dependent antibody responses. The underlying mechanisms that enhance their function is therefore critical for vaccine development. Here we apply gene array analysis identifying adenosine deaminase (ADA) as a key molecule that delineates a human Tfh helper program in proliferating circulating Tfh (cTfh) cells and Germinal Centers Tfh (GC-Tfh). ADA-1 expression and enzymatic activity are increased in efficient cTfh2-17/GC-Tfh cells. Exogenous ADA-1 enhances less efficient cTfh1 and pro-follicular Tfh PD-1+ CXCR5+ cells to provide B cell help, while pharmacological inhibition of ADA-1 activity impedes cTfh2-17/GC-Tfh function and diminished antibody response. Mechanistically, ADA-1 controls the Tfh program by influencing IL6/IL-2 production, controlling CD26 extracellular expression and could balance signals through adenosine receptors. Interestingly, dysfunctional Tfh from HIV infected-individual fail to regulate the ADA pathway. Thus, ADA-1 regulates human Tfh and represents a potential target for development of vaccine strategy.


Assuntos
Adenosina Desaminase/metabolismo , Infecções por HIV/patologia , Linfócitos T Auxiliares-Indutores/fisiologia , Adenosina Desaminase/genética , Adenilil Ciclases/metabolismo , Linfócitos B/citologia , Técnicas de Cocultura , Dipeptidil Peptidase 4/metabolismo , Centro Germinativo/metabolismo , Infecções por HIV/metabolismo , Humanos , Interleucina-2/metabolismo , Interleucina-6/metabolismo , Linfócitos T Auxiliares-Indutores/virologia
19.
Cancer Res ; 79(7): 1493-1506, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30679180

RESUMO

Checkpoint inhibitors like anti-PD1/PD-L1 have demonstrated significant therapeutic efficacy in a subset of patients partly through reinvigoration of CD8 T cells. However, their impact on myeloid cells remains largely unknown. Here, we report that anti-PD-L1 treatment favorably impacts the phenotype and function of tumor macrophages by polarizing the macrophage compartment toward a more proinflammatory phenotype. This phenotype was characterized by a decrease in Arginase-I (ARG1) expression and an increase in iNOS, MHCII, and CD40 expression. Whole-transcriptome profiling further confirmed extensive polarization of both tumor monocytes and macrophages from a suppressive to a proinflammatory, immunostimulatory phenotype. This polarization was driven mainly through IFNγ and was associated with enhanced T-cell activity. Transfer of monocytes into anti-PD-L1-treated tumor-bearing mice led to macrophage differentiation into a more proinflammatory phenotype, with an increase in CD8 T cells expressing granzyme-B and an increase in the CD8/Treg ratio compared with control-treated mice. Although in responsive tumor models, anti-PD-L1 treatment remodeled the macrophage compartment with beneficial effects on T cells, both macrophage reprogramming and depletion were needed to maximize anti-PD-L1 responses in a tumor immune contexture with high macrophage burden. Our results demonstrate that anti-PD-L1 treatment can favorably remodel the macrophage compartment in responsive tumor models toward a more proinflammatory phenotype, mainly through increased IFNγ levels. They also suggest that directly targeting these cells with reprogramming and depleting agents may further augment the breadth and depth of response to anti-PD-L1 treatment in less responsive or more macrophage-dense tumor microenvironments. SIGNIFICANCE: This work demonstrates that increased IFNγ signaling following anti-PD-L1 treatment can remodel the macrophage compartment to enhance T-cell responses.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/79/7/1493/F1.large.jpg.


Assuntos
Antígeno B7-H1/antagonistas & inibidores , Macrófagos/metabolismo , Neoplasias/metabolismo , Animais , Linfócitos T CD8-Positivos/imunologia , Linhagem Celular Tumoral , Polaridade Celular , Proliferação de Células , Feminino , Humanos , Interferon gama/metabolismo , Macrófagos/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Neoplasias/imunologia , Linfócitos T/citologia , Linfócitos T/imunologia , Microambiente Tumoral
20.
Cancer Immunol Res ; 7(6): 963-976, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31064777

RESUMO

Exhausted T cells have been described in cancer patients and murine tumor models largely based on their expression of various inhibitory receptors. Understanding of the functional attributes of these cells is limited. Here, we report that among CD8+ T cells in commonly used syngeneic tumor models, the coexpression of inhibitory receptors PD-1, LAG3, and TIM3 defined a group of highly activated and functional effector cells. Coexpression of these receptors further enriched for antigen-specific cells with increased T-cell receptor clonality. Anti-PD-L1 treatment increased the number and activation of these triple-positive CD8+ T cells without affecting the density of PD-1- cells. The intratumoral density of CD8+ T cells coexpressing inhibitory receptors negatively correlated with tumor burden. The density ratio and pretreatment phenotype of CD8+ T cells coexpressing inhibitory receptors was positively correlated with response across a variety of tumor models. Our results demonstrate that coexpression of inhibitory receptors is not a signifier of exhausted T cells, but rather can define a group of activated and functional effector cells in syngeneic tumor models. In the cancer setting, these cells could represent a heterogeneous population of not only exhausted but also highly activated cells responsive to treatment.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Receptores Coestimuladores e Inibidores de Linfócitos T/genética , Ativação Linfocitária/genética , Ativação Linfocitária/imunologia , Neoplasias/etiologia , Neoplasias/metabolismo , Animais , Antígeno B7-H1/antagonistas & inibidores , Biomarcadores Tumorais , Linhagem Celular Tumoral , Citotoxicidade Imunológica , Modelos Animais de Doenças , Epitopos de Linfócito T/imunologia , Feminino , Fator 1-alfa Nuclear de Hepatócito/genética , Fator 1-alfa Nuclear de Hepatócito/metabolismo , Isoenxertos , Camundongos , Neoplasias/patologia , Proteínas com Domínio T/genética , Proteínas com Domínio T/metabolismo
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