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1.
Adv Exp Med Biol ; 1189: 213-232, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31758536

RESUMO

Co-receptors cooperatively regulate the function of immune cells to optimize anti-infectious immunity while limiting autoimmunity by providing stimulatory and inhibitory co-signals. Among various co-receptors, those in the CD28/CTLA-4 family play fundamental roles in the regulation of lymphocytes by modulating the strength, quality, and/or duration of the antigen receptor signal. The development of the lethal lymphoproliferative disorder and various tissue-specific autoimmune diseases in mice deficient for CTLA-4 and PD-1, respectively, clearly demonstrates their pivotal roles in the development and the maintenance of immune tolerance. The recent success of immunotherapies targeting CTLA-4 and PD-1 in the treatment of various cancers highlights their critical roles in the regulation of cancer immunity in human. In addition, the development of multifarious autoimmune diseases as immune-related adverse events of anti-CTLA-4 and anti-PD-1/PD-L1 therapies and the successful clinical application of the CD28 blocking therapy using CTLA-4-Ig to the treatment of arthritis assure their crucial roles in the regulation of autoimmunity in human. Accumulating evidences in mice and humans indicate that genetic and environmental factors strikingly modify effects of the targeted inhibition and potentiation of co-signals. In this review, we summarize our current understanding of the roles of CD28, CTLA-4, and PD-1 in autoimmunity. Deeper understandings of the context-dependent and context-independent functions of co-signals are essential for the appropriate usage and the future development of innovative immunomodulatory therapies for a diverse array of diseases.


Assuntos
Autoimunidade , Antígenos CD28/metabolismo , Antígeno CTLA-4/metabolismo , Receptor de Morte Celular Programada 1/metabolismo , Animais , Humanos , Tolerância Imunológica , Imunoterapia , Camundongos
2.
Scand J Immunol ; 90(6): e12821, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31589347

RESUMO

As a result of the cancer immunotherapy revolution, more than 2000 immuno-oncology agents are currently being tested or are in use to improve responses. Not unexpectedly, the 2018 Nobel Prize in Physiology or Medicine was awarded to James P. Allison and Tasuku Honjo for their development of cancer therapy by the blockade of co-inhibitory signals. Unfortunately, manipulation of the co-inhibitory receptors has also resulted in a safety issue: widespread iatrogenic immune-related adverse events (irAEs). Autoimmunity is emerging as the nemesis of immunotherapy. Originally, it was assumed that CTLA-4 blockade selectively targets T cells relevant to the antitumour immune response. However, an uncontrolled pan T cell activation was induced compromising tolerance to healthy self-tissues. The irAEs are very similar to that of a chronic graft-versus-host-disease (GVHD) reaction following allogeneic bone marrow transplantation (BMT). We hypothesized that ipilimumab induced a graft-versus-malignancy (GVM) effect, which eradicated metastatic melanoma in a minority of patients, but also involved an auto-GVHD reaction that resulted in widespread autoimmunity in the majority. Therefore, we argued for a profound theoretical point against the consensus of experts. The task is not to desperately put the genie back in the bottle by immune-suppressive treatments, but instead to harness the autoimmune forces. In this way, the same goal could be achieved by an antibody as by the adoptive transfer of alloreactive donor lymphocytes, but without severe GVHD. The proof-of-principle of a low-dose-combination immune checkpoint therapy, consisting only of approved drugs and treatments, was demonstrated in 111 stage IV cancer patients.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Autoimunidade/efeitos dos fármacos , Biomarcadores Tumorais/antagonistas & inibidores , Terapia de Alvo Molecular , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Antineoplásicos Imunológicos/administração & dosagem , Antineoplásicos Imunológicos/efeitos adversos , Antígeno CTLA-4/antagonistas & inibidores , Antígeno CTLA-4/genética , Antígeno CTLA-4/metabolismo , Humanos , Ativação Linfocitária/efeitos dos fármacos , Ativação Linfocitária/imunologia , Metástase Neoplásica , Estadiamento de Neoplasias , Neoplasias/genética , Neoplasias/patologia , Uso Off-Label , Estudo de Prova de Conceito , Transdução de Sinais/efeitos dos fármacos , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Linfócitos T/metabolismo , Resultado do Tratamento
3.
Anticancer Res ; 39(10): 5531-5539, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31570447

RESUMO

BACKGROUND: Possible correlations between the expression of immune checkpoint molecules and prognosis in childhood acute leukemia were investigated. MATERIALS AND METHODS: The expression of programmed-death 1 (PD1), cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), and B- and T-lymphocyte attenuator (BTLA) was determined by flow cytometry on peripheral αß+ and γδ+ T-cells from patients with newly diagnosed acute lymphoblastic leukemia (ALL) (n=9) or acute myeloid leukemia (AML) (n=12), and from healthy volunteers (n=7). The expression of programmed-death ligand 1 (PD-L1), B7-1, B7-2, human leukocyte antigen-ABC (HLA-ABC), and herpesvirus-entry mediator (HVEM) ligands was determined on leukemia blasts. RESULTS: PD1 expression on αß+ and γδ+ T-cells was significantly higher in patients with ALL than in those with AML (p=0.0019 and 0.0239, respectively). CTLA-4 expression was moderately higher on αß+ and γδ+ T-cells in ALL (p=0.077 and 0.077, respectively), whereas HLA-ABC expression was significantly higher in AML blast cells (p=0.0182). The expression of CTLA-4 on γδ+ T-cells and the B7-2 ligand on blasts was higher in patients with high-risk ALL (p=0.02 and 0.02, respectively). In AML, PD1 expression on αß+ T-cells was higher in the intermediate-risk group (p=0.05), whereas HVEM expression was significantly higher in the low-risk group (p=0.02). Expression of CTLA-4 on γδ+ T-cells and PD-L1 on blasts were both associated with poor relapse-free survival outcomes in ALL (p=0.049). CONCLUSION: The higher expression of immune checkpoint molecules, in particular, CTLA-4 and PD-L1 are associated with a poorer prognosis in ALL, suggesting that selective use of the immune checkpoint blockade might improve the clinical outcomes in patients with ALL.


Assuntos
Leucemia/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Linfócitos T/imunologia , Doença Aguda , Adolescente , Adulto , Antígeno B7-H1/metabolismo , Antígeno CTLA-4/metabolismo , Criança , Pré-Escolar , Intervalo Livre de Doença , Feminino , Humanos , Lactente , Ligantes , Masculino , Pessoa de Meia-Idade , Recidiva , Adulto Jovem
4.
Infect Immun ; 87(12)2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31570560

RESUMO

Chronic helminth infections are known to be associated with the modulation of antigen-specific T-cell responses. Strongyloides stercoralis infection is characterized by the downmodulation of antigen-specific Th1 and Th17 responses and the upregulation of Th2 and Th9 responses. Immune homeostasis is partially maintained by negative regulators of T-cell activation, cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and programmed death 1 (PD-1), which dampen effector responses during chronic infections. However, their roles in S. stercoralis infection are yet to be defined. Therefore, we sought to determine the role of CTLA-4 and PD-1 in regulating CD4+ and CD8+ T-cell responses and examined the frequencies of monofunctional and dual functional Th1/T cytotoxic type 1 (Tc1), Th17/Tc17, Th2/Tc2, and Th9/Tc9 cells in S. stercoralis infection in 15 infected individuals stimulated with parasite antigen following CTLA-4 or PD-1 blockade. Our data reveal that CTLA-4 or PD-1 blockade results in significantly enhanced frequencies of monofunctional and dual functional Th1/Tc1 and Th17/Tc17 cells and, in contrast, diminishes the frequencies of monofunctional and dual functional Th2/Tc2 and Th9/Tc9 cells with parasite antigen stimulation in whole-blood cultures. Thus, we demonstrate that CTLA-4 and PD-1 limit the induction of particular T-cell subsets in S. stercoralis infection, which suggests the importance of CTLA-4 and PD-1 in immune modulation in a chronic helminth infection.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Antígeno CTLA-4/metabolismo , Receptor de Morte Celular Programada 1/metabolismo , Strongyloides stercoralis/imunologia , Células Th1/imunologia , Células Th17/imunologia , Células Th2/imunologia , Adulto , Animais , Humanos , Índia , Ativação Linfocitária/imunologia , Pessoa de Meia-Idade , Estrongiloidíase/imunologia , Estrongiloidíase/parasitologia , Subpopulações de Linfócitos T/imunologia , Adulto Jovem
5.
Int J Mol Sci ; 20(17)2019 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-31470642

RESUMO

The concept of leukemic stem cells (LSC) has been developed with the idea to explain the clonal hierarchies and architectures in leukemia, and the more or less curative anti-neoplastic effects of various targeted drugs. It is now widely accepted that curative therapies must have the potential to eliminate or completely suppress LSC, as only these cells can restore and propagate the malignancy for unlimited time periods. Since LSC represent a minor cell fraction in the leukemic clone, little is known about their properties and target expression profiles. Over the past few years, several cell-specific immunotherapy concepts have been developed, including new generations of cell-targeting antibodies, antibody-toxin conjugates, bispecific antibodies, and CAR-T cell-based strategies. Whereas such concepts have been translated and may improve outcomes of therapy in certain lymphoid neoplasms and a few other malignancies, only little is known about immunological targets that are clinically relevant and can be employed to establish such therapies in myeloid neoplasms. In the current article, we provide an overview of the immunologically relevant molecular targets expressed on LSC in patients with acute myeloid leukemia (AML) and chronic myeloid leukemia (CML). In addition, we discuss the current status of antibody-based therapies in these malignancies, their mode of action, and successful examples from the field.


Assuntos
Fatores Imunológicos/uso terapêutico , Imunoterapia/métodos , Leucemia Mielogênica Crônica BCR-ABL Positiva/terapia , Leucemia Mieloide/terapia , Células-Tronco Neoplásicas/efeitos dos fármacos , Doença Aguda , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/imunologia , Antígeno B7-H1/metabolismo , Antígeno CTLA-4/antagonistas & inibidores , Antígeno CTLA-4/imunologia , Antígeno CTLA-4/metabolismo , Humanos , Imunoterapia/tendências , Leucemia Mielogênica Crônica BCR-ABL Positiva/imunologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , Leucemia Mieloide/imunologia , Leucemia Mieloide/metabolismo , Terapia de Alvo Molecular/métodos , Terapia de Alvo Molecular/tendências , Células-Tronco Neoplásicas/imunologia , Células-Tronco Neoplásicas/metabolismo
6.
Chemotherapy ; 64(2): 62-80, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31387102

RESUMO

BACKGROUND: Immune checkpoints are critical regulatory pathways of the immune system which finely tune the response to biological threats. Among them, the CD-28/CTLA-4 and PD-1/PD-L1 axes play a key role in tumour immune escape and are well-established targets of cancer immunotherapy. SUMMARY: The clinical experience accumulated to date provides unequivocal evidence that anti-CTLA-4, PD-1, or PD-L1 monoclonal antibodies, used as monotherapy or in combination regimes, are effective in a variety of advanced/metastatic types of cancer, with improved clinical outcomes compared to conventional chemotherapy. However, the therapeutic success is currently restricted to a limited subset of patients and reliable predictive biomarkers are still lacking. Key Message: The identification and characterization of additional co-inhibitory pathways as novel pharmacological targets to improve the clinical response in refractory patients has led to the development of different immune checkpoint inhibitors, the activities of which are currently under investigation. In this review, we discuss recent literature data concerning the mechanisms of action of next-generation monoclonal antibodies targeting LAG-3, TIM-3, and TIGIT co-inhibitory molecules that are being explored in clinical trials, as single agents or in combination with other immune-stimulating agents.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Neoplasias/tratamento farmacológico , Antígenos CD/imunologia , Antígenos CD/metabolismo , Antígeno CTLA-4/imunologia , Antígeno CTLA-4/metabolismo , Ensaios Clínicos como Assunto , Receptor Celular 2 do Vírus da Hepatite A/imunologia , Receptor Celular 2 do Vírus da Hepatite A/metabolismo , Humanos , Neoplasias/imunologia , Receptor de Morte Celular Programada 1/imunologia , Receptor de Morte Celular Programada 1/metabolismo , Receptores Imunológicos/imunologia , Receptores Imunológicos/metabolismo , Microambiente Tumoral
7.
Curr Top Med Chem ; 19(16): 1464-1483, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31264549

RESUMO

The great clinical success of chimeric antigen receptor T cell (CAR-T) and PD-1/PDL-1 inhibitor therapies suggests the drawing of a cancer immunotherapy age. However, a considerable proportion of cancer patients currently receive little benefit from these treatment modalities, indicating that multiple immunosuppressive mechanisms exist in the tumor microenvironment. In this review, we mainly discuss recent advances in small molecular regulators targeting G Protein-Coupled Receptors (GPCRs) that are associated with oncology immunomodulation, including chemokine receptors, purinergic receptors, prostaglandin E receptor EP4 and opioid receptors. Moreover, we outline how they affect tumor immunity and neoplasia by regulating immune cell recruitment and modulating tumor stromal cell biology. We also summarize the data from recent clinical advances in small molecular regulators targeting these GPCRs, in combination with immune checkpoints blockers, such as PD-1/PDL-1 and CTLA4 inhibitors, for cancer treatments.


Assuntos
Imunoterapia , Terapia de Alvo Molecular , Neoplasias/metabolismo , Neoplasias/terapia , Receptores Acoplados a Proteínas-G/antagonistas & inibidores , Bibliotecas de Moléculas Pequenas/farmacologia , Animais , Antígeno CTLA-4/antagonistas & inibidores , Antígeno CTLA-4/metabolismo , Humanos , Receptores Acoplados a Proteínas-G/metabolismo , Bibliotecas de Moléculas Pequenas/química
8.
Nat Commun ; 10(1): 3106, 2019 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-31308374

RESUMO

Immune responses need to be controlled tightly to prevent autoimmune diseases, yet underlying molecular mechanisms remain partially understood. Here, we identify biallelic mutations in three patients from two unrelated families in differentially expressed in FDCP6 homolog (DEF6) as the molecular cause of an inborn error of immunity with systemic autoimmunity. Patient T cells exhibit impaired regulation of CTLA-4 surface trafficking associated with reduced functional CTLA-4 availability, which is replicated in DEF6-knockout Jurkat cells. Mechanistically, we identify the small GTPase RAB11 as an interactor of the guanine nucleotide exchange factor DEF6, and find disrupted binding of mutant DEF6 to RAB11 as well as reduced RAB11+CTLA-4+ vesicles in DEF6-mutated cells. One of the patients has been treated with CTLA-4-Ig and achieved sustained remission. Collectively, we uncover DEF6 as player in immune homeostasis ensuring availability of the checkpoint protein CTLA-4 at T-cell surface, identifying a potential target for autoimmune and/or cancer therapy.


Assuntos
Antígeno CTLA-4/metabolismo , Proteínas de Ligação a DNA/deficiência , Fatores de Troca do Nucleotídeo Guanina/deficiência , /genética , Antígeno B7-1/metabolismo , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/imunologia , Técnicas de Inativação de Genes , Fatores de Troca do Nucleotídeo Guanina/genética , Fatores de Troca do Nucleotídeo Guanina/imunologia , Homeostase , Humanos , Células Jurkat , Linfócitos T/metabolismo , Linfócitos T/fisiologia , Proteínas rab de Ligação ao GTP/genética , Proteínas rab de Ligação ao GTP/metabolismo
9.
Immunohorizons ; 3(1): 13-25, 2019 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-31356173

RESUMO

Inhibitory receptors (IR) are a diverse group of cell surface molecules that modulate T cell activation, but there are gaps in our knowledge of the cell-extrinsic factors that regulate their expression. The present study found that in vivo overexpression of IL-27 in mice led to increased T cell expression of PD-L1, LAG-3, TIGIT, and TIM-3. In vitro, TCR stimulation alone promoted expression of multiple IRs, whereas IL-27 alone induced expression of PD-L1. However, the combination of intermediate TCR stimulation and IL-27 resulted in synergistic induction of LAG-3, CTLA-4, and TIGIT. In vivo, infection with Toxoplasma gondii resulted in parasite-specific effector T cells that expressed high levels of IR, and at local sites of infection where IL-27 production was highest, IL-27 was required for maximal effector cell expression of PD-L1, LAG-3, CTLA-4, and TIGIT. Together, these results affirm the critical role of TCR signals in the induction of IR expression but find that during infection, IL-27 promotes T cell expression of IR.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Receptores Coestimuladores e Inibidores de Linfócitos T/metabolismo , Interleucinas/metabolismo , Receptores de Antígenos de Linfócitos T/metabolismo , Animais , Antígeno B7-H1/metabolismo , Linfócitos T CD4-Positivos/parasitologia , Linfócitos T CD8-Positivos/parasitologia , Antígeno CTLA-4/metabolismo , Receptores Coestimuladores e Inibidores de Linfócitos T/genética , Feminino , Interleucinas/genética , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Receptores de Antígenos de Linfócitos T/genética , Receptores Imunológicos/metabolismo , Baço/patologia , Toxoplasma , Toxoplasmose/imunologia , Transcriptoma , Transfecção
10.
Genomics Proteomics Bioinformatics ; 17(2): 129-139, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-31229590

RESUMO

The activation mechanism of chimeric antigen receptor (CAR)-engineered T cells may differ substantially from T cells carrying native T cell receptor, but this difference remains poorly understood. We present the first comprehensive portrait of single-cell level transcriptional and cytokine signatures of anti-CD19/4-1BB/CD28/CD3ζ CAR-T cells upon antigen-specific stimulation. Both CD4+ helper T (TH) cells and CD8+ cytotoxic CAR-T cells are equally effective in directly killing target tumor cells and their cytotoxic activity is associated with the elevation of a range of TH1 and TH2 signature cytokines, e.g., interferon γ, tumor necrotic factor α, interleukin 5 (IL5), and IL13, as confirmed by the expression of master transcription factor genes TBX21 and GATA3. However, rather than conforming to stringent TH1 or TH2 subtypes, single-cell analysis reveals that the predominant response is a highly mixed TH1/TH2 function in the same cell. The regulatory T cell activity, although observed in a small fraction of activated cells, emerges from this hybrid TH1/TH2 population. Granulocyte-macrophage colony stimulating factor (GM-CSF) is produced from the majority of cells regardless of the polarization states, further contrasting CAR-T to classic T cells. Surprisingly, the cytokine response is minimally associated with differentiation status, although all major differentiation subsets such as naïve, central memory, effector memory, and effector are detected. All these suggest that the activation of CAR-engineered T cells is a canonical process that leads to a highly mixed response combining both type 1 and type 2 cytokines together with GM-CSF, supporting the notion that polyfunctional CAR-T cells correlate with objective response of patients in clinical trials. This work provides new insights into the mechanism of CAR activation and implies the necessity for cellular function assays to characterize the quality of CAR-T infusion products and monitor therapeutic responses in patients.


Assuntos
Diferenciação Celular , Ativação Linfocitária/imunologia , Receptores de Antígenos Quiméricos/metabolismo , Análise de Célula Única/métodos , Células Th1/citologia , Células Th2/citologia , Antígenos/metabolismo , Antígeno CTLA-4/metabolismo , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular , Citocinas/metabolismo , Citotoxicidade Imunológica/efeitos dos fármacos , Fator Estimulador de Colônias de Granulócitos e Macrófagos/farmacologia , Humanos , Ativação Linfocitária/efeitos dos fármacos , Subpopulações de Linfócitos/efeitos dos fármacos , Subpopulações de Linfócitos/metabolismo , Fenótipo , Proteômica , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/metabolismo , Células Th1/efeitos dos fármacos , Células Th2/efeitos dos fármacos , Transcrição Genética/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos
11.
Arch Immunol Ther Exp (Warsz) ; 67(5): 335-349, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31177287

RESUMO

Major causes of chronic kidney disease are primary proliferative and nonproliferative glomerulonephritides (PGN and NPGN). However, the pathogenesis of PGN and NPGN is still not fully understood. Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) is a T-cell membrane receptor that plays a key role in T-cell inhibition. Despite its role in autoimmunological diseases, little is known about the involvement of CTLA-4 in the pathogenesis of PGN and NPGN. The objective of this study was to determine the role of CTLA-4 in the pathogenesis of PGN and NPGN by evaluating the frequencies of T and B lymphocytes expressing CTLA-4 and the serum concentration of the sCTLA-4 isoform in patients with PGN and NPGN in relation to clinical parameters. The study included peripheral blood (PB) samples from 40 PGN and NPGN patients and 20 healthy age- and sex-matched volunteers (control group). The viable PB lymphocytes were labeled with fluorochrome-conjugated monoclonal anti-CTLA-4 antibodies and analyzed using flow cytometry. The serum concentration of sCTLA-4 was measured using ELISA. The frequencies and absolute counts of CD4+/CTLA-4+ T lymphocytes, CD8+/CTLA-4+ T lymphocytes and CD19+/CTLA-4+ B lymphocytes and the serum sCTLA-4 concentration were lower in PGN and NPGN patients that in the control group. Reduced sCTLA-4 expression was associated with a lower concentration of serum immunoglobulins. Our results indicate that deregulation of CTLA-4 expression may result in continuous activation of T cells and contribute to the pathogenesis of PGN and NPGN.


Assuntos
Antígeno CTLA-4/genética , Regulação da Expressão Gênica , Glomerulonefrite/imunologia , Glomerulonefrite/fisiopatologia , Imunoglobulinas/sangue , Rim/fisiopatologia , Subpopulações de Linfócitos/metabolismo , Adulto , Idoso , Antígenos CD/metabolismo , Antígeno CTLA-4/sangue , Antígeno CTLA-4/metabolismo , Feminino , Humanos , Ativação Linfocitária , Contagem de Linfócitos , Subpopulações de Linfócitos/imunologia , Masculino , Pessoa de Meia-Idade , Curva ROC , Adulto Jovem
12.
Biomed Res Int ; 2019: 9056417, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31179334

RESUMO

Immunotherapy, and in particular immune-checkpoints blockade therapy (ICB), represents a new pillar in cancer therapy. Antibodies targeting Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4) and Programmed Death 1 (PD-1)/Programmed Death Ligand-1 (PD-L1) demonstrated a relevant clinical value in a large number of solid tumors, leading to an improvement of progression free survival and overall survival in comparison to standard chemotherapy. However, across different solid malignancies, the immune-checkpoints inhibitors efficacy is limited to a relative small number of patients and, for this reason, the identification of positive or negative predictive biomarkers represents an urgent need. Despite the expression of PD-L1 was largely investigated in various malignancies, (i.e., melanoma, head and neck malignancies, urothelial and renal carcinoma, metastatic colorectal cancer, and pancreatic cancer) as a biomarker for ICB treatment-patients selection, it showed an important, but still imperfect, role as positive predictor of response only in nonsmall cell lung cancer (NSCLC). Importantly, other tumor and/or microenvironments related characteristics are currently under clinical evaluation, in combination or in substitution of PD-L1 expression. In particular, tumor-infiltrating immune cells, gene expression analysis, mismatch- repair deficiency, and tumor mutational landscape may play a central role in predicting clinical benefits of CTLA-4 and/or PD-1/PD-L1 checkpoint inhibitors. In this review, we will focus on the clinical evaluation of emerging biomarkers and how these may improve the naïve vision of a single- feature patients-based selection.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/uso terapêutico , Biomarcadores Tumorais , Imunoterapia/métodos , Neoplasias/tratamento farmacológico , Antígeno B7-H1/metabolismo , Neoplasias da Mama , Antígeno CTLA-4/metabolismo , Carcinoma Pulmonar de Células não Pequenas , Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Neoplasias Gastrointestinais/tratamento farmacológico , Neoplasias de Cabeça e Pescoço , Humanos , Neoplasias Renais/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Melanoma , Neoplasias/genética , Neoplasias Pancreáticas/tratamento farmacológico , Receptor de Morte Celular Programada 1/metabolismo
13.
Cell Oncol (Dordr) ; 42(5): 609-626, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31201647

RESUMO

BACKGROUND: The discovery of immune checkpoint proteins and the mechanisms by which cancer cells utilize them to evade the immune system has transformed our approach to cancer immunotherapy. Checkpoint blockade antibodies targeting cytotoxic T lymphocyte antigen 4 (CTLA-4), programmed cell death 1 (PD-1) and its ligands such as programmed cell death ligand 1 (PD-L1) have already revolutionized the treatment of multiple types of cancer and have significantly improved treatment and survival outcomes of patients affected by these malignancies. CONCLUSIONS: Herein, we summarize current knowledge about the role of, and the mechanisms underlying PD-1/PD-L1 signaling pathways in antitumor immune responses, with particular emphasis on clinical studies evaluating the efficacy of anti-PD-1/PD-L1 blockade in various tumor types. Preliminary clinical investigations with immune-checkpoint blockers highlight broad opportunities with a high potential to enhance antitumor immunity and, as such, to generate significant clinical responses. These preliminary successes open up new avenues towards efficient therapeutics offered to patients.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Antígeno CTLA-4/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Antígeno B7-H1/genética , Antígeno B7-H1/imunologia , Antígeno B7-H1/metabolismo , Antígeno CTLA-4/genética , Antígeno CTLA-4/imunologia , Antígeno CTLA-4/metabolismo , Humanos , Imunoterapia , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/imunologia , Receptor de Morte Celular Programada 1/metabolismo , Transdução de Sinais , Linfócitos T/imunologia
14.
J Immunol Res ; 2019: 1242979, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31198791

RESUMO

Cervical cancer is the second most frequent cancer in women in Mexico, and its development depends on the presence of human papillomaviruses in the uterine cervix. These oncogenic viruses transform cells where the control over cell cycle disappears, and the capacity to induce apoptosis is absent. On the other hand, some mutations confer to the transformed cells the ability to evade recognition by the immune system. The expression of markers of the immune system such as CD95, MICA/B, CD39, CD73, NKp30, NKp46, CD44, CD24, NKG2A, and CTLA-4 was analysed by flow cytometry on cervical cancer cells INBL (HPV 18, stage IVB), HeLa (HPV 18), CaSki (HPV 16), and C33A (HPV-). Our results showed the presence of atypical markers on cervical cancer cells; some of them are molecules involved in tumour cell recognition such as MICA/B and CD95. Other markers associated with immune system escape, such as CD39, CD73, and CTLA-4, were also present. Furthermore, we found that some cervical cancer cells expressed typical markers of NK cells like NKp30, NKp46, NKG2A, and KIR3DL1. It is not clear whether these molecules confer any gain to the tumour cells or if they represent a disadvantage, but we hypothesise that these molecules that are present in cervical cancer cells allow them to mimic in front of the immune system.


Assuntos
Papillomavirus Humano 16/fisiologia , Papillomavirus Humano 18/fisiologia , Células Matadoras Naturais/imunologia , Infecções por Papillomavirus/metabolismo , Neoplasias do Colo do Útero/metabolismo , 5'-Nucleotidase/metabolismo , Antígenos CD/metabolismo , Apirase/metabolismo , Antígeno CTLA-4/metabolismo , Feminino , Células HeLa , Antígenos de Histocompatibilidade Classe I/metabolismo , Humanos , Vigilância Imunológica , Receptores de Células Matadoras Naturais/metabolismo , Evasão Tumoral , Receptor fas/metabolismo
15.
Cancer Sci ; 110(7): 2080-2089, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31102428

RESUMO

Regulatory T (Treg) cells suppress abnormal/excessive immune responses to self- and nonself-antigens to maintain immune homeostasis. In tumor immunity, Treg cells are involved in tumor development and progression by inhibiting antitumor immunity. There are several Treg cell immune suppressive mechanisms: inhibition of costimulatory signals by CD80 and CD86 expressed by dendritic cells through cytotoxic T-lymphocyte antigen-4, interleukin (IL)-2 consumption by high-affinity IL-2 receptors with high CD25 (IL-2 receptor α-chain) expression, secretion of inhibitory cytokines, metabolic modulation of tryptophan and adenosine, and direct killing of effector T cells. Infiltration of Treg cells into the tumor microenvironment (TME) occurs in multiple murine and human tumors. Regulatory T cells are chemoattracted to the TME by chemokine gradients such as CCR4-CCL17/22, CCR8-CCL1, CCR10-CCL28, and CXCR3-CCL9/10/11. Regulatory T cells are then activated and inhibit antitumor immune responses. A high infiltration by Treg cells is associated with poor survival in various types of cancer. Therefore, strategies to deplete Treg cells and control of Treg cell functions to increase antitumor immune responses are urgently required in the cancer immunotherapy field. Various molecules that are highly expressed by Treg cells, such as immune checkpoint molecules, chemokine receptors, and metabolites, have been targeted by Abs or small molecules, but additional strategies are needed to fine-tune and optimize for augmenting antitumor effects restricted in the TME while avoiding systemic autoimmunity. Here, we provide a brief synopsis of these cells in cancer and how they can be controlled to achieve therapeutic outcomes.


Assuntos
Antineoplásicos/uso terapêutico , Imunoterapia/métodos , Neoplasias/tratamento farmacológico , Linfócitos T Reguladores/imunologia , Animais , Antineoplásicos/farmacologia , Antineoplásicos Imunológicos/farmacologia , Antineoplásicos Imunológicos/uso terapêutico , Antígeno CTLA-4/metabolismo , Citocinas/metabolismo , Humanos , Interleucina-2/metabolismo , Subunidade alfa de Receptor de Interleucina-2/metabolismo , Camundongos , Neoplasias/imunologia , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Bibliotecas de Moléculas Pequenas/farmacologia , Bibliotecas de Moléculas Pequenas/uso terapêutico , Linfócitos T Reguladores/efeitos dos fármacos
16.
PLoS Biol ; 17(5): e3000270, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31125332

RESUMO

Regulatory T (Treg) cells play central roles in maintaining immune homeostasis and self-tolerance. However, the molecular mechanisms underlying Treg cell homeostasis and suppressive function are still not fully understood. Here, we report that the deletion of another P subfamily members of the forkhead box (Foxp) subfamily member Foxp1 in Treg cells led to increased numbers of activated Treg (aTreg) cells at the expense of quiescent Treg cells, and also resulted in impaired Treg suppressive function. Mice with Foxp1-deficient Treg cells developed spontaneous inflammatory disease with age; they also had more severe inflammatory disease in colitis and experimental autoimmune encephalomyelitis (EAE) models. Mechanistically, we found that Foxp1 bound to the conserved noncoding sequence 2 (CNS2) element of the Foxp3 locus and helped maintain Treg suppressive function by stabilizing the Foxp3 expression. Furthermore, we found that Foxp1 and Foxp3 coordinated the regulation of cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) expression levels. Taken together, our study demonstrates that Foxp1 plays critical roles in both maintaining Treg cell quiescence during homeostasis and regulating Treg suppressive function.


Assuntos
Fatores de Transcrição Forkhead/metabolismo , Homeostase , Proteínas Repressoras/metabolismo , Linfócitos T Reguladores/metabolismo , Animais , Antígeno CTLA-4/metabolismo , Diferenciação Celular , Células HEK293 , Humanos , Ativação Linfocitária/imunologia , Camundongos Transgênicos , Transcrição Genética
17.
Comput Biol Chem ; 80: 433-440, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31146119

RESUMO

High production cost, instability, low tumor penetration are some of the shortcomings that have characterized and undermined the use of antibodies as a target for Cytotoxic T-lymphocytes associated protein 4 (CTLA-4). Design and discovery of small molecule inhibitors have therefore become a sine qua non in targeting immune proteins implicated in immune disorders. In this study, we utilized a drug repositioning approach to explore the characteristic feature of unrelated proteins to have similar binding sites and the promiscuity of drugs to repurpose an existing drug to target CTLA-4. CTLA-4 and Kallikrein-7 were found to have similar binding sites, we therefore used 1, 3, 6-trisubstituted 1, 4-diazepane-7-ones (TDSO) which is an inhibitor of Kallikrein-7 as our lead compound. High throughput screening using TDSO as a lead compound resulted in 9 hits with ZINC04515726 and ZINC08985213 having the highest binding score. We went ahead to investigate the interaction of these compounds with CTLA-4 by conducting a molecular dynamic simulation. Molecular Mechanics/Poisson-Boltzmann Surface Area (MM/PBSA) estimations revealed that TDSO had the highest binding energy value of -28.51Kcal/mol, with ZINC04515726 and ZINC08985213 having -23.76Kcal/mol and -21.03Kcal/mol respectively. The per-residue decomposition highlighted Tyr24, Ala25, Gly28, Ala30, Tyr53 and Asn72 as having significantly high electrostatic energy contributions and the main contributing residues to the binding of TDSO, ZINC04515726 and ZINC08985213 to Cytotoxic T lymphocytes CTLA-4. Summarily, from the results gathered, we proposed that TDSO can be an effective immune check point small molecule inhibitor against the suppression of T-cell activation, proliferation, and tumor cell eradication.


Assuntos
Azepinas/metabolismo , Antígeno CTLA-4/antagonistas & inibidores , Antígeno CTLA-4/metabolismo , Reposicionamento de Medicamentos , Polifarmacologia , Sequência de Aminoácidos , Azepinas/química , Azepinas/farmacocinética , Sítios de Ligação , Antígeno CTLA-4/química , Ensaios de Triagem em Larga Escala , Humanos , Calicreínas/química , Simulação de Dinâmica Molecular , Ligação Proteica
18.
Int J Radiat Biol ; 95(7): 936-939, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31120369

RESUMO

Purpose: The aim of this review is to highlight key evidence supporting the effect of radiation therapy on tumor immunity. Conclusions: Recent findings in both the preclinical and clinical settings have provided convincing evidence of the ability of radiation therapy to influence tumor-directed immune responses, and have offered critical insights into the underlying mechanisms. Not only does radiation therapy convert the tumor microenvironment to promote robust tumor immunity, but it also enhances the generation of neoantigens and neoepitopes. Radiation therapy also shapes the TCR repertoire of CD8+ T cells in conjunction with immune checkpoint blockade. In conclusion, a high priority should be placed on developing rational strategies to integrate radiation therapy with immunotherapy in the clinical setting, with an emphasis on careful patient selection and identifying important correlative endpoints.


Assuntos
Imunoterapia/métodos , Neoplasias/imunologia , Neoplasias/radioterapia , Radioterapia/métodos , Antígenos/metabolismo , Linfócitos T CD8-Positivos/citologia , Antígeno CTLA-4/metabolismo , Terapia Combinada , Epitopos/metabolismo , Humanos , Metástase Neoplásica , Radiocirurgia , Receptores de Antígenos de Linfócitos T/metabolismo , Microambiente Tumoral
19.
J Manag Care Spec Pharm ; 25(8): 869-877, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30945965

RESUMO

BACKGROUND: The treatment landscape for patients with metastatic melanoma has changed dramatically with the introduction of novel therapies, such as targeted therapies and immunotherapies, in recent years. Health care resource utilization (HCRU) and cost data are needed to further evaluate these treatments in a value-based health care system. OBJECTIVE: To examine HCRU and total cost of care among U.S. metastatic melanoma patients treated with first-line systemic therapies, including immunotherapies, targeted therapies, and chemotherapy. METHODS: A retrospective observational study was conducted using a U.S. claims database. Adults with ≥ 2 claims for melanoma and ≥ 1 claim for metastasis between January 1, 2012, and June 30, 2017, were identified. Patients had pharmacy and medical enrollment ≥ 6 months before and ≥ 3 months following first-line treatment start. Per patient per month (PPPM) HCRU and costs were calculated by first-line treatment drug class: PD-1 inhibitors, CTLA-4 inhibitors, CTLA-4 + PD-1 combination, BRAF monotherapy, BRAF + MEK combination, and chemotherapy. Adjusted odds ratios (ORs) for HCRU were estimated by logistic regressions and adjusted costs were estimated by generalized linear models using log-link with gamma distribution to control for differences in patient characteristics across groups. RESULTS: Among 1,599 metastatic melanoma patients (PD-1, n = 255; CTLA-4, n = 555; CTLA-4 + PD-1, n = 88; BRAF, n = 210; BRAF + MEK, n=102; chemotherapy=389), mean age ranged from 59-68 years, and the majority were male (62%). Any hospitalization during first-line treatment was less frequent among PD-1-treated patients (25.9%) compared with 34.7%-45.5% of all other groups (all P < 0.05). PPPM hospitalizations were lowest in PD-1 (0.06) compared with 0.09-0.16 across all other groups (all P < 0.05), and PPPM emergency department (ED) visits were lowest in PD-1 (0.09) compared with 0.13-0.18 across all other groups (all P < 0.05), except for BRAF + MEK (0.14, P = 0.08). CTLA-4, CTLA-4 + PD-1, and BRAF + MEK had increased odds of hospitalization compared to PD-1 (adjusted ORs = 2.10, 2.35, 2.15, respectively; all P < 0.05). Total adjusted PPPM costs were significantly lower for PD-1 ($13,059) compared with CTLA-4 ($25,583), CTLA-4 + PD-1 ($31,310), and BRAF + MEK ($21,517) and higher compared to BRAF ($8,158) and chemotherapy ($6,361). CONCLUSIONS: Hospitalizations and ED visits represent important HCRU for metastatic melanoma patients and were lowest among PD-1-treated patients compared with any other systemic therapies (except for ED visits when compared with BRAF + MEK). Total monthly costs varied substantially across first-line regimens and were significantly lower in PD-1-treated patients compared with patients treated with CTLA-4, CTLA-4 + PD-1, and BRAF + MEK. DISCLOSURES: This study was funded by Merck Sharp & Dohme, a subsidiary of Merck & Co. Klink, Feinberg, and Nero are employees of Cardinal Health Specialty Solutions, which received funding from Merck to conduct this study. Chmielsowki is a consultant to Merck but received no funding for the development of this manuscript. Ahsan and Liu are employees of Merck. Chmielowski reports advisory board/speaker fees from Bristol-Myers Squibb, Merck, Genentech/Roche, Iovance Biotherapeutics, HUYA Bioscience International, Compugen, Array BioPharma, Regeneron, Biothera, Janssen, and Novartis. Ahsan has a patent (US20160008380A1) pending.


Assuntos
Assistência à Saúde/economia , Melanoma/economia , Idoso , Antígeno CTLA-4/metabolismo , Feminino , Custos de Cuidados de Saúde , Recursos em Saúde , Hospitalização/economia , Humanos , Imunoterapia/economia , Masculino , Melanoma/metabolismo , Pessoa de Meia-Idade , Aceitação pelo Paciente de Cuidados de Saúde , Receptor de Morte Celular Programada 1/metabolismo , Estudos Retrospectivos , Estados Unidos
20.
Clin Drug Investig ; 39(6): 503-519, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30937824

RESUMO

Management of metastatic renal cell carcinoma has drastically changed in the last few years, witnessing the advent of more and more target therapies and, recently, of immune-checkpoint inhibitors. On the other hand, the adjuvant setting still lacks a clear beneficial treatment. Medical treatment still remains a compelling challenge. A large number of clinical trials is ongoing with the aim to identify new therapeutic approaches to expand the options in our repertoire. Several strategies are under investigation in renal cell carcinoma (RCC). These include new targeted agents and combinations of target therapy and immunotherapy. Programmed death receptor-1 (PD-1), programmed death receptor ligand 1 (PD-L1) and cytotoxic T-lymphocyte antigen 4 (CTLA4) are just part of the intricate network that regulates our immune response to cancer cells. Co-stimulators, such as glucocorticoid-induced TNFR-related protein (GITR) and tumor necrosis factor receptor superfamily, member 4 (OX40), and co-repressors, example.g. T cell immunoglobulin and mucin domain 3 (TIM-3) and lymphocyte-activation gene 3 (LAG-3), also take part. As knowledge of the functioning of the immune system grows, so do these pathways to target with new drugs. This review is an overview of the current state of the clinical research, providing a report of ongoing Phase I, II and III clinical trials for localized and metastatic RCC, including novel target therapies, novel immunotherapy agents and new combinations strategies.


Assuntos
Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/tratamento farmacológico , Terapia de Alvo Molecular , Antineoplásicos Imunológicos/administração & dosagem , Antígeno B7-H1/metabolismo , Antígeno CTLA-4/metabolismo , Humanos , Imunoterapia/métodos
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