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1.
Nat Rev Immunol ; 20(12): 739-755, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32728220

RESUMO

The ATP-adenosine pathway functions as a key modulator of innate and adaptive immunity within the tumour microenvironment. Consequently, multiple clinical strategies are being explored to target this pathway for the treatment of cancer; in particular, recent clinical data with CD73 antagonists and inhibitors of A2A receptors have demonstrated the therapeutic potential of modulating this pathway. Now, inhibitors of the ectonucleotidase CD39, the rate-limiting enzyme in the conversion of ATP to immunomodulatory adenosine, are entering clinical trials. Consequently, there is currently a focus on understanding the impact of CD39 enzymatic function on innate and adaptive immunity and how therapeutic modulation of this pathway alters their functional potential within the tumour microenvironment. Recent findings reveal multipronged mechanisms of action of CD39 antagonism that rely not only on preventing the accumulation of adenosine but also on the stabilization of pro-inflammatory extracellular ATP to restore antitumour immunity. Here, we review the impact of CD39 expression and ectonucleotidase activity on immunity with a focus on the setting of oncology. Additionally, we discuss the implications for immunotherapy strategies targeting CD39, including their inclusion in rational combination therapies.


Assuntos
Antígenos CD/imunologia , Apirase/imunologia , Neoplasias/imunologia , Animais , Humanos , Imunidade/imunologia , Imunomodulação/imunologia , Imunoterapia/métodos , Transdução de Sinais/imunologia
2.
Cancer Immunol Res ; 8(3): 356-367, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31992567

RESUMO

Natural killer (NK) cell protection from tumor metastases is a critical feature of the host immune response to cancer, but various immunosuppression mechanisms limit NK cell effector function. The ectoenzyme, CD39, expressed on tumor-infiltrating myeloid cells, granulocytes, and lymphocytes, including NK cells, converts extracellular ATP (eATP) into AMP and, thus, potentially suppresses eATP-mediated proinflammatory responses. A CD39-targeting monoclonal antibody (mAb) that inhibits the mouse ectoenzyme CD39 suppressed experimental and spontaneous metastases in a number of different tumor models and displayed superior antimetastatic activity compared with the CD39 inhibitor POM1 and inhibitors and mAbs that block other members of the adenosinergic family (e.g., A2AR and CD73). The antimetastatic activity of anti-CD39 was NK cell and IFNγ dependent, and anti-CD39 enhanced the percentage and quantity of IFNγ produced and CD107a expression in lung-infiltrating NK cells following tumor challenge and anti-CD39 therapy. Using conditional Cd39 gene-targeted mouse strains and adoptive NK cell transfers, we showed that CD39 expressed on bone marrow-derived myeloid cells was essential for anti-CD39's antimetastatic activity, but NK cell expression of CD39 was not critical. The eATP receptor P2X7 and the NALP3 inflammasome, including downstream IL18, were critical in the mechanism of action of anti-CD39, and the frequency of P2X7 and CD39 coexpressing lung alveolar macrophages was specifically reduced 1 day after anti-CD39 therapy. The data provide a mechanism of action involving NK cells and myeloid cells, and anti-CD39 combined with anti-PD-1, NK cell-activating cytokines IL15 or IL2, or an inhibitor of A2AR to effectively suppress tumor metastases.


Assuntos
Anticorpos Monoclonais/farmacologia , Antígenos CD/imunologia , Apirase/imunologia , Neoplasias Renais/imunologia , Células Matadoras Naturais/imunologia , Neoplasias Pulmonares/imunologia , Melanoma Experimental/imunologia , Animais , Anticorpos Monoclonais/imunologia , Apirase/antagonistas & inibidores , Tolerância Imunológica , Inflamassomos/imunologia , Neoplasias Renais/metabolismo , Neoplasias Renais/patologia , Neoplasias Renais/terapia , Células Matadoras Naturais/efeitos dos fármacos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/secundário , Neoplasias Pulmonares/terapia , Melanoma Experimental/metabolismo , Melanoma Experimental/patologia , Melanoma Experimental/terapia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Células Mieloides/efeitos dos fármacos , Células Mieloides/imunologia , Células Tumorais Cultivadas
3.
Cancer Discov ; 9(12): 1754-1773, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31699796

RESUMO

We explored the mechanism of action of CD39 antibodies that inhibit ectoenzyme CD39 conversion of extracellular ATP (eATP) to AMP and thus potentially augment eATP-P2-mediated proinflammatory responses. Using syngeneic and humanized tumor models, we contrast the potency and mechanism of anti-CD39 mAbs with other agents targeting the adenosinergic pathway. We demonstrate the critical importance of an eATP-P2X7-ASC-NALP3-inflammasome-IL18 pathway in the antitumor activity mediated by CD39 enzyme blockade, rather than simply reducing adenosine as mechanism of action. Efficacy of anti-CD39 activity was underpinned by CD39 and P2X7 coexpression on intratumor myeloid subsets, an early signature of macrophage depletion, and active IL18 release that facilitated the significant expansion of intratumor effector T cells. More importantly, anti-CD39 facilitated infiltration into T cell-poor tumors and rescued anti-PD-1 resistance. Anti-human CD39 enhanced human T-cell proliferation and Th1 cytokine production and suppressed human B-cell lymphoma in the context of autologous Epstein-Barr virus-specific T-cell transfer. SIGNIFICANCE: Overall, these data describe a potent and novel mechanism of action of antibodies that block mouse or human CD39, triggering an eATP-P2X7-inflammasome-IL18 axis that reduces intratumor macrophage number, enhances intratumor T-cell effector function, overcomes anti-PD-1 resistance, and potentially enhances the efficacy of adoptive T-cell transfer.This article is highlighted in the In This Issue feature, p. 1631.


Assuntos
Trifosfato de Adenosina/metabolismo , Antineoplásicos Imunológicos/administração & dosagem , Apirase/antagonistas & inibidores , Inflamassomos/metabolismo , Neoplasias/tratamento farmacológico , Animais , Antineoplásicos Imunológicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Masculino , Camundongos , Transplante de Neoplasias , Neoplasias/imunologia , Receptores Purinérgicos P2X7/metabolismo , Transdução de Sinais
4.
Clin Cancer Res ; 23(20): 6190-6202, 2017 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-28706012

RESUMO

Purpose: Talimogene laherparepvec, a new oncolytic immunotherapy, has been recently approved for the treatment of melanoma. Using a murine version of the virus, we characterized local and systemic antitumor immune responses driving efficacy in murine syngeneic models.Experimental Design: The activity of talimogene laherparepvec was characterized against melanoma cell lines using an in vitro viability assay. Efficacy of OncoVEXmGM-CSF (talimogene laherparepvec with the mouse granulocyte-macrophage colony-stimulating factor transgene) alone or in combination with checkpoint blockade was characterized in A20 and CT-26 contralateral murine tumor models. CD8+ depletion, adoptive T-cell transfers, and Enzyme-Linked ImmunoSpot assays were used to study the mechanism of action (MOA) of systemic immune responses.Results: Treatment with OncoVEXmGM-CSF cured all injected A20 tumors and half of contralateral tumors. Viral presence was limited to injected tumors and was not responsible for systemic efficacy. A significant increase in T cells (CD3+/CD8+) was observed in injected and contralateral tumors at 168 hours. Ex vivo analyses showed these cytotoxic T lymphocytes were tumor-specific. Increased neutrophils, monocytes, and chemokines were observed in injected tumors only. Importantly, depletion of CD8+ T cells abolished all systemic efficacy and significantly decreased local efficacy. In addition, immune cell transfer from OncoVEXmGM-CSF-cured mice significantly protected from tumor challenge. Finally, combination of OncoVEXmGM-CSF and checkpoint blockade resulted in increased tumor-specific CD8+ anti-AH1 T cells and systemic efficacy.Conclusions: The data support a dual MOA for OncoVEXmGM-CSF that involves direct oncolysis of injected tumors and activation of a CD8+-dependent systemic response that clears injected and contralateral tumors when combined with checkpoint inhibition. Clin Cancer Res; 23(20); 6190-202. ©2017 AACR.


Assuntos
Fator Estimulador de Colônias de Granulócitos e Macrófagos/metabolismo , Imunoterapia , Neoplasias/imunologia , Neoplasias/metabolismo , Terapia Viral Oncolítica , Linfócitos T Citotóxicos/imunologia , Linfócitos T Citotóxicos/metabolismo , Adenoviridae/genética , Transferência Adotiva , Animais , Linhagem Celular Tumoral , Modelos Animais de Doenças , Feminino , Terapia Genética/métodos , Vetores Genéticos/administração & dosagem , Vetores Genéticos/genética , Fator Estimulador de Colônias de Granulócitos e Macrófagos/genética , Humanos , Imunomodulação , Imunoterapia/métodos , Estimativa de Kaplan-Meier , Depleção Linfocítica , Melanoma/imunologia , Melanoma/metabolismo , Melanoma/patologia , Melanoma/terapia , Camundongos , Neoplasias/patologia , Neoplasias/terapia , Terapia Viral Oncolítica/métodos , Transgenes , Carga Tumoral , Replicação Viral , Ensaios Antitumorais Modelo de Xenoenxerto
5.
Front Immunol ; 3: 336, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-23189078

RESUMO

Interactions between killer immunoglobulin-like receptors (KIRs) and their HLA-A, -B, and -C ligands diversify the functions of human natural killer cells. Consequently, combinations of KIR and HLA genotypes affect resistance to infection and autoimmunity, success of reproduction and outcome of hematopoietic cell transplantation. HLA-C, with its C1 and C2 epitopes, evolved in hominids to be specialized KIR ligands. The system's foundation was the C1 epitope, with C2 a later addition, by several million years. The human inhibitory receptor for C1 is encoded by KIR2DL2/3, a gene having two divergent allelic lineages: KIR2DL2 is a B KIR haplotype component and KIR2DL3 an A KIR haplotype component. Although KIR2DL2 and KIR2DL3 exhibit quantitative differences in specificity and avidity for HLA-C, they qualitatively differ in their genetics, functional effect, and clinical influence. This is due to linkage disequilibrium between KIR2DL2 and KIR2DS2, a closely related activating receptor that was selected for lost recognition of HLA-C.

6.
J Immunol ; 182(6): 3628-37, 2009 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-19265141

RESUMO

Humans and chimpanzees have orthologous MHC class I, but few orthologous killer cell Ig-like receptors (KIR). Most divergent are lineage III KIR, which in humans include the inhibitory KIR2DL1 and 2DL2/3 specific for HLA-C. Six lineage III chimpanzee KIR were identified as candidate inhibitory MHC-C receptors and studied using cytolytic assays, to assess the capacity of a defined KIR to function with a defined MHC class I allotype, and direct binding assays with KIR-Fc fusion proteins. Pt-KIR2DL6 and 2DL8 were demonstrated to be inhibitory C1 receptors with a specificity and specificity-determining residue (lysine 44) like KIR2DL3. Analogously, Pt-KIR2DL7 is like KIR2DL1, an inhibitory C2 receptor having methionine 44. Pt-KIR3DL4 and 3DL5 are unusual lineage III KIR with D0 domains, which are also inhibitory C2 receptors with methionine 44. Removal of D0 from KIR3DL, or its addition to KIR2DL, had no effect on KIR function. Pt-KIR2DL9, a fourth inhibitory C2 receptor, has glutamate 44, a previously uncharacterized specificity-determining residue that is absent from human KIR. Reconstruction of the ancestral hominoid KIR sequence shows it encoded lysine 44, indicating that KIR having methionine 44 and glutamate 44 subsequently evolved by independent point substitutions. Thus, MHC-C2-specific KIR have evolved independently on at least two occasions. None of the six chimpanzee KIR studied resembles KIR2DL2, which interacts strongly with C1 and cross-reacts with C2. Whereas human HLA-B allotypes that have functional C1 epitopes are either rare (HLA-B*73) or geographically localized (HLA-B*46), some 25% of Patr-B allotypes have the C1 epitope and are functional KIR ligands.


Assuntos
Epitopos/classificação , Epitopos/metabolismo , Antígenos HLA/metabolismo , Antígenos de Histocompatibilidade/metabolismo , Pan troglodytes/imunologia , Receptores KIR/metabolismo , Sequência de Aminoácidos , Animais , Linhagem Celular Tumoral , Testes Imunológicos de Citotoxicidade , Epitopos/genética , Antígenos HLA/genética , Antígenos de Histocompatibilidade/genética , Humanos , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Células Matadoras Naturais/patologia , Ligantes , Lisina/química , Lisina/metabolismo , Dados de Sequência Molecular , Pan troglodytes/genética , Receptores KIR/genética , Receptores KIR2DL4/genética , Receptores KIR2DL4/metabolismo , Receptores KIR2DL5/genética , Receptores KIR2DL5/metabolismo
7.
J Immunol ; 180(6): 3969-79, 2008 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-18322206

RESUMO

Interactions between HLA-C ligands and inhibitory killer cell Ig-like receptors (KIR) control the development and response of human NK cells. This regulatory mechanism is usually described by mutually exclusive interactions of KIR2DL1 with C2 having lysine 80, and KIR2DL2/3 with C1 having asparagine 80. Consistent with this simple rule, we found from functional analysis and binding assays to 93 HLA-A, HLA-B, and HLA-C isoforms that KIR2DL1*003 bound all C2, and only C2, allotypes. The allotypically related KIR2DL2*001 and KIR2DL3*001 interacted with all C1, but they violated the simple rule through interactions with several C2 allotypes, notably Cw*0501 and Cw*0202, and two HLA-B allotypes (B*4601 and B*7301) that share polymorphisms with HLA-C. Although the specificities of the "cross-reactions" were similar for KIR2DL2*001 and KIR2DL3*001, they were stronger for KIR2DL2*001, as were the reactions with C1. Mutagenesis explored the avidity difference between KIR2DL2*001 and KIR2DL3*001. Recombinant mutants mapped the difference to the Ig-like domains, where site-directed mutagenesis showed that the combination, but not the individual substitutions, of arginine for proline 16 in D1 and cysteine for arginine 148 in D2 made KIR2DL2*001 a stronger receptor than KIR2DL3*001. Neither residue 16 or 148 is part of, or near to, the ligand-binding site. Instead, their juxtaposition near the flexible hinge between D1 and D2 suggests that their polymorphisms affect the ligand-binding site by changing the hinge angle and the relative orientation of the two domains. This study demonstrates how allelic polymorphism at sites distal to the ligand-binding site of KIR2DL2/3 has diversified this receptor's interactions with HLA-C.


Assuntos
Antígenos HLA-C/metabolismo , Polimorfismo Genético , Receptores KIR2DL2/genética , Receptores KIR2DL2/metabolismo , Receptores KIR2DL3/genética , Receptores KIR2DL3/metabolismo , Alelos , Substituição de Aminoácidos/genética , Substituição de Aminoácidos/imunologia , Sítios de Ligação/genética , Sítios de Ligação/imunologia , Linhagem Celular Tumoral , Citotoxicidade Imunológica/genética , Antígenos HLA-C/genética , Humanos , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Ligantes , Mutagênese Sítio-Dirigida , Ligação Proteica/genética , Ligação Proteica/imunologia , Receptores KIR2DL1/genética , Receptores KIR2DL1/imunologia , Receptores KIR2DL1/metabolismo , Receptores KIR2DL2/biossíntese , Receptores KIR2DL3/biossíntese
8.
Mol Immunol ; 40(14-15): 1033-9, 2004 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-15036907

RESUMO

Degeneracy in immune recognition is usually thought of in terms of the astonishing ability of the T cell receptor to recognize an enormously diverse array of peptides bound to major histocompatibility complex (MHC) molecules. However, in this essay we discuss an alternative aspect of degeneracy in T cell recognition: the notion that peptides can assume different "registers" in the groove of a single MHC molecule, as first suggested and demonstrated by Sercarz and co-workers (reviewed in [J. autoimmun. 16 (2001) 201]). There is now abundant evidence, derived from functional, biochemical and structural studies, that single peptides can assume alternative, unpredictable binding registers by frameshifting within the MHC groove [Nat. Immunol. 3 (2002) 175;; J. Exp. Med. 187 (1998) 1505; J. Mol. Biol. 304 (2000) 177; Biochemistry 38 (1999) 16663; J. Exp. Med. 197 (2003) 1391; Eur. J. Immunol. 19 (1989) 681]. Hence, register shifting adds an additional dimension to the concept of degeneracy. In fact, the possibility of register shifting multiplies the universe of peptide-MHC (pMHC) surfaces that a TCR must recognize by an unknown, perhaps enormous factor. Register shifting also has profound implication for autoimmunity: (1) as a mechanism to "mask" autoantigenic epitopes during thymic education [Immunol. Rev. 169 (1999) 147; Immunity 17 (2002) 83]; and (2) as a possible source for pMHC complexes capable of molecular mimicry.


Assuntos
Antígenos de Histocompatibilidade/metabolismo , Peptídeos/metabolismo , Receptores de Antígenos de Linfócitos T/imunologia , Animais , Autoimunidade/imunologia , Antígenos de Histocompatibilidade/imunologia , Humanos , Peptídeos/imunologia , Ligação Proteica , Estrutura Terciária de Proteína , Linfócitos T/imunologia
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