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1.
Eur J Immunol ; 45(5): 1560-9, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25726929

RESUMO

Clinical studies suggest that triple negative breast cancer (TNBC) patients with epidermal growth factor receptor (EGFR)-expressing tumors could benefit from therapy with Cetuximab, which targets EGFR. NK cells are the primary effectors of antibody (Ab)-dependent cell-mediated cytotoxicity (ADCC) and thus play a role in Ab-based therapies. We have previously described diminished levels of Cetuximab-mediated ADCC in vitro in patients with advanced breast cancer. Here, we investigated the potential causes of this NK-cell functional deficiency. We characterized NK-cell activating/inhibitory receptors in the peripheral blood of breast cancer patients and found CD85j inhibitory receptor overexpression. The capacity of NK cells to perform Cetuximab-triggered ADCC against TNBC cells correlated inversely with CD85j expression, even in the presence of the stimulatory cytokines IL-2 or IL-15. Hence, patients expressing high levels of CD85j had an impaired ability to lyse TNBC cells in the presence of Cetuximab. We also found that CD85j overexpression was associated with HLA-I and soluble HLA-G expression by tumors. A CD85j functional blockade with a CD85j antagonist Ab restored ADCC levels in breast cancer patients and reverted this negative effect. Our data suggest that strategies that overcome the hurdles of immune activation could improve Cetuximab clinical efficacy.


Assuntos
Anticorpos Monoclonais Humanizados/farmacologia , Citotoxicidade Celular Dependente de Anticorpos , Antígenos CD/metabolismo , Células Matadoras Naturais/imunologia , Receptores Imunológicos/antagonistas & inibidores , Receptores Imunológicos/metabolismo , Neoplasias de Mama Triplo Negativas/imunologia , Neoplasias de Mama Triplo Negativas/terapia , Adulto , Antineoplásicos/farmacologia , Estudos de Casos e Controles , Cetuximab , Receptores ErbB/antagonistas & inibidores , Feminino , Antígenos HLA/metabolismo , Antígenos HLA-G/metabolismo , Humanos , Células K562 , Receptor B1 de Leucócitos Semelhante a Imunoglobulina , Pessoa de Meia-Idade , Adulto Jovem
2.
Cancer Immunol Immunother ; 62(1): 3-15, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22722447

RESUMO

Gamma irradiation is one of the methods used to sterilize melanoma cells prior to coculturing them with monocyte-derived immature dendritic cells in order to develop antitumor vaccines. However, the changes taking place in tumor cells after irradiation and their interaction with dendritic cells have been scarcely analyzed. We demonstrate here for the first time that after irradiation a fraction of tumor cells present large lipid bodies, which mainly contain triglycerides that are several-fold increased as compared to viable cells as determined by staining with Oil Red O and BODIPY 493/503 and by biochemical analysis. Phosphatidyl-choline, phosphatidyl-ethanolamine and sphingomyelin are also increased in the lipid bodies of irradiated cells. Lipid bodies do not contain the melanoma-associated antigen MART-1. After coculturing immature dendritic cells with irradiated melanoma cells, tumor cells tend to form clumps to which dendritic cells adhere. Under such conditions, dendritic cells are unable to act as stimulating cells in a mixed leukocyte reaction. However, when a maturation cocktail composed of TNF-alpha, IL-6, IL-1beta and prostaglandin E2 is added to the coculture, the tumor cells clumps disaggregate, dendritic cells remain free in suspension and their ability to efficiently stimulate allogeneic lymphocytes is restored. These results help to understand the events following melanoma cell irradiation, shed light about interactions between irradiated cells and dendritic cells, and may help to develop optimized dendritic cell vaccines for cancer therapy.


Assuntos
Vacinas Anticâncer/química , Vacinas Anticâncer/imunologia , Citocinas/imunologia , Células Dendríticas/imunologia , Melanoma/química , Melanoma/imunologia , Western Blotting , Vacinas Anticâncer/síntese química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos da radiação , Técnicas de Cocultura , Citometria de Fluxo , Raios gama , Humanos , Lipídeos , Melanoma/patologia
3.
Breast Cancer Res Treat ; 136(3): 659-71, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23065032

RESUMO

Triple-negative breast cancer (TNBC) patients do not benefit from target-specific treatments and is associated with a high relapse rate. Epidermal growth factor receptor is frequently expressed in TNBC and is a candidate for new therapies. In this work, we studied Cetuximab-mediated immune activity by NK cells. Thirteen activating/inhibitory receptors were examined on peripheral blood and tumor infiltrating NK cells. NK-cell functionality was evaluated using as effectors tumor-modulated NK cells and NK cells from patients. We evaluated the treatment with Cetuximab plus IL-2 or IL-15 in vivo in TNBC xenografts. Tumor NK-cells receptor profile showed upregulation of inhibitory receptors and downregulation of activating ones. Tumor-modulated NK cells were less cytotoxic. They could perform antibody-dependent cellular cytotoxicity (ADCC) triggered by Cetuximab, although impaired, it could still be restored by stimulation with IL-2 or IL-15. Patients with advanced disease displayed diminished levels of ADCC compared to healthy volunteers. ADCC was restored and potentiated with both cytokines, which were also effective in enhancing the therapeutic activity of Cetuximab in vivo. The combination of Cetuximab with IL-15 and IL-2 may be considered an attractive therapeutic approach to enhance the clinical efficacy of Cetuximab in TNBC.


Assuntos
Anticorpos Monoclonais Humanizados/farmacologia , Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/imunologia , Interleucina-15/farmacologia , Interleucina-2/farmacologia , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/imunologia , Adulto , Animais , Citotoxicidade Celular Dependente de Anticorpos/efeitos dos fármacos , Citotoxicidade Celular Dependente de Anticorpos/imunologia , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Cetuximab , Feminino , Humanos , Camundongos , Camundongos Nus , Pessoa de Meia-Idade , Ensaios Antitumorais Modelo de Xenoenxerto
4.
Nat Med ; 27(8): 1432-1441, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34239137

RESUMO

Treatment with combined immune checkpoint blockade (CICB) targeting CTLA-4 and PD-1 is associated with clinical benefit across tumor types, but also a high rate of immune-related adverse events. Insights into biomarkers and mechanisms of response and toxicity to CICB are needed. To address this, we profiled the blood, tumor and gut microbiome of 77 patients with advanced melanoma treated with CICB, with a high rate of any ≥grade 3 immune-related adverse events (49%) with parallel studies in pre-clinical models. Tumor-associated immune and genomic biomarkers of response to CICB were similar to those identified for ICB monotherapy, and toxicity from CICB was associated with a more diverse peripheral T-cell repertoire. Profiling of gut microbiota demonstrated a significantly higher abundance of Bacteroides intestinalis in patients with toxicity, with upregulation of mucosal IL-1ß in patient samples of colitis and in pre-clinical models. Together, these data offer potential new therapeutic angles for targeting toxicity to CICB.


Assuntos
Antígeno CTLA-4/imunologia , Microbioma Gastrointestinal , Receptor de Morte Celular Programada 1/imunologia , Animais , Linhagem Celular Tumoral , Feminino , Humanos , Interleucina-1beta/imunologia , Melanoma , Camundongos , Camundongos Endogâmicos C57BL
5.
Cell Res ; 29(10): 846-861, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31481761

RESUMO

PD-1 blockade represents a major therapeutic avenue in anticancer immunotherapy. Delineating mechanisms of secondary resistance to this strategy is increasingly important. Here, we identified the deleterious role of signaling via the type I interferon (IFN) receptor in tumor and antigen presenting cells, that induced the expression of nitric oxide synthase 2 (NOS2), associated with intratumor accumulation of regulatory T cells (Treg) and myeloid cells and acquired resistance to anti-PD-1 monoclonal antibody (mAb). Sustained IFNß transcription was observed in resistant tumors, in turn inducing PD-L1 and NOS2 expression in both tumor and dendritic cells (DC). Whereas PD-L1 was not involved in secondary resistance to anti-PD-1 mAb, pharmacological or genetic inhibition of NOS2 maintained long-term control of tumors by PD-1 blockade, through reduction of Treg and DC activation. Resistance to immunotherapies, including anti-PD-1 mAb in melanoma patients, was also correlated with the induction of a type I IFN signature. Hence, the role of type I IFN in response to PD-1 blockade should be revisited as sustained type I IFN signaling may contribute to resistance to therapy.


Assuntos
Anticorpos Monoclonais/farmacologia , Interferon Tipo I/metabolismo , Receptor de Morte Celular Programada 1/imunologia , Transdução de Sinais/efeitos dos fármacos , Animais , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/uso terapêutico , Antígeno B7-H1/metabolismo , Linhagem Celular Tumoral , Células Dendríticas/citologia , Células Dendríticas/metabolismo , Resistencia a Medicamentos Antineoplásicos , Humanos , Estimativa de Kaplan-Meier , Melanoma/tratamento farmacológico , Melanoma/mortalidade , Melanoma/patologia , Camundongos , Camundongos Endogâmicos C57BL , Neoplasias/tratamento farmacológico , Neoplasias/mortalidade , Neoplasias/patologia , Óxido Nítrico Sintase Tipo II/metabolismo , Linfócitos T Reguladores/citologia , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo
6.
Science ; 359(6371): 91-97, 2018 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-29097494

RESUMO

Immune checkpoint inhibitors (ICIs) targeting the PD-1/PD-L1 axis induce sustained clinical responses in a sizable minority of cancer patients. We found that primary resistance to ICIs can be attributed to abnormal gut microbiome composition. Antibiotics inhibited the clinical benefit of ICIs in patients with advanced cancer. Fecal microbiota transplantation (FMT) from cancer patients who responded to ICIs into germ-free or antibiotic-treated mice ameliorated the antitumor effects of PD-1 blockade, whereas FMT from nonresponding patients failed to do so. Metagenomics of patient stool samples at diagnosis revealed correlations between clinical responses to ICIs and the relative abundance of Akkermansia muciniphila Oral supplementation with A. muciniphila after FMT with nonresponder feces restored the efficacy of PD-1 blockade in an interleukin-12-dependent manner by increasing the recruitment of CCR9+CXCR3+CD4+ T lymphocytes into mouse tumor beds.


Assuntos
Transplante de Microbiota Fecal , Microbioma Gastrointestinal/imunologia , Imunoterapia/métodos , Neoplasias/terapia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Animais , Antibacterianos/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Antígenos CD4/imunologia , Fezes/microbiologia , Microbioma Gastrointestinal/genética , Humanos , Interleucina-12/imunologia , Metagenoma/genética , Camundongos , Receptores CCR/imunologia , Receptores CXCR3/imunologia , Linfócitos T/imunologia , Verrucomicrobia/genética , Verrucomicrobia/imunologia
7.
Science ; 350(6264): 1079-84, 2015 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-26541610

RESUMO

Antibodies targeting CTLA-4 have been successfully used as cancer immunotherapy. We find that the antitumor effects of CTLA-4 blockade depend on distinct Bacteroides species. In mice and patients, T cell responses specific for B. thetaiotaomicron or B. fragilis were associated with the efficacy of CTLA-4 blockade. Tumors in antibiotic-treated or germ-free mice did not respond to CTLA blockade. This defect was overcome by gavage with B. fragilis, by immunization with B. fragilis polysaccharides, or by adoptive transfer of B. fragilis-specific T cells. Fecal microbial transplantation from humans to mice confirmed that treatment of melanoma patients with antibodies against CTLA-4 favored the outgrowth of B. fragilis with anticancer properties. This study reveals a key role for Bacteroidales in the immunostimulatory effects of CTLA-4 blockade.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Bacteroides/imunologia , Antígeno CTLA-4/antagonistas & inibidores , Microbioma Gastrointestinal/imunologia , Melanoma/terapia , Neoplasias Cutâneas/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Antibacterianos/farmacologia , Anticorpos Monoclonais/efeitos adversos , Antígeno CTLA-4/imunologia , Disbiose/imunologia , Transplante de Microbiota Fecal , Feminino , Microbioma Gastrointestinal/efeitos dos fármacos , Vida Livre de Germes/imunologia , Humanos , Memória Imunológica , Imunoterapia , Intestinos/imunologia , Intestinos/microbiologia , Ipilimumab , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Linfócitos T/imunologia
8.
Innate Immun ; 19(1): 76-85, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-22781631

RESUMO

Despite NK cells being originally identified because of their ability to kill tumor cells in vitro, only limited information is available on NK cells infiltration of malignant tumors, especially in humans. NK cells infiltrating human colorectal carcinomas (CRCs) were analyzed to identify their potential protective role in an antitumor immune response. The expression and function of relevant molecules were analyzed from different sources, comparing tumor-associated NK cells (TANKs) with autologous peripheral blood NK cells (PB-NKs) from CRC patients-the latter in comparison with PB-NKs from normal donors. TANKs displayed a profound alteration of their phenotype with a drastic reduction of NK cell receptor expression. Co-culture experiments showed that CRC cells produce modulation in NK phenotype and functionality. Moreover, PB-NKs from CRC patients also exhibited an altered phenotype and profound defects in the ability to activate degranulation and IFN-γ production. For the first time, TANK and PB-NK cells from CRC patients have been characterized. It is shown that they are not capable of producing relevant cytokines and degranulate. Taken together, our results suggest that NK cells from CRC patients present alterations of phenotype and function therefore supporting the progression of cancer.


Assuntos
Células Sanguíneas/imunologia , Neoplasias Colorretais/imunologia , Células Matadoras Naturais/imunologia , Linfócitos do Interstício Tumoral/imunologia , Receptores de Células Matadoras Naturais/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Degranulação Celular , Transformação Celular Neoplásica , Células Cultivadas , Feminino , Humanos , Imunofenotipagem , Interferon gama/metabolismo , Masculino , Pessoa de Meia-Idade , Receptores de Células Matadoras Naturais/genética
9.
Front Immunol ; 3: 375, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-23248625

RESUMO

In recent decades, tumor surveillance by the immune system and its impact on disease outcomes in cancer patients in general and in breast cancer (BC) patients in particular has been documented. Natural killer (NK) cells are central components of the innate immunity and existing data indicate that they play a role in preventing and controlling tumor growth and metastasis. Their biological significance was first recognized by their ability to exert direct cellular cytotoxicity without prior sensitization. This is important in tumors, as transforming events are likely to result in downregulation of self-ligands and expression of stress-induced ligands which can be recognized by NK cells. Their activation also leads to secretion of stimulatory cytokines which participate in cancer elimination by several direct mechanisms as well as by stimulating the adaptive immune system. In this regard, it was recently revealed a dendritic cell (DC)-NK-cell crosstalk which provides another novel pathway linking innate and adaptive immunity. In addition, NK cells are feasible targets of stimulation in immunotherapeutic approaches such as antibody-based strategies and adoptive cell transfer. Nevertheless, NK cells display impaired functionality and capability to infiltrate tumors in BC patients. This review compiles information about NK-cell biology in BC and the attempts which aim to manipulate them in novel therapeutic approaches in this pathology.

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