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1.
Nat Commun ; 12(1): 769, 2021 02 03.
Artigo em Inglês | MEDLINE | ID: mdl-33536445

RESUMO

Some breast tumors metastasize aggressively whereas others remain dormant for years. The mechanism governing metastatic dormancy remains largely unknown. Through high-parametric single-cell mapping in mice, we identify a discrete population of CD39+PD-1+CD8+ T cells in primary tumors and in dormant metastasis, which is hardly found in aggressively metastasizing tumors. Using blocking antibodies, we find that dormancy depends on TNFα and IFNγ. Immunotherapy reduces the number of dormant cancer cells in the lungs. Adoptive transfer of purified CD39+PD-1+CD8+ T cells prevents metastatic outgrowth. In human breast cancer, the frequency of CD39+PD-1+CD8+ but not total CD8+ T cells correlates with delayed metastatic relapse after resection (disease-free survival), thus underlining the biological relevance of CD39+PD-1+CD8+ T cells for controlling experimental and human breast cancer. Thus, we suggest that a primary breast tumor could prime a systemic, CD39+PD-1+CD8+ T cell response that favors metastatic dormancy in the lungs.


Assuntos
Antígenos CD/imunologia , Apirase/imunologia , Neoplasias da Mama/imunologia , Linfócitos T CD8-Positivos/imunologia , Neoplasias Mamárias Experimentais/imunologia , Receptor de Morte Celular Programada 1/imunologia , Animais , Antígenos CD/metabolismo , Apirase/metabolismo , Neoplasias da Mama/patologia , Neoplasias da Mama/terapia , Linfócitos T CD8-Positivos/metabolismo , Linhagem Celular Tumoral , Humanos , Imunoterapia , Pulmão/imunologia , Pulmão/patologia , Neoplasias Mamárias Experimentais/patologia , Neoplasias Mamárias Experimentais/terapia , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos NOD , Camundongos Knockout , Metástase Neoplásica , Receptor de Morte Celular Programada 1/metabolismo
2.
Curr Oncol ; 28(1): 294-300, 2021 01 08.
Artigo em Inglês | MEDLINE | ID: mdl-33430131

RESUMO

BACKGROUND: The current Coronavirus disease 2019 (COVID-19) pandemic is a highly stressful event that may lead to significant psychological symptoms, particularly in cancer patients who are at a greater risk of contracting viruses. This study examined the frequency of stressors experienced in relation to the ongoing coronavirus pandemic and its relationship with psychological symptoms (i.e., anxiety, depression, insomnia, fear of cancer recurrence) in breast cancer patients. METHODS: Thirty-six women diagnosed with a non-metastatic breast cancer completed the Insomnia Severity Index, the Hospital Anxiety and Depression Scale, the severity subscale of the Fear of Cancer Recurrence Inventory, and the COVID-19 Stressors Questionnaire developed by our research team. Participants either completed the questionnaires during (30.6%) or after (69.4%) their chemotherapy treatment. RESULTS: Results revealed that most of the participants (63.9%) have experienced at least one stressor related to the COVID-19 pandemic (one: 27.8%, two: 22.2%, three: 11.1%). The most frequently reported stressor was increased responsibilities at home (33.3%). Higher levels of concerns related to the experienced stressors were significantly correlated with higher levels of anxiety, depressive symptoms, insomnia, and fear of cancer recurrence, rs(32) = 0.36 to 0.59, all ps < 0.05. CONCLUSIONS: Cancer patients experience a significant number of stressors related to the COVID-19 pandemic, which are associated with increased psychological symptoms. These results contribute to a better understanding of the psychological consequences of a global pandemic in the context of cancer and they highlight the need to better support patients during such a challenging time.


Assuntos
Neoplasias da Mama/complicações , Sobreviventes de Câncer/psicologia , Pandemias , Estresse Psicológico/epidemiologia , Adulto , Ansiedade/diagnóstico , Ansiedade/epidemiologia , Ansiedade/psicologia , Neoplasias da Mama/imunologia , Neoplasias da Mama/psicologia , Neoplasias da Mama/terapia , /psicologia , Sobreviventes de Câncer/estatística & dados numéricos , Estudos Transversais , Depressão/diagnóstico , Depressão/epidemiologia , Depressão/psicologia , Medo , Feminino , Humanos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/psicologia , Questionário de Saúde do Paciente/estatística & dados numéricos , Índice de Gravidade de Doença , Distúrbios do Início e da Manutenção do Sono/diagnóstico , Distúrbios do Início e da Manutenção do Sono/epidemiologia , Distúrbios do Início e da Manutenção do Sono/psicologia , Estresse Psicológico/diagnóstico , Estresse Psicológico/etiologia , Estresse Psicológico/psicologia
3.
Anticancer Res ; 41(2): 661-670, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33517270

RESUMO

BACKGROUND: To investigate the correlation between circulating tumor cells (CTCs) bearing cancer stem cell (CSC) and epithelial-to-mesenchymal (EMT) phenotypes and the different immunosuppressive cells in peripheral blood of patients with metastatic breast cancer (mBC). MATERIALS AND METHODS: Blood was obtained from 38 pre-treated patients with mBC before a new line of treatment. CTC detection and characterization was performed by triple immunofluorescent staining, while Myeloid-derived Suppressor Cells (MDSCs) and T regulatory cells (Tregs) were analyzed by multi-flow cytometry. RESULTS: CTCs were detected in 16 (42.1%) of patients. Based on the co-expression of ALDH1, TWIST and CK, CTCs revealed an important heterogeneity: CTCs with a CSC/partial-EMT, CSC/Epithelial-like, non-CSC/partial-EMT and non-CSC/Epithelial-like phenotype were detected in 7 (18.4%), 7 (18.4%), 1 (1.4%) and 9 (23.7%) of patients, respectively. Immunophenotyping of MDSCs identified 2 monocytic [M-MDSCs; CD14+CD15+CD11b+CD33+HLA-DR-Lin- (CD14+CD15+) and CD14+CD15-CD11b+CD33+ HLA-DR-Lin- (CD14+CD15-)] and one granulocytic [G-MDSCs; CD14-CD15+CD11b+CD33+HLA-DR-Lin- (CD14- CD15+)] subpopulations, expressing inducible nitric oxide synthase (iNOS) and reactive oxygen species (ROS), respectively. Patients with detectable CTCs had a higher frequency of Tregs (CD3+CD4+CD25high; p=0.022) whereas a positive correlation was found between CTC counts and the percentage of Tregs (p=0.005) and CD14+CD15+ M-MDSCs (p=0.024). Patients with a partial-EMT phenotype had a higher frequency of CD14+CD15+ M-MDSCs (p=0.023). Patients harboring the non-CSC/epithelial-like CTC subpopulation had an increased frequency of CD14-CD15+ G-MDSCs (p=0.020), along with decreased levels of CD3+CD4+CD25high FoxP3+ Tregs (p=0.020). CONCLUSION: These findings provide evidence that CTCs in ER+/HER2- mBC patients may be under the control of the immune system and various immune escape mechanisms might be involved during the different stages of their biological evolution.


Assuntos
Neoplasias da Mama/imunologia , Transição Epitelial-Mesenquimal , Células Supressoras Mieloides/imunologia , Células Neoplásicas Circulantes/imunologia , Células-Tronco Neoplásicas/imunologia , Linfócitos T Reguladores/imunologia , Evasão Tumoral , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/sangue , Neoplasias da Mama/sangue , Neoplasias da Mama/patologia , Estudos de Casos e Controles , Feminino , Citometria de Fluxo , Humanos , Imunofenotipagem , Pessoa de Meia-Idade , Células Supressoras Mieloides/metabolismo , Células Neoplásicas Circulantes/metabolismo , Células Neoplásicas Circulantes/patologia , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Fenótipo , Linfócitos T Reguladores/metabolismo
4.
Int J Nanomedicine ; 15: 10007-10028, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33376321

RESUMO

Purpose: The treatment of breast cancer is often ineffective due to the protection of the tumor microenvironment and the low immunogenicity of tumor cells, leading to a poor therapeutic effect. In this study, we designed a nano-theranostic platform for these obstacles: a photothermal effect mediated by a gold shell could remodel the tumor microenvironment by decreasing cancer-associated fibroblasts (CAFs) and promote the release of doxorubicin (DOX) from nanoparticles. In addition, it could realize photoacoustic (PA)/MRI dual-model imaging for diagnose breast cancer and targeted identification of Her2-positive breast cancer. Methods: Her2-DOX-superparamagnetic iron oxide nanoparticles (SPIOs)@Poly (D, L-lactide-co-glycolide) acid (PLGA)@Au nanoparticles (Her2-DSG NPs) were prepared based on a single emulsion oil-in-water (O/W) solvent evaporation method, gold seed growing method, and carbon diimide method. The size distribution, morphology, PA/MRI imaging, drug loading capacity, and drug release were investigated. Cytotoxicity, antitumor effect, cellular uptake, immunogenic cell death (ICD) effect, and targeted performance on human Her2-positive BT474 cell line were investigated in vitro. BT474/Adr cells were constructed and the antitumor effect of NPs on it was evaluated in vitro. Moreover, chemical-photothermal therapy effect, PA/MRI dual-model imaging, ICD effect induced by NPs, and tumor microenvironment remodeling in human BT474 breast cancer nude mice model were also investigated. Results: Nanoparticles were spherical, uniform in size and covered with a gold shell. NPs had a photothermal effect, and can realize photothermal-controlled drug release in vitro. Chemical-photothermal therapy had a good antitumor effect on BT474/Adr cells and on BT474 cells in vitro. The targeting evaluation in vitro showed that Her2-DSG NPs could actively target and identify Her2-positive tumor cells. The PA/MRI imaging was successfully validated in vitro/vivo. Similarly, NPs could enhance the ICD effect in vitro/vivo, which could activate an immune response. Immunofluorescence results also proved that photothermal effect could decrease CAFs to remodel the tumor microenvironment and enhance the accessibility of NPs to tumor cells. According to the toxicity results, targeted drug delivery combined with photothermal-responsive drug release proved that NPs had good biosafety in vivo. Chemical-photothermal therapy of Her2-targeted NPs has a good antitumor effect in the BT474 nude mice model. Conclusion: Our study showed that chemical-photothermal therapy combined with tumor microenvironment remodeling and immune activation based on the Her2-DSG NPs we developed are very promising for Her2-positive breast cancer.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/imunologia , Terapia de Alvo Molecular , Receptor ErbB-2/metabolismo , Nanomedicina Teranóstica/métodos , Microambiente Tumoral/efeitos dos fármacos , Animais , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Fibroblastos Associados a Câncer/efeitos dos fármacos , Fibroblastos Associados a Câncer/patologia , Linhagem Celular Tumoral , Doxorrubicina/química , Doxorrubicina/farmacologia , Doxorrubicina/uso terapêutico , Liberação Controlada de Fármacos , Humanos , Camundongos , Camundongos Nus
5.
Nat Commun ; 11(1): 6433, 2020 12 22.
Artigo em Inglês | MEDLINE | ID: mdl-33353943

RESUMO

Molecular profiling of breast cancer has enabled the development of more robust molecular prognostic signatures and therapeutic options for breast cancer patients. However, non-Caucasian populations remain understudied. Here, we present the mutational, transcriptional, and copy number profiles of 560 Malaysian breast tumours and a comparative analysis of breast cancers arising in Asian and Caucasian women. Compared to breast tumours in Caucasian women, we show an increased prevalence of HER2-enriched molecular subtypes and higher prevalence of TP53 somatic mutations in ER+ Asian breast tumours. We also observe elevated immune scores in Asian breast tumours, suggesting potential clinical response to immune checkpoint inhibitors. Whilst HER2-subtype and enriched immune score are associated with improved survival, presence of TP53 somatic mutations is associated with poorer survival in ER+ tumours. Taken together, these population differences unveil opportunities to improve the understanding of this disease and lay the foundation for precision medicine in different populations.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Neoplasias da Mama/genética , Genética Populacional , Neoplasias da Mama/imunologia , Neoplasias da Mama/patologia , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Genoma Humano , Humanos , Mutação/genética , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Receptores Estrogênicos/metabolismo , Análise de Sobrevida , Microambiente Tumoral/imunologia , Proteína Supressora de Tumor p53/genética
6.
Medicine (Baltimore) ; 99(44): e22886, 2020 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-33126339

RESUMO

BACKGROUND: Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate that retains the antitumor effects of trastuzumab while also delivering the cytotoxic antimicrotubule agent, DM1, directly to tumor cells that overexpress human epidermal growth factor receptor 2. The pharmacokinetic (PK) profile of T-DM1 has been well characterized in Western, Asian, and Japanese patients; this single-center, phase I study (NCT03153163) examined the PK of T-DM1 and safety specifically in Chinese patients. METHODS: Patients with locally advanced or metastatic breast cancer, previously treated with trastuzumab and a taxane, received open-label T-DM1 at 3.6 mg/kg every 3 weeks. Serum T-DM1 and total trastuzumab, and plasma DM1 were evaluated, and PK parameters were calculated using standard noncompartmental approaches. Adverse events (AEs) were assessed, and immunogenicity was evaluated by measuring antidrug antibodies to T-DM1. RESULTS: Among 11 Chinese patients, mean (±standard deviation) PK parameters (maximum serum concentration, 77.6 ±â€Š17.4 µg/mL; clearance 11.0 ±â€Š2.6 mL/d/kg; terminal half-life 3.8 ±â€Š1.0 days) were similar to those previously reported in Western and Japanese patients. One patient transiently developed antidrug antibodies, which did not appear to influence safety or PK. T-DM1 was generally well tolerated. Grade 3-4 AEs occurred in 7 patients (63.6%) and serious AEs occurred in 4 patients (36.4%). Platelet count decrease was the most common all-grade AE (10/11; 90.9%), grade 3-4 AE (5/11; 45.5%), and serious AE (3/11; 27.3%), but did not appear to be associated with any clinically significant bleeding events. CONCLUSIONS: T-DM1 PK in Chinese patients was consistent with those in global and Asian populations, supporting its use in patients with advanced human epidermal growth factor receptor 2-positive breast cancer following progression on trastuzumab and a taxane. The safety profile of T-DM1 was consistent with prior experience.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Receptor ErbB-2/análise , Trastuzumab , Antineoplásicos Imunológicos/administração & dosagem , Antineoplásicos Imunológicos/efeitos adversos , Antineoplásicos Imunológicos/farmacocinética , Neoplasias da Mama/imunologia , Neoplasias da Mama/patologia , China , Monitoramento de Medicamentos/métodos , Feminino , Humanos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Trastuzumab/administração & dosagem , Trastuzumab/efeitos adversos , Trastuzumab/farmacocinética , Resultado do Tratamento
7.
Breast Cancer Res ; 22(1): 117, 2020 10 30.
Artigo em Inglês | MEDLINE | ID: mdl-33126915

RESUMO

Severe coronavirus disease 2019 (COVID-19) causes a hyperactivation of immune cells, resulting in lung inflammation. Recent studies showed that COVID-19 induces the production of factors previously implicated in the reawakening of dormant breast cancer cells such as neutrophil extracellular traps (NETs). The presence of NETs and of a pro-inflammatory microenvironment may therefore promote breast cancer reactivation, increasing the risk of pulmonary metastasis. Further studies will be required to confirm the link between COVID-19 and cancer recurrence. However, an increased awareness on the potential risks for breast cancer patients with COVID-19 may lead to improved treatment strategies to prevent metastatic relapse.


Assuntos
Neoplasias da Mama/imunologia , Neoplasias da Mama/virologia , Infecções por Coronavirus/imunologia , Recidiva Local de Neoplasia/imunologia , Recidiva Local de Neoplasia/virologia , Pneumonia Viral/imunologia , Betacoronavirus/imunologia , Neoplasias da Mama/patologia , Infecções por Coronavirus/virologia , Armadilhas Extracelulares/imunologia , Feminino , Humanos , Pulmão/imunologia , Pulmão/patologia , Recidiva Local de Neoplasia/patologia , Neutrófilos/imunologia , Pandemias , Pneumonia/imunologia , Pneumonia/virologia , Pneumonia Viral/virologia , Microambiente Tumoral/imunologia
8.
Nat Commun ; 11(1): 5332, 2020 10 21.
Artigo em Inglês | MEDLINE | ID: mdl-33087697

RESUMO

Cytotoxic T lymphocyte (CTL)-based cancer immunotherapies have shown great promise for inducing clinical regressions by targeting tumor-associated antigens (TAA). To expand the TAA landscape of pancreatic ductal adenocarcinoma (PDAC), we performed tandem mass spectrometry analysis of HLA class I-bound peptides from 35 PDAC patient tumors. This identified a shared HLA-A*0101 restricted peptide derived from co-transcriptional activator Vestigial-like 1 (VGLL1) as a putative TAA demonstrating overexpression in multiple tumor types and low or absent expression in essential normal tissues. Here we show that VGLL1-specific CTLs expanded from the blood of a PDAC patient could recognize and kill in an antigen-specific manner a majority of HLA-A*0101 allogeneic tumor cell lines derived not only from PDAC, but also bladder, ovarian, gastric, lung, and basal-like breast cancers. Gene expression profiling reveals VGLL1 as a member of a unique group of cancer-placenta antigens (CPA) that may constitute immunotherapeutic targets for patients with multiple cancer types.


Assuntos
Antígenos de Neoplasias/imunologia , Neoplasias da Mama/imunologia , Proteínas de Ligação a DNA/imunologia , Neoplasias Pancreáticas/imunologia , Fatores de Transcrição/imunologia , Antígenos de Neoplasias/genética , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/imunologia , Neoplasias da Mama/genética , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/imunologia , Carcinoma Ductal Pancreático/terapia , Linhagem Celular Tumoral , Citotoxicidade Imunológica , Proteínas de Ligação a DNA/genética , Feminino , Perfilação da Expressão Gênica , Antígeno HLA-A1/imunologia , Humanos , Imunoterapia Adotiva , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/terapia , Placenta/imunologia , Gravidez , Prognóstico , Linfócitos T Citotóxicos/imunologia , Fatores de Transcrição/genética
9.
Proc Natl Acad Sci U S A ; 117(38): 23684-23694, 2020 09 22.
Artigo em Inglês | MEDLINE | ID: mdl-32907939

RESUMO

Immune checkpoint blockade (ICB) is efficacious in many diverse cancer types, but not all patients respond. It is important to understand the mechanisms driving resistance to these treatments and to identify predictive biomarkers of response to provide best treatment options for all patients. Here we introduce a resection and response-assessment approach for studying the tumor microenvironment before or shortly after treatment initiation to identify predictive biomarkers differentiating responders from nonresponders. Our approach builds on a bilateral tumor implantation technique in a murine metastatic breast cancer model (E0771) coupled with anti-PD-1 therapy. Using our model, we show that tumors from mice responding to ICB therapy had significantly higher CD8+ T cells and fewer Gr1+CD11b+ myeloid-derived suppressor cells (MDSCs) at early time points following therapy initiation. RNA sequencing on the intratumoral CD8+ T cells identified the presence of T cell exhaustion pathways in nonresponding tumors and T cell activation in responding tumors. Strikingly, we showed that our derived response and resistance signatures significantly segregate patients by survival and associate with patient response to ICB. Furthermore, we identified decreased expression of CXCR3 in nonresponding mice and showed that tumors grown in Cxcr3 -/- mice had an elevated resistance rate to anti-PD-1 treatment. Our findings suggest that the resection and response tumor model can be used to identify response and resistance biomarkers to ICB therapy and guide the use of combination therapy to further boost the antitumor efficacy of ICB.


Assuntos
Neoplasias da Mama , Imunoterapia , Neoplasias Mamárias Experimentais , Microambiente Tumoral/imunologia , Animais , Biomarcadores Tumorais/imunologia , Neoplasias da Mama/imunologia , Neoplasias da Mama/terapia , Linfócitos T CD8-Positivos/imunologia , Feminino , Regulação Neoplásica da Expressão Gênica/imunologia , Humanos , Neoplasias Mamárias Experimentais/imunologia , Neoplasias Mamárias Experimentais/terapia , Camundongos , Camundongos Endogâmicos C57BL , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Transcriptoma/imunologia
10.
Nat Commun ; 11(1): 3819, 2020 07 30.
Artigo em Inglês | MEDLINE | ID: mdl-32732875

RESUMO

Hormone receptor (HR)+ breast cancer (BC) causes most BC-related deaths, calling for improved therapeutic approaches. Despite expectations, immune checkpoint blockers (ICBs) are poorly active in patients with HR+ BC, in part reflecting the lack of preclinical models that recapitulate disease progression in immunocompetent hosts. We demonstrate that mammary tumors driven by medroxyprogesterone acetate (M) and 7,12-dimethylbenz[a]anthracene (D) recapitulate several key features of human luminal B HR+HER2- BC, including limited immune infiltration and poor sensitivity to ICBs. M/D-driven oncogenesis is accelerated by immune defects, demonstrating that M/D-driven tumors are under immunosurveillance. Safe nutritional measures including nicotinamide (NAM) supplementation efficiently delay M/D-driven oncogenesis by reactivating immunosurveillance. NAM also mediates immunotherapeutic effects against established M/D-driven and transplantable BC, largely reflecting increased type I interferon secretion by malignant cells and direct stimulation of immune effector cells. Our findings identify NAM as a potential strategy for the prevention and treatment of HR+ BC.


Assuntos
Neoplasias da Mama/terapia , Imunoterapia/métodos , Niacinamida/administração & dosagem , Receptor ErbB-2/imunologia , 9,10-Dimetil-1,2-benzantraceno , Animais , Neoplasias da Mama/imunologia , Neoplasias da Mama/metabolismo , Carcinogênese/efeitos dos fármacos , Carcinogênese/imunologia , Progressão da Doença , Feminino , Humanos , Interferon Tipo I/imunologia , Interferon Tipo I/metabolismo , Neoplasias Mamárias Experimentais/induzido quimicamente , Neoplasias Mamárias Experimentais/imunologia , Neoplasias Mamárias Experimentais/prevenção & controle , Acetato de Medroxiprogesterona , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptor ErbB-2/metabolismo , Análise de Sobrevida
11.
Life Sci ; 259: 118297, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32822718

RESUMO

Triple-negative breast cancer (TNBC) is heterogeneous cancer with poor prognosis among the other breast tumors. Rapid recurrence and increased progression rate could be reasons for the poor prognosis of this type of breast cancer. Recently, because of the lack of specific targets in multiple cancer treatment, immune checkpoint blockade therapies with targeting PD-1/PD-L1 axis have displayed significant advances and improved survival. Among different types of breast cancers, TNBC is considered more immunogenic with high T-cell and other immune cells infiltration compared to other breast cancer subtypes. This immunogenic characteristic of TNBC is a beneficial marker in the immunotherapy of these tumors. Clinical studies with a focus on immune checkpoint therapy have demonstrated promising results in TNBC treatment. In this review, we summarize clinical trials with the immunotherapy-based treatment of different cancers and also discuss the interaction between infiltrating immune cells and breast tumor microenvironment. In addition, we focus on the signaling pathway that controls PD-L1 expression and continues with CAR T-cell therapy and siRNA as novel strategies and potential tools in targeted therapy.


Assuntos
Antígeno B7-H1/metabolismo , Receptor de Morte Celular Programada 1/metabolismo , Microambiente Tumoral/imunologia , Animais , Neoplasias da Mama/imunologia , Neoplasias da Mama/metabolismo , Feminino , Humanos , Neoplasias de Mama Triplo Negativas/imunologia , Neoplasias de Mama Triplo Negativas/metabolismo
12.
Life Sci ; 257: 118117, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32693243

RESUMO

AIMS: B cells can promote or inhibit immune responses against breast cancer. We investigated changes in the frequency of B cells with stimulatory or regulatory capacity in breast tumor draining lymph nodes during cancer progression. MAIN METHODS: We isolated mononuclear cells from fresh axillary lymph nodes (LNs) of 44 patients with breast cancer and stained lymphocytes with antibodies against CD19, CD80, CD86, CD39 and CD73. To assess programmed death-1 (PD-1) and PD-ligand 1 (PD-L1) expression, lymphocytes were briefly stimulated, stained for CD19, PD-1 and PD-L1, and examined with flow cytometry. KEY FINDINGS: The frequency of CD80+ B cells was higher in nonmetastatic lymph nodes, while the percentage of CD86+ B cells showed a positive relationship with higher tumor grade and higher numbers of involved LNs. A small proportion of unstimulated B cells expressed PD-1 or PD-L1 but these molecules were rapidly upregulated on B cells following activation. The frequency of stimulated PD-L1+ B cells showed an inverse association with estrogen and progesterone receptor expression and a nonsignificant positive association with tumor grade. In addition, the percentage of unstimulated PD-1+ B cells was higher in patients with higher-grade tumors. CD73 expression on B cells was associated with lower numbers of involved LNs, and the frequency of CD39+ B cells was higher in patients with larger tumors. SIGNIFICANCE: CD86+, CD39+, PD-1+ and PD-L1+ B cells showed associations with poor prognostic factors, therefore their potential role in the suppression of the immune responses against breast cancer should be evaluated in greater detail.


Assuntos
Subpopulações de Linfócitos B/patologia , Linfócitos B Reguladores/patologia , Neoplasias da Mama/imunologia , Linfonodos/patologia , Adulto , Idoso , Apirase/imunologia , Axila , Subpopulações de Linfócitos B/imunologia , Linfócitos B Reguladores/imunologia , Antígeno B7-2/imunologia , Antígeno B7-H1/metabolismo , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/patologia , Feminino , Citometria de Fluxo , Humanos , Linfonodos/citologia , Linfonodos/imunologia , Pessoa de Meia-Idade , Prognóstico , Receptor de Morte Celular Programada 1/metabolismo
13.
Cancer Immunol Immunother ; 69(10): 1943-1945, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32725361

RESUMO

We discussed the potentialities of tumor mutation burden (TMB) as a predictive marker for immunotherapy in breast cancer, also highlighting the limits that have hindered its introduction in the clinical practice. Although some studies have demonstrated the possibility to select patients more responsive to immune-checkpoint inhibitors by evaluating TMB, some issues emerged regarding the complexity of the methodologies for its determination, the costs of the analysis, and the necessity to improve the TMB determination with that of neoantigen identification.


Assuntos
Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/genética , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Terapia de Alvo Molecular , Mutação , Biomarcadores Tumorais/antagonistas & inibidores , Neoplasias da Mama/imunologia , Neoplasias da Mama/patologia , Análise Mutacional de DNA , Feminino , Humanos , Prognóstico
14.
Anticancer Res ; 40(8): 4405-4412, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32727770

RESUMO

BACKGROUND: Axillary dissection is routinely conducted for all patients with sentinel node (SN)-positive breast cancer. Metastasis to non SNs is not often found after axillary dissection in patients with SN-positive breast cancer. Thus, we investigated clinicopathological features, including immune cells in peripheral blood, in order to identify factors related to metastasis to non-SNs. PATIENTS AND METHODS: We retrospectively investigated 184 patients with SN-positive disease, treated at our institution during the 2013 through 2018 period. All clinicopathological data were obtained before and during surgery. RESULTS: Metastasis to non SNs was observed in 64 cases (35%). The platelet-to-lymphocyte ratio (PLR) and the number of SN metastases were independent of metastasis to non SNs (p=0.023 and p=0.017, respectively). Patients with metastasis to non SNs had significantly lower PLR and more SN metastases. High lymphocyte number and low platelet number resulted in a low PLR. CONCLUSION: PLR might be a marker of metastasis to non SNs.


Assuntos
Neoplasias da Mama/imunologia , Neoplasias da Mama/cirurgia , Metástase Linfática/imunologia , Linfonodo Sentinela/cirurgia , Adulto , Idoso , Feminino , Humanos , Contagem de Linfócitos , Pessoa de Meia-Idade , Contagem de Plaquetas , Estudos Retrospectivos , Fatores de Risco , Carga Tumoral
15.
Nat Med ; 26(9): 1452-1458, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32661390

RESUMO

Disruption of systemic homeostasis by either chronic or acute stressors, such as obesity1 or surgery2, alters cancer pathogenesis. Patients with cancer, particularly those with breast cancer, can be at increased risk of cardiovascular disease due to treatment toxicity and changes in lifestyle behaviors3-5. While elevated risk and incidence of cardiovascular events in breast cancer is well established, whether such events impact cancer pathogenesis is not known. Here we show that myocardial infarction (MI) accelerates breast cancer outgrowth and cancer-specific mortality in mice and humans. In mouse models of breast cancer, MI epigenetically reprogrammed Ly6Chi monocytes in the bone marrow reservoir to an immunosuppressive phenotype that was maintained at the transcriptional level in monocytes in both the circulation and tumor. In parallel, MI increased circulating Ly6Chi monocyte levels and recruitment to tumors and depletion of these cells abrogated MI-induced tumor growth. Furthermore, patients with early-stage breast cancer who experienced cardiovascular events after cancer diagnosis had increased risk of recurrence and cancer-specific death. These preclinical and clinical results demonstrate that MI induces alterations in systemic homeostasis, triggering cross-disease communication that accelerates breast cancer.


Assuntos
Neoplasias da Mama/patologia , Monócitos/imunologia , Infarto do Miocárdio/patologia , Animais , Antígenos Ly/metabolismo , Neoplasias da Mama/imunologia , Neoplasias da Mama/mortalidade , Proliferação de Células/fisiologia , Modelos Animais de Doenças , Feminino , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Infarto do Miocárdio/imunologia , Estudos Retrospectivos
16.
Breast Cancer Res ; 22(1): 76, 2020 07 14.
Artigo em Inglês | MEDLINE | ID: mdl-32665033

RESUMO

BACKGROUND: Early luminal breast cancer (BC) represents 70% of newly diagnosed BC cases. Among them, small (under 2 cm) BC without lymph node metastasis (classified as T1N0) have been rarely studied, as their prognosis is generally favorable. Nevertheless, up to 5% of luminal T1N0 BC patients relapse with distant metastases that ultimately prove fatal. The aim of our work was to identify the mechanisms involved in metastatic recurrence in these patients. METHODS: Our study addresses the role that autonomous and non-autonomous tumor cell features play with regard to distant recurrence in early luminal BC patients. We created a cohort of T1N0 luminal BC patients (tumors between 0.5-2 cm without lymph node metastasis) with metastatic recurrence ("cases") and corresponding "controls" (without relapse) matched 1:1 on main prognostic factors: age, grade, and proliferation. We deciphered different characteristics of cancer cells and their tumor micro-environment (TME) by deep analyses using immunohistochemistry. We performed in vitro functional assays and highlighted a new mechanism of cooperation between cancer cells and one particular subset of cancer-associated fibroblasts (CAF). RESULTS: We found that specific TME features are indicative of relapse in early luminal BC. Indeed, quantitative histological analyses reveal that "cases" are characterized by significant accumulation of a particular CAF subset (CAF-S1) and decrease in CD4+ T lymphocytes, without any other association with immune cells. In multivariate analysis, TME features, in particular CAF-S1 enrichment, remain significantly associated with recurrence, thereby demonstrating their clinical relevance. Finally, by performing functional analyses, we demonstrated that CAF-S1 pro-metastatic activity is mediated by the CDH11/osteoblast cadherin, consistent with bones being a major site of metastases in luminal BC patients. CONCLUSIONS: This study shows that distant recurrence in T1N0 BC is strongly associated with the presence of CAF-S1 fibroblasts. Moreover, we identify CDH11 as a key player in CAF-S1-mediated pro-metastatic activity. This is independent of tumor cells and represents a new prognostic factor. These results could assist clinicians in identifying luminal BC patients with high risk of relapse. Targeted therapies against CAF-S1 using anti-FAP antibody or CDH11-targeting compounds might help in preventing relapse for such patients with activated stroma.


Assuntos
Neoplasias da Mama/patologia , Fibroblastos Associados a Câncer/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/imunologia , Neoplasias da Mama/metabolismo , Neoplasias da Mama/terapia , Fibroblastos Associados a Câncer/imunologia , Carcinoma Ductal de Mama/imunologia , Carcinoma Ductal de Mama/metabolismo , Carcinoma Ductal de Mama/patologia , Carcinoma Ductal de Mama/terapia , Carcinoma Lobular/imunologia , Carcinoma Lobular/metabolismo , Carcinoma Lobular/patologia , Carcinoma Lobular/terapia , Estudos de Casos e Controles , Terapia Combinada , Feminino , Seguimentos , Humanos , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/patologia , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/imunologia , Recidiva Local de Neoplasia/metabolismo , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/terapia , Prognóstico , Receptor ErbB-2/metabolismo , Receptores Estrogênicos/metabolismo , Receptores de Progesterona/metabolismo , Taxa de Sobrevida , Microambiente Tumoral/imunologia
17.
Anticancer Res ; 40(7): 4147-4156, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32620664

RESUMO

BACKGROUND/AIM: We investigated the efficacy of neutrophil-to-lymphocyte ratio (NLR), absolute lymphocyte count (ALC), and C-reactive protein (CRP) in predicting overall survival of metastatic breast cancer patients treated with eribulin. PATIENTS AND METHODS: Overall, 74 patients treated with eribulin were enrolled and their baseline levels of NLR, ALC, and CRP retrieved. Cutoff values of NLR, ALC, and CRP were set at 3.0, 1500/µl, and 0.3 mg/dl, respectively. Overall survival (OS) was compared according to marker levels. RESULTS: The OS of NLR-low, ALC-high, and CRP-low groups at baseline was significantly longer than that of NLR-high, ALC-low, and CRP-high groups (p=0.0027, p=0.0013, and p=0.0164, respectively). The combination of ALC and CRP was significantly associated with OS by multivariate analysis (p=0.048). CONCLUSION: Baseline levels of NLR, ALC, and CRP were significantly associated with OS in patients treated with eribulin. The combination of ALC and CRP improved the predictive efficacy compared to individual markers.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Furanos/uso terapêutico , Cetonas/uso terapêutico , Linfócitos/efeitos dos fármacos , Neutrófilos/efeitos dos fármacos , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/sangue , Neoplasias da Mama/imunologia , Neoplasias da Mama/patologia , Proteína C-Reativa/análise , Feminino , Humanos , Contagem de Leucócitos , Pessoa de Meia-Idade
18.
Oncol Rep ; 44(4): 1758-1770, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32700745

RESUMO

Breast cancer is the leading cause of cancer­-associated deaths in women. Combination immunotherapy attracts great interest as a treatment for breast cancer. However, there are no studies on the use of cytotoxic T­lymphocyte antigen 4 (CTLA­4) monoclonal antibody in combination with the melanoma­associated antigen A family (MAGE­As) co­antigen peptide (p248V9) for treating breast cancer, which should be explored. To this aim, in the present study, the samples of 115 patients with breast cancer were collected, and MAGE­As and CTLA­4 levels in breast cancer and adjacent normal tissues were assessed by immunohistochemical staining. The effect of 5­aza­2'­deoxycytidine (5DC) on the expression of MAGE­As in breast cancer cell lines was assessed by reverse transcription­quantitative PCR and western blot assay. Cytotoxic T cells (CTLs) were induced by MAGE­As co­antigen peptide. The specific lytic rate and IFN­Î³ level were examined by CCK­8 assay and ELISA, respectively. It was found that MAGE­As were highly expressed in breast cancer tissues. 5DC treatment promoted the expression of MAGE­As in breast cancer cells. The upregulation of the expression of MAGE­As specifically enhanced the ability of CTLs to kill breast cancer cells. CTLA­4 was highly expressed in breast cancer tissues and cells, and patients with breast cancer exhibiting high expression of CTLA­4 had low overall survival. CTLA­4 promoted the lytic efficiency of CTLs in breast cancer cells, and the combination of an anti­CTLA­4 antibody and 10 µM 5DC exhibited the highest cell lysis ability of CTLs. The present study demonstrated that MAGE­As co­antigen peptide­specific CTLs in combination with an anti­CTLA­4 monoclonal antibody and 5DC, have potent tumor cell­killing effects. It provides a novel theory for the development of breast cancer therapies.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Antígeno CTLA-4/antagonistas & inibidores , Carcinoma Ductal de Mama/tratamento farmacológico , Antígenos Específicos de Melanoma/metabolismo , Linfócitos T Citotóxicos/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antimetabólitos Antineoplásicos/administração & dosagem , Neoplasias da Mama/imunologia , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Antígeno CTLA-4/imunologia , Carcinoma Ductal de Mama/imunologia , Carcinoma Ductal de Mama/metabolismo , Carcinoma Ductal de Mama/patologia , Linhagem Celular Tumoral , Decitabina/administração & dosagem , Feminino , Seguimentos , Humanos , Metástase Linfática , Células MCF-7 , Antígenos Específicos de Melanoma/genética , Pessoa de Meia-Idade , Invasividade Neoplásica , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/imunologia , Recidiva Local de Neoplasia/metabolismo , Recidiva Local de Neoplasia/patologia , Prognóstico , Taxa de Sobrevida , Linfócitos T Citotóxicos/efeitos dos fármacos
19.
Clin Breast Cancer ; 20(5): e651-e662, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32709505

RESUMO

INTRODUCTION: We aimed to analyze the psychological status in patients with breast cancer (BC) in the epicenter of the coronavirus disease 2019 (COVID-19) pandemic. PATIENTS AND METHODS: A total of 658 individuals were recruited from multiple BC centers in Hubei Province. Online questionnaires were conducted, and these included demographic information, clinical features, and 4 patient-reported outcome scales (Generalized Anxiety Disorder Questionnaire [GAD-7], Patient Health Questionnaire [PHQ-9], Insomnia Severity Index [ISI], and Impact of Events Scale-Revised [IES-R]). Multivariable logistic regression analysis was designed to identify potential factors on mental health outcomes. RESULTS: Questionnaires were collected from February 16, 2020 to February 19, 2020, the peak time point of the COVID-19 outbreak in China. Of patients with BC, 46.2% had to modify planned necessary anti-cancer treatment during the outbreak. Severe anxiety and severe depression were reported by 8.9% and 9.3% of patients, respectively. Severe distress and insomnia were reported by 20.8% and 4.0% of patients, respectively. Multivariable logistic regression analysis demonstrated poor general condition, shorter duration after BC diagnosis, aggressive BC molecular subtypes, and close contact with patients with COVID-19 as independent factors associated with anxiety. Poor general condition and central venous catheter flushing delay were factors that were independently associated with depression. In terms of insomnia, poor generation condition was the only associated independent factor. Poor physical condition and treatment discontinuation were underlying risk factors for distress based on multivariable analysis. CONCLUSION: High rates of anxiety, depression, distress, and insomnia were observed in patients with BC during the COVID-19 outbreak. Special attention should be paid to the psychological status of patients with BC, especially those with poor general condition, treatment discontinuation, aggressive molecular subtypes, and metastatic BC.


Assuntos
Neoplasias da Mama/psicologia , Infecções por Coronavirus/psicologia , Medidas de Resultados Relatados pelo Paciente , Pneumonia Viral/psicologia , Adulto , Idoso , Ansiedade/epidemiologia , Ansiedade/psicologia , Betacoronavirus/imunologia , Betacoronavirus/patogenicidade , Neoplasias da Mama/imunologia , Neoplasias da Mama/patologia , Neoplasias da Mama/terapia , China/epidemiologia , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/prevenção & controle , Infecções por Coronavirus/transmissão , Estudos Transversais , Depressão/epidemiologia , Depressão/psicologia , Feminino , Acesso aos Serviços de Saúde/normas , Humanos , Controle de Infecções/normas , Masculino , Pessoa de Meia-Idade , Pandemias/prevenção & controle , Pneumonia Viral/epidemiologia , Pneumonia Viral/prevenção & controle , Pneumonia Viral/transmissão , Fatores de Risco , Distúrbios do Início e da Manutenção do Sono/epidemiologia , Distúrbios do Início e da Manutenção do Sono/psicologia , Estresse Psicológico/epidemiologia , Estresse Psicológico/psicologia , Inquéritos e Questionários/estatística & dados numéricos
20.
Life Sci ; 258: 118128, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32710947

RESUMO

Although breast cancer is one of the leading troublesome cancers, the available therapeutic options have not fulfilled the desired outcomes. Immune-based therapy has gained special attention for breast cancer treatment. Although this approach is highly tolerable, its low response rate has rendered it as an undesirable approach. This review aims to describe the essential oncogenic pathways involved in breast cancer, elucidate the immunosuppression and oncogenic effect of Mucin1, and introduce myeloid-derived suppressor cells, which are the main culprits of anti-tumoral immune response attenuation. The various auto-inductive loops between Mucin1 and myeloid-derived suppressor cells are focal in the suppression of anti-tumoral immune responses in patients with breast cancer. These cross-talks between the Mucin1 and myeloid-derived suppressor cells can be the underlying causes of immunotherapy's impotence for patients with breast cancer. This approach can pave the road for the development of a potent vaccine for patients with breast cancer and is translated into clinical settings.


Assuntos
Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Mucina-1/metabolismo , Células Supressoras Mieloides/metabolismo , Vacinação , Animais , Neoplasias da Mama/imunologia , Carcinogênese/metabolismo , Carcinogênese/patologia , Ensaios Clínicos como Assunto , Feminino , Humanos
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