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1.
Neoplasia ; 27: 100786, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35366464

RESUMO

BACKGROUND: Stromal and immune cell composition alterations in benign breast tissue associate with future cancer risk. Pilot data suggest the innate microbiome of normal breast tissue differs between women with and without breast cancer. Microbiome alterations might explain tissue microenvironment variations associated with disease status. METHODS: Prospectively-collected sterile normal breast tissues from women with benign (n=16) or malignant (n=17) disease underwent 16SrRNA sequencing with Illumina MiSeq and Hybrid-denovo pipeline processing. Breast tissue was scored for fibrosis and fat percentages and immune cell infiltrates (lobulitis) classified as absent/mild/moderate/severe. Alpha and beta diversity were calculated on rarefied OTU data and associations analyzed with multiple linear regression and PERMANOVA. RESULTS: Breast tissue stromal fat% was lower and fibrosis% higher in benign disease versus cancer (median 30% versus 60%, p=0.01, 70% versus 30%, p=0.002, respectively). The microbiome varied with stromal composition. Alpha diversity (Chao1) correlated with fat% (r=0.38, p=0.02) and fibrosis% (r=-0.32, p=0.05) and associated with different microbial populations as indicated by beta diversity metrics (weighted UniFrac, p=0.08, fat%, p=0.07, fibrosis%). Permutation testing with FDR control revealed taxa differences for fat% in Firmicutes, Bacilli, Bacillales, Staphylococcaceae and genus Staphylococcus, and fibrosis% in Firmicutes, Spirochaetes, Bacilli, Bacillales, Spirochaetales, Proteobacteria RF32, Sphingomonadales, Staphylococcaceae, and genera Clostridium, Staphylococcus, Spirochaetes, Actinobacteria Adlercreutzia. Moderate/severe lobulitis was more common in cancer (73%) than benign disease (13%), p=0.003, but no significant microbial associations were seen. CONCLUSION: These data suggest a link between breast tissue stromal alterations and its microbiome, further supporting a connection between the breast tissue microenvironment and breast cancer.


Assuntos
Neoplasias da Mama/microbiologia , Mama/microbiologia , Microbiota , Microambiente Tumoral , Bactérias/genética , Mama/imunologia , Mama/patologia , Neoplasias da Mama/imunologia , Neoplasias da Mama/patologia , Feminino , Fibrose , Humanos , Projetos Piloto , Estudos Prospectivos , RNA Ribossômico 16S/química , Células Estromais/microbiologia
2.
Dis Markers ; 2022: 5621441, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35242245

RESUMO

OBJECTIVE: Tumor microenvironment as an important element of malignancy could help predict cancer prognosis and therapeutic response; thus, a prognostic landscape map of the tumor microenvironment in luminal B breast cancers should be developed. METHODS: The GEO and TCGA databases were employed to retrieve clinical follow-up data and expression profiles of luminal B breast cancer. CIBERSORT was applied to assess the infiltration of the tumor microenvironment of 209 patients and to construct tumor microenvironment-based subtypes of luminal B breast cancer. We also conducted Cox multivariate regression analysis to select features that could be used to develop a microenvironment signature for cancer. Samples were categorized as having low and high TME scores according to the median TME score. The correlations of prognosis and TME score, expression levels of immune factors and genomic variation, and clinical features were further investigated. RESULTS: We found that high TME scores were correlated with poor prognosis. The current findings showed that the expressions of multiple immune-related genes, including CXCL9, CXCL10, GZMB, and PDCD1LG2, were upregulated in cancer with high TME scores. The high-risk group showed lower TP53 gene mutation frequency as opposed to that of the low-risk group. For the purpose of developing a TME scoring system, the TME infiltration levels of 209 patients with luminal B breast cancer from TCGA were comprehensively analyzed. CONCLUSIONS: Our analysis revealed that the TME score was an indicator of patients' response to immune checkpoint modulators and an effective prognostic biomarker. TME scoring improves current immunotherapy on luminal B breast cancer.


Assuntos
Neoplasias da Mama/genética , Bases de Dados Genéticas , Perfilação da Expressão Gênica , Prognóstico , Microambiente Tumoral , Idoso , Neoplasias da Mama/imunologia , Neoplasias da Mama/patologia , Feminino , Genes p53 , Humanos , Imunoterapia , Pessoa de Meia-Idade , Mutação/genética , Linfócitos T/imunologia , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia
3.
Cell ; 185(7): 1189-1207.e25, 2022 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-35325594

RESUMO

Macrophage infiltration is a hallmark of solid cancers, and overall macrophage infiltration correlates with lower patient survival and resistance to therapy. Tumor-associated macrophages, however, are phenotypically and functionally heterogeneous. Specific subsets of tumor-associated macrophage might be endowed with distinct roles on cancer progression and antitumor immunity. Here, we identify a discrete population of FOLR2+ tissue-resident macrophages in healthy mammary gland and breast cancer primary tumors. FOLR2+ macrophages localize in perivascular areas in the tumor stroma, where they interact with CD8+ T cells. FOLR2+ macrophages efficiently prime effector CD8+ T cells ex vivo. The density of FOLR2+ macrophages in tumors positively correlates with better patient survival. This study highlights specific roles for tumor-associated macrophage subsets and paves the way for subset-targeted therapeutic interventions in macrophages-based cancer therapies.


Assuntos
Neoplasias da Mama , Macrófagos , Mama/imunologia , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/imunologia , Linfócitos T CD8-Positivos , Feminino , Receptor 2 de Folato , Humanos , Linfócitos do Interstício Tumoral , Prognóstico
4.
BMC Cancer ; 22(1): 297, 2022 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-35313846

RESUMO

BACKGROUND: ITPR1 is a key gene for autophagy, but its biological function is still unclear, and there are few studies on the correlation between ITPR1 gene expression and the occurrence and development of breast cancer. METHODS: Analyze the expression of ITPR1 through online databases such as Oncomine and TIMER. Kaplan-Meier plotter and other databases were used to evaluate the impact of ITPR1 on clinical prognosis. The expression of ITPR1 in analysis of 145 cases of breast cancer and 30 cases of adjacent normal tissue was detected by Immunohistochemistry. Statistical analysis was used to evaluate the clinical relevance and prognostic significance of abnormally expressed proteins. And the Western Blot was used to detect the expression of ITPR1 between breast cancer tissues and cells. The TIMER database studied the relationship between ITPR1 and cancer immune infiltration. And used the ROC plotter database to predict the response of ITPR1 to chemotherapy, endocrine therapy and anti-HER2 therapy in patients with breast cancer. RESULTS: Compared with normal breast samples, ITPR1 was significantly lower in patients with breast cancer. And the increased expression of ITPR1 mRNA was closely related to longer overall survival (OS), distant metastasis free survival (DMFS), disease specific survival (DSS) and relapse free survival (RFS) in breast cancer. And the expression level of ITPR1 was higher in patients treated with chemotherapy than untreated patients. In addition, the expression of ITPR1 was positively correlated with related gene markers of immune cells in different types of breast cancer, especially with BRCA basal tissue breast cancer. CONCLUSION: ITPR1 was lower expressed in breast cancer. The higher expression of ITPR1 suggested favorable prognosis for patients. ITPR1 was related to the level of immune infiltration, especially in BRCA-Basal patients. All research results indicated that ITPR1 might affect breast cancer prognosis and participate in immune regulation. In short, ITPR1 might be a potential target for breast cancer therapy.


Assuntos
Neoplasias da Mama/genética , Neoplasias da Mama/imunologia , Regulação Neoplásica da Expressão Gênica , Receptores de Inositol 1,4,5-Trifosfato/genética , Linfócitos do Interstício Tumoral/metabolismo , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Feminino , Humanos , Pessoa de Meia-Idade , Prognóstico , RNA Mensageiro/genética
5.
J Biol Chem ; 298(4): 101753, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35189139

RESUMO

Despite the enormous successes of anti-PD-1/PD-L1 immunotherapy in multiple other cancer types, the overall response rates of breast cancer remain suboptimal. Therefore, exploring additional immune checkpoint molecules for potential cancer treatment is crucial. B7H3, a T-cell coinhibitory molecule, is specifically overexpressed in breast cancer compared with normal breast tissue and benign lesions, making it an attractive therapeutic target. However, the mechanism by which B7H3 contributes to the cancer phenotype is unclear. Here we show that the expression of B7H3 is negatively related to the number of CD8+ T cells in breast tumor sites. In addition, analysis of the differentially expressed B7H3 reveals that it is inversely correlated to autophagic flux both in breast cancer cell lines and clinical tumor tissues. Furthermore, block of autophagy by bafilomycin A1 (Baf A1) increases B7H3 levels and attenuates CD8+ T cell activation, while promotion of autophagy by V9302, a small-molecule inhibitor of glutamine metabolism, decreases B7H3 expression and enhances granzyme B (GzB) production of CD8+ T cells via regulation of reactive oxygen species (ROS) accumulation. We demonstrate that combined treatment with V9302 and anti-PD-1 monoclonal antibody (mAb) enhances antitumor immunity in syngeneic mouse models. Collectively, our findings unveil the beneficial effect of V9302 in boosting antitumor immune response in breast cancer and illustrate that anti-PD-1 together with V9302 treatment may provide synergistic effects in the treatment of patients insensitive to anti-PD-1 therapy.


Assuntos
Antígenos B7 , Neoplasias da Mama , Linfócitos T CD8-Positivos , Glutamina , Animais , Anticorpos Monoclonais/genética , Anticorpos Monoclonais/uso terapêutico , Autofagia , Antígenos B7/metabolismo , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/imunologia , Linhagem Celular Tumoral , Feminino , Glutamina/antagonistas & inibidores , Humanos , Camundongos , Espécies Reativas de Oxigênio
6.
BMC Cancer ; 22(1): 167, 2022 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-35164691

RESUMO

BACKGROUND: Therapeutic agents for dyslipidaemia, in particular statins, have been recently reported to suppress growth and metastasis of breast cancer. However, the predictive value of lipid control in breast cancer patients has not been discussed sufficiently. In addition, though immunometabolism is a relatively novel approach for tumour immunotherapy, the relationship between lipid metabolism and immune status has not been well documented. We therefore investigated the effects of lipid metabolism on antitumour immune response and cancer prognosis. METHODS: Except for patients with ductal carcinoma in situ, 938 patients treated with curative surgery were examined. The correlation between treatment for dyslipidaemia or serum lipid levels and clinicopathological features, including the prognosis, was evaluated retrospectively. Also, we stratified these results by intrinsic subtype of breast cancer, menopause, and type of therapeutic agents for dyslipidaemia. Moreover, neutrophil- to-lymphocyte ratio (NLR) and tumour-infiltrating lymphocytes (TILs) were used as indicators of systemic and local immune status, respectively. RESULTS: Of 194 patients treated for dyslipidaemia, recurrence-free survival (RFS) and overall survival (OS) did not differ significantly between users of drugs for dyslipidaemia and non-users (p = 0.775 and p = 0.304, log-rank, respectively). Among postmenopausal, hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative breast cancer patients treated for dyslipidaemia, the good serum lipid control group had significantly better RFS (p = 0.014, log-rank), lower postoperative NLR (p = 0.012), and higher TILs in resected tissues (p = 0.024) than the poor control group. Multivariate analysis showed that postoperative serum lipid levels were a risk factor for recurrence (hazard ratio = 4.722, 95% confidence interval 1.006-22.161, p = 0.049). CONCLUSIONS: Good control of serum lipid metabolism may improve the tumour immune microenvironment and prognosis in postmenopausal HR-positive/HER2-negative breast cancer patients.


Assuntos
Neoplasias da Mama/imunologia , Dislipidemias/sangue , Dislipidemias/tratamento farmacológico , Hipolipemiantes/uso terapêutico , Lipídeos/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/sangue , Neoplasias da Mama/complicações , Dislipidemias/complicações , Feminino , Humanos , Linfócitos do Interstício Tumoral/imunologia , Pessoa de Meia-Idade , Pós-Menopausa , Prognóstico , Estudos Retrospectivos , Resultado do Tratamento , Microambiente Tumoral/imunologia , Adulto Jovem
7.
Sci Rep ; 12(1): 2742, 2022 02 17.
Artigo em Inglês | MEDLINE | ID: mdl-35177712

RESUMO

L-type amino acid transporter 1 (LAT1), also referred to as SLC7A5, is believed to regulate tumor metabolism and be associated with tumor proliferation. In invasive breast cancer, we clinicopathologically investigated the utility of LAT1 expression. LAT1 expression was evaluated via immunohistochemistry analyses in 250 breast cancer patients undergoing long-term follow-up. We assessed the relationships between LAT1 expression and patient outcomes and clinicopathological factors. Breast cancer-specific survival stratified by LAT1 expression was assessed. Human epidermal growth factor receptor 2 (HER2)-positive patients with metastasis received trastuzumab therapy. The density of tumor-infiltrating lymphocytes (TILs) was evaluated according to the International Working Group guidelines. In the current study, high LAT1 expression was significantly correlated with estrogen receptor (ER) negativity, progesterone receptor negativity, high histological grade, increased TILs, and programmed death ligand 1 positivity. Among the ER-positive and HER2-negative patients, high LAT1 was an independent indicator of poor outcomes (hazard ratio (HR) = 2.97; 95% confidence interval (CI), 1.16-7.62; p = 0.023). Moreover, high LAT1 expression was an independent poor prognostic factor in luminal B-like breast cancer with aggressive features (HR = 3.39; 95% CI 1.35-8.52; p = 0.0094). In conclusion, high LAT1 expression could be used to identify a subgroup of invasive breast cancer characterized by aggressive behavior and high tumor immunoreaction. Our findings suggest that LAT1 might be a candidate therapeutic target for breast cancer patients, particularly those with luminal B-like type breast cancer.


Assuntos
Neoplasias da Mama , Transportador 1 de Aminoácidos Neutros Grandes/imunologia , Adulto , Idoso , Antígeno B7-H1/imunologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/imunologia , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Intervalo Livre de Doença , Feminino , Humanos , Linfócitos do Interstício Tumoral/imunologia , Pessoa de Meia-Idade , Invasividade Neoplásica , Metástase Neoplásica , Receptor ErbB-2/metabolismo , Taxa de Sobrevida
8.
J Immunother Cancer ; 10(1)2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-35101946

RESUMO

BACKGROUND: Hormones are identified as key biological variables in tumor immunity. However, previous researches mainly focused on the immune effect of steroid hormones, while the roles that thyroid-stimulating hormone (TSH) played in the antitumor response were far from clear. METHODS: The source of TSH was determined using single-cell transcriptomic, histologic, quantitative PCR, and ELISA analysis. The influence of TSH on tumor proliferation, invasion, and immune evasion was evaluated in multiple cell lines of thyroid cancer, glioma, and breast cancer. Then transcriptomic sequencing and cellular experiments were used to identify signaling pathways. TSH receptor (TSHR) inhibitor was injected into homograft mouse tumor models with or without anti-programmed cell death protein-1 antibody. RESULTS: Monocyte-derived dendritic cells (moDCs) highly expressed TSHα and TSHß2 and were the primary source of TSH in the tumor microenvironment. TSH released by moDCs promoted proliferation and invasion of tumors with high TSHR expressions, such as thyroid cancers and glioma. TSH also induced tumor programmed death-ligand 1 (PD-L1) expression through the TSHR-AC-PKA-JNK-c-JUN pathway. TSHR inhibitors reversed tumor immune evasion by inhibiting PD-L1 expression in tumor and myeloid cells and enhancing Teff activation. CONCLUSIONS: TSH-TSHR axis promotes tumor evasion in thyroid cancers and glioma. TSH suppression therapy is an effective therapeutic strategy for combination in immune checkpoint blockades.


Assuntos
Neoplasias da Mama/imunologia , Glioma/imunologia , Receptores da Tireotropina/imunologia , Neoplasias da Glândula Tireoide/imunologia , Tireotropina/imunologia , Evasão Tumoral , Animais , Linhagem Celular , Células Dendríticas/imunologia , Feminino , Humanos , Inibidores de Checkpoint Imunológico , Camundongos Endogâmicos C57BL , Receptores da Tireotropina/genética , Tireotropina/genética , Microambiente Tumoral
9.
Front Immunol ; 13: 805184, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35154121

RESUMO

Breast cancer is characterized by some types of heterogeneity, high aggressive behaviour, and low immunotherapeutic efficiency. Detailed immune stratification is a prerequisite for interpreting resistance to treatment and escape from immune control. Hence, the immune landscape of breast cancer needs further understanding. We systematically clustered breast cancer into six immune subtypes based on the mRNA expression patterns of immune signatures and comprehensively depicted their characteristics. The immunotherapeutic benefit score (ITBscore) was validated to be a superior predictor of the response to immunotherapy in cohorts from various datasets. Six distinct immune subtypes related to divergences in biological functions, signatures of immune or stromal cells, extent of the adaptive immune response, genomic events, and clinical prognostication were identified. These six subtypes were characterized as immunologically quiet, chemokine dominant, lymphocyte depleted, wounding dominant, innate immune dominant, and IFN-γ dominant and exhibited features of the tumor microenvironment (TME). The high ITBscore subgroup, characterized by a high proportion of M1 macrophages:M2 macrophages, an activated inflammatory response, and increased mutational burden (such as mutations in TP53, CDH1 and CENPE), indicated better immunotherapeutic benefits. A low proportion of tumor-infiltrating lymphocytes (TILs) and an inadequate response to immune treatment were associated with the low ITBscore subgroup, which was also associated with poor survival. Analyses of four cohorts treated with immune checkpoint inhibitors (ICIs) suggested that patients with a high ITBscore received significant therapeutic advantages and clinical benefits. Our work may facilitate the understanding of immune phenotypes in shaping different TME landscapes and guide precision immuno-oncology and immunotherapy strategies.


Assuntos
Neoplasias da Mama/genética , Neoplasias da Mama/imunologia , Imunoterapia , Transcriptoma , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia , Biomarcadores Tumorais/genética , Neoplasias da Mama/terapia , Estudos de Coortes , Feminino , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica , Genoma , Humanos , Imunofenotipagem , Linfócitos do Interstício Tumoral/imunologia , Mutação , Prognóstico
10.
Nat Commun ; 13(1): 897, 2022 02 16.
Artigo em Inglês | MEDLINE | ID: mdl-35173168

RESUMO

The formation of pre-metastatic niche is a key step in the metastatic burden. The pluripotent factor Lin28B is frequently expressed in breast tumors and is particularly upregulated in the triple negative breast cancer subtype. Here, we demonstrate that Lin28B promotes lung metastasis of breast cancer by building an immune-suppressive pre-metastatic niche. Lin28B enables neutrophil recruitment and N2 conversion. The N2 neutrophils are then essential for immune suppression in pre-metastatic lung by PD-L2 up-regulation and a dysregulated cytokine milieu. We also identify that breast cancer-released exosomes with low let-7s are a prerequisite for Lin28B-induced immune suppression. Moreover, Lin28B-induced breast cancer stem cells are the main sources of low-let-7s exosomes. Clinical data further verify that high Lin28B and low let-7s in tumors are both indicators for poor prognosis and lung metastasis in breast cancer patients. Together, these data reveal a mechanism by which Lin28B directs the formation of an immune-suppressive pre-metastatic niche.


Assuntos
Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Exossomos/metabolismo , Neoplasias Pulmonares/secundário , Proteínas de Ligação a RNA/metabolismo , Animais , Neoplasias da Mama/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Linhagem Celular Tumoral , Feminino , Fibroblastos/metabolismo , Regulação Neoplásica da Expressão Gênica/genética , Células HEK293 , Humanos , Tolerância Imunológica/imunologia , Pulmão/patologia , Macrófagos/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , MicroRNAs/genética , Infiltração de Neutrófilos/imunologia , Neutrófilos/imunologia , Prognóstico , Proteínas de Ligação a RNA/genética
11.
Front Immunol ; 13: 828386, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35154149

RESUMO

Breast cancer has become the most commonly diagnosed cancer globally. The relapse and metastasis of breast cancer remain a great challenge despite advances in chemotherapy, endocrine therapy, and HER2 targeted therapy in the past decades. Innovative therapeutic strategies are still critically in need. Cancer vaccine is an attractive option as it aims to induce a durable immunologic response to eradicate tumor cells. Different types of breast cancer vaccines have been evaluated in clinical trials, but none has led to significant benefits. Despite the disappointing results at present, new promise from the latest study indicates the possibility of applying vaccines in combination with anti-HER2 monoclonal antibodies or immune checkpoint blockade. This review summarizes the principles and mechanisms underlying breast cancer vaccines, recapitulates the type and administration routes of vaccine, reviews the current results of relevant clinical trials, and addresses the potential reasons for the setbacks and future directions to explore.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Vacinas Anticâncer/uso terapêutico , Antígenos de Neoplasias/imunologia , Antígenos de Neoplasias/uso terapêutico , Neoplasias da Mama/imunologia , Neoplasias da Mama/patologia , Vacinas Anticâncer/classificação , Vacinas Anticâncer/imunologia , Sistemas de Liberação de Medicamentos , Quimioterapia Combinada , Feminino , Humanos , Imunoterapia/métodos , Ensaios Clínicos Controlados Aleatórios como Assunto , Receptor ErbB-2/imunologia
12.
Front Immunol ; 13: 791975, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35185887

RESUMO

Human leukocyte antigen (HLA)-G is a nonclassical MHC Class I molecule, which was initially reported as a mediator of immune tolerance when expressed in extravillous trophoblast cells at the maternal-fetal interface. HLA-G is the only known ligand of killer cell immunoglobulin-like receptor 2DL4 (KIR2DL4), an atypical family molecule that is widely expressed on the surface of NK cells. Unlike other KIR receptors, KIR2DL4 contains both an arginine-tyrosine activation motif in its transmembrane region and an immunoreceptor tyrosine-based inhibitory motif (ITIM) in its cytoplasmic tail, suggesting that KIR2DL4 may function as an activating or inhibitory receptor. The immunosuppressive microenvironment exemplified by a rewired cytokine network and upregulated immune checkpoint proteins is a hallmark of advanced and therapy-refractory tumors. Accumulating evidence has shown that HLA-G is an immune checkpoint molecule with specific relevance in cancer immune escape, although the role of HLA-G/KIR2DL4 in antitumor immunity is still uncharacterized. Our previous study had shown that HLA-G was a pivotal mediator of breast cancer resistance to trastuzumab, and blockade of the HLA-G/KIR2DL4 interaction can resensitize breast cancer to trastuzumab treatment. In this review, we aim to summarize and discuss the role of HLA-G/KIR2DL4 in the immune microenvironment of breast cancer. A better understanding of HLA-G is beneficial to identifying novel biomarker(s) for breast cancer, which is important for precision diagnosis and prognostic assessment. In addition, it is also necessary to unravel the mechanisms underlying HLA-G/KIR2DL4 regulation of the immune microenvironment in breast cancer, hopefully providing a rationale for combined HLA-G and immune checkpoints targeting for the effective treatment of breast cancer.


Assuntos
Neoplasias da Mama/genética , Antígenos HLA-G/genética , Receptores KIR2DL4/genética , Microambiente Tumoral/genética , Neoplasias da Mama/imunologia , Neoplasias da Mama/patologia , Resistencia a Medicamentos Antineoplásicos/genética , Resistencia a Medicamentos Antineoplásicos/imunologia , Feminino , Antígenos HLA-G/imunologia , Humanos , Células Matadoras Naturais/imunologia , Receptores KIR2DL4/imunologia , Microambiente Tumoral/imunologia
13.
Anticancer Res ; 42(3): 1327-1332, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-35220223

RESUMO

BACKGROUND/AIM: Tumor interstitial fluid (TIF), a component of the tumor microenvironment, is a valuable source of molecules and substances that help in diagnosis and prognosis of solid tumors. There is still no consensus on the optimal method for collecting TIF. Therefore, this study aimed to evaluate the effectiveness of a new method of collecting TIF in invasive ductal carcinoma (IDC) samples for cytokine interleukin 1ß (IL1ß) quantification. MATERIALS AND METHODS: Forty women allowed the collection of TIF using absorbent paper strips during the performance of the core biopsy. The samples were stored at a temperature of -80°C and then analyzed using an enzyme-linked immunoassay. RESULTS: The mean values for IL1ß and total protein were 11.39 mg/ml and 2.15 mg/ml, respectively. CONCLUSION: it was possible to quantify the cytokine IL1ß and the total protein concentration present in the tumor tissue through TIF collection with the use of absorbent paper filters, demonstrating the effectiveness of this new method in oncology.


Assuntos
Biomarcadores Tumorais/análise , Neoplasias da Mama/imunologia , Carcinoma Ductal de Mama/imunologia , Líquido Extracelular/imunologia , Interleucina-1beta/análise , Adulto , Idoso , Biópsia com Agulha de Grande Calibre , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Pessoa de Meia-Idade , Microambiente Tumoral
14.
Anticancer Res ; 42(3): 1421-1431, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-35220235

RESUMO

BACKGROUND/AIM: Tumor-infiltrating lymphocytes (TILs), which are indicators of immune response monitoring, are generally mononuclear immunocytes that aggregate with tumors and are thought to have a close relationship with cancer cells. On the other hand, a fibrotic focus (FF) within the stroma of a tumor is a histological formation that plays an important role in the cancer microenvironment with regard to proliferation and development. Here, we focused on TILs that exist within the FF and performed pathological evaluations. PATIENTS AND METHODS: Of the 320 patients treated with neoadjuvant chemotherapy (NAC), 239 subjects who were able to evaluate FF-TILs were targeted. Lymphocytes that infiltrate the FF are FF-TILs. RESULTS: The disease-free survival (DFS) period after NAC for the high-FF-TIL group was found to be significantly longer than that for the low-FF-TIL group for all cases (p<0.001) and for all subtypes of triple-negative breast cancer (TNBC) (p=0.001), human epidermal growth factor receptor 2-enriched breast cancer (HER2BC) (p=0.010), and hormone receptor-positive breast cancer (HRBC) (p=0.003). In multivariable analysis as well, high-FF-TIL group classification was an independent factor for recurrence after NAC for all cases [p<0.001, hazard ratio (HR)=0.198] and all subtypes of TNBC (p=0.006, HR=0.172), HER2BC (p=0.025, HR=0.135), and HRBC (p=0.007, HR=0.228). CONCLUSION: FF-TILs are possibly a useful factor for predicting recurrence of breast cancer after NAC.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Linfócitos do Interstício Tumoral/imunologia , Terapia Neoadjuvante , Células Estromais/imunologia , Microambiente Tumoral/imunologia , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias da Mama/imunologia , Neoplasias da Mama/patologia , Quimioterapia Adjuvante , Intervalo Livre de Doença , Feminino , Fibrose , Humanos , Pessoa de Meia-Idade , Terapia Neoadjuvante/efeitos adversos , Recidiva Local de Neoplasia , Estadiamento de Neoplasias , Valor Preditivo dos Testes , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Células Estromais/patologia , Fatores de Tempo
15.
Cell Mol Life Sci ; 79(2): 83, 2022 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-35048182

RESUMO

Breast cancer is the leading cause of cancer death in female. Until now, advanced breast cancer is still lack effective treatment strategies and reliable prognostic markers. In the present article, we introduced the physiologic and pathologic functions and regulation mechanisms of ZBTB28, a tumor suppressor gene, in breast cancer. ZBTB28 is frequently silenced in breast cancer due to promoter CpG methylation, and its expression is positively correlated with breast cancer patient survival. The antineoplastic effect of ZBTB28 in breast cancer was elucidated through a series of in vitro and in vivo measurements, including cell proliferation, apoptosis, cell cycle, epithelial mesenchymal transition (EMT), and growth of xenografts. Furthermore, ZBTB28 can directly regulate IFNAR to activate interferon-stimulated genes and potentiate macrophage activation. Ectopic ZBTB28 expression in breast cancer cells was sufficient to downregulate CD24 and CD47 to promote phagocytosis of macrophages, demonstrating that ZBTB28 was beneficial for the combination treatment of anti-CD24 and anti-CD47. Collectively, our results reveal a mode of action of ZBTB28 as a tumor suppressor gene and suggest that ZBTB28 is an important regulator of macrophage phagocytosis in breast cancer, holding promise for the development of novel therapy strategies for breast cancer patients.


Assuntos
Neoplasias da Mama/genética , Antígeno CD24/genética , Antígeno CD47/genética , Fagocitose , Receptor de Interferon alfa e beta/genética , Proteínas Repressoras/genética , Animais , Neoplasias da Mama/imunologia , Antígeno CD24/imunologia , Antígeno CD47/imunologia , Linhagem Celular Tumoral , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Ativação de Macrófagos , Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos Endogâmicos BALB C , Camundongos Nus , Receptor de Interferon alfa e beta/imunologia , Proteínas Repressoras/imunologia , Células THP-1
16.
Anticancer Res ; 42(2): 939-946, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-35093893

RESUMO

BACKGROUND/AIM: Eribulin, a non-taxane microtubule inhibitor, improves the tumor immune microenvironment via vascular remodeling. Systemic peripheral immune markers such as absolute lymphocyte count (ALC) and neutrophil-to-lymphocyte ratio (NLR) have been reported as prognostic factors of patients treated with eribulin. However, the usefulness of the longitudinal changes of these blood parameters during eribulin treatment remains unknown. PATIENTS AND METHODS: A total of 97 patients with locally advanced or metastatic breast cancer treated with eribulin were recruited. ALC and NLR values were collected at each cycle of treatment. The correlation between ALC and NLR and prognosis and antitumor effects was retrospectively evaluated. RESULTS: Progression-free and overall survival for patients with a base line ALC ≥1,500/µl was significantly better than that for those with a lower ALC (p=0.049 and p=0.004, respectively). The mean ALC in the non-progressive disease (PD) group increased, while that in the PD group slightly decreased over time. A low ALC at the last cycle was significantly correlated with PD (p=0.030). Of the 64 patients with PD, 47 were classified as having progression due to a pre-existing lesion (PPL), and 17 patients were classified as having progression due to new metastasis (PNM). The mean ALC for the PPL group slightly increased during eribulin treatment, while that for the PNM group decreased. CONCLUSION: Eribulin treatment may have improved the immune status in eribulin responders. Monitoring ALC values may be useful for early assessment of response to therapy.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Furanos/uso terapêutico , Cetonas/uso terapêutico , Linfócitos/patologia , Biomarcadores Tumorais/sangue , Neoplasias da Mama/imunologia , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Feminino , Humanos , Contagem de Leucócitos , Pessoa de Meia-Idade , Neutrófilos/patologia , Prognóstico , Intervalo Livre de Progressão , Estudos Retrospectivos
18.
Med Sci Monit ; 28: e934597, 2022 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-35091527

RESUMO

BACKGROUND Lipid metabolism has been proved to be related to the prognosis of breast cancer patients in previous studies, and the tumor immune microenvironment (TIME) plays an important role in tumorigenesis and development, but the dynamic regulation of these is still a challenge. MATERIAL AND METHODS This study used lipid metabolism-related pathways to score the gene expression of 980 breast cancer patients in the TCGA database. We used 4 pathways in HALLMARK related to lipid metabolism to score the genes in the database. The differentially expressed genes (DEGs) were further analyzed through survival analysis and Cox regression analysis, and MS4A1, which is associated with better prognosis, was finally determined to be a predictor. In-depth analysis found that MS4A1 was negatively correlated with patient age, clinical stage, tumor size, and distant metastasis. In the MS4A1 high-expression group, most genes were enriched in immune-related pathways, and CIBERSORT analysis found that MS4A1 expression was positively correlated with the abundance of 10 kinds of immune cells, such as CD8+T cells, which are related to the active immune status. RESULTS Our results suggest that MS4A1 expression can indicate the situation of lipid metabolism in breast cancer patients and reflect the status of the immune microenvironment. CONCLUSIONS MS4A1 has the potential to be an independent indicator of prognosis. Since the expression of MS4A1 is also related to the immune checkpoint mutation burden, detecting its expression level can also provide guidance for choosing treatment options.


Assuntos
Neoplasias da Mama/genética , Neoplasias da Mama/imunologia , Glicoproteínas/genética , Metabolismo dos Lipídeos/genética , Microambiente Tumoral/imunologia , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/imunologia , Bases de Dados Genéticas , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Genoma/genética , Genoma/imunologia , Humanos , Linfócitos do Interstício Tumoral/imunologia , Prognóstico
19.
J Immunother Cancer ; 10(1)2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34992092

RESUMO

BACKGROUND: Sentinel lymph nodes (LNs) are regarded as key immune surveillance sites in cancer wherein mature dendritic cells present tumor-derived antigens to prime and activate T cells, which then migrate to the tumor site. However, it is unclear whether the tumor-specific T cells can be elicited within the tumor independent of the sentinel LNs. METHODS: We performed an integrative analysis of gene expression profiles of 65,285 cells and T cell receptor sequences of 15,831 T cells from 5 paired primary breast tumors and sentinel LNs to identify where clonal T cells come from and the characteristics of those clonal T cells. RESULTS: The proportion of clonal T cells was higher in the primary tumors compared with the sentinel LNs, whereas all expanded clones identified in the sentinel LN were also present in the primary tumors. In contrast, 10.91% of the expanded clones in the primary tumors were not found in the sentinel LNs. These novel intratumoral T cell clones were characterized by high tissues retention capacity (CXCR6 +ITGAE+) and a distinct coinhibitory pattern (CD39 +NKG2A+) compared with the expanded T cell clones common to both sites. Furthermore, multiplex immunofluorescence imaging showed the presence of tertiary lymphoid structures (TLS) in the primary breast tumors wherein the activated cytolytic T cells were concentrated, indicating its possible role in eliciting non-sentinel LN-derived T cell clones. CONCLUSIONS: Our study revealed expanded intratumor non-sentinel LN derived T cell clones located in the TLS, which points to the need for exploring the role of TLS in antitumor immunity.


Assuntos
Neoplasias da Mama/imunologia , Linfócitos T CD8-Positivos/metabolismo , Linfonodos/metabolismo , Metástase Linfática/patologia , Linfócitos T/metabolismo , Feminino , Humanos
20.
Sci Rep ; 12(1): 1222, 2022 01 24.
Artigo em Inglês | MEDLINE | ID: mdl-35075167

RESUMO

The significance of N6-methyladenosine (m6A) RNA modifications in the progression of breast cancer (BC) has been recognised. However, their potential role and mechanism of action in the tumour microenvironment (TME) and immune response has not been demonstrated. Thus, the role of m6A regulators and their downstream target gene components in BC remain to be explored. In this study, we used a series of bioinformatics methods and experiments to conduct exploratory research on the possible role of m6A regulators in BC. First, two regulatory modes of immune activation and inactivation were determined by tumour classification. The TME, immune cell infiltration, and gene set variation analysis results confirmed the reliability of this pattern. The prognostic model of the m6A regulator was established by the least absolute shrinkage and selection operator and univariate and multivariate Cox analyses, with the two regulators most closely related to survival verified by real-time quantitative reverse transcription polymerase chain reaction. Next, the prognostic m6A regulator identified in the model was crossed with the differential copy number of variant genes in invasive BC (IBC), and it was determined that YTHDF1 was a hub regulator. Subsequently, single-cell analysis revealed the expression patterns of m6A regulators in different IBC cell populations and found that YTHDF1 had significantly higher expression in immune-related IBC cells. Therefore, we selected the intersection of the BC differential expression gene set and the differential expression gene set of a cell line with knocked-down YTHDF1 in literature to identify downstream target genes of YTHDF1, in which we found IFI6, EIR, and SPTBN1. A polymerase chain reaction was conducted to verify the results. Finally, we confirmed the role of YTHDF1 as a potential prognostic biomarker through pan-cancer analysis. Furthermore, our findings revealed that YTHDF1 can serve as a new molecular marker for BC immunotherapy.


Assuntos
Adenosina/análogos & derivados , Neoplasias da Mama/metabolismo , Carcinoma/metabolismo , RNA/metabolismo , Microambiente Tumoral , Adenosina/metabolismo , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/imunologia , Neoplasias da Mama/mortalidade , Carcinoma/tratamento farmacológico , Carcinoma/imunologia , Carcinoma/mortalidade , Estudos de Casos e Controles , Humanos , Linfócitos do Interstício Tumoral , Terapia de Alvo Molecular , Prognóstico , Proteínas de Ligação a RNA/metabolismo
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