RESUMEN
Various histopathological, clinical and imaging parameters have been evaluated to identify a subset of women diagnosed with lesions with uncertain malignant potential (B3 or BIRADS 3/4A lesions) who could safely be observed rather than being treated with surgical excision, with little impact on clinical practice. The primary reason for surgery is to rule out an upgrade to either ductal carcinoma in situ or invasive breast cancer, which occurs in up to 30% of patients. We hypothesised that the stromal immune microenvironment could indicate the presence of carcinoma associated with a ductal B3 lesion and that this could be detected in biopsies by counting lymphocytes as a predictive biomarker for upgrade. A higher number of lymphocytes in the surrounding specialised stroma was observed in upgraded ductal and papillary B3 lesions than non-upgraded (p < 0.01, negative binomial model, n = 307). We developed a model using lymphocytes combined with age and the type of lesion, which was predictive of upgrade with an area under the curve of 0.82 [95% confidence interval 0.77-0.87]. The model can identify some patients at risk of upgrade with high sensitivity, but with limited specificity. Assessing the tumour microenvironment including stromal lymphocytes may contribute to reducing unnecessary surgeries in the clinic, but additional predictive features are needed.
Asunto(s)
Neoplasias de la Mama , Linfocitos , Células del Estroma , Microambiente Tumoral , Humanos , Femenino , Neoplasias de la Mama/patología , Neoplasias de la Mama/inmunología , Microambiente Tumoral/inmunología , Persona de Mediana Edad , Anciano , Linfocitos/inmunología , Linfocitos/patología , Células del Estroma/patología , Adulto , Clasificación del Tumor , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/metabolismo , Carcinoma Intraductal no Infiltrante/patología , Carcinoma Intraductal no Infiltrante/inmunología , Carcinoma Ductal de Mama/patología , Carcinoma Ductal de Mama/inmunología , Biomarcadores de TumorRESUMEN
A checkpoint protein called the V-domain Ig suppressor of T cell activation (VISTA) is important for controlling immune responses. Immune cells that interact with VISTA have molecules, or receptors, known as VISTA receptors. Immune system activity can be modified by the interaction between VISTA and its receptors. Since targeting VISTA or its receptors may be beneficial in certain conditions, VISTA has been studied in relation to immunotherapy for cancer and autoimmune illnesses. The purpose of this study was to examine the expression levels and interactions between VISTA and its receptors, VSIG3 and PSGL-1, in breast cancer tissues. IHC analysis revealed higher levels of proteins within the VISTA/VSIG3/PSGL-1 axis in cancer tissues than in the reference samples (mastopathies). VISTA was found in breast cancer cells and intratumoral immune cells, with membranous and cytoplasmic staining patterns. VISTA was also linked with pathological grade and VSIG3 and PSGL-1 levels. Furthermore, we discovered that the knockdown of one axis member boosted the expression of the other partners. This highlights the significance of VISTA/VSIG3/PSGL-1 in tumor stroma and microenvironment remodeling. Our findings indicate the importance of the VISTA/VSIG3/PSGL-1 axis in the molecular biology of cancer cells and the immune microenvironment.
Asunto(s)
Antígenos B7 , Neoplasias de la Mama , Carcinoma Ductal de Mama , Glicoproteínas de Membrana , Humanos , Femenino , Neoplasias de la Mama/inmunología , Neoplasias de la Mama/patología , Neoplasias de la Mama/metabolismo , Glicoproteínas de Membrana/metabolismo , Glicoproteínas de Membrana/inmunología , Antígenos B7/metabolismo , Carcinoma Ductal de Mama/inmunología , Carcinoma Ductal de Mama/patología , Carcinoma Ductal de Mama/metabolismo , Microambiente Tumoral/inmunología , Persona de Mediana EdadRESUMEN
BACKGROUND: Response to neoadjuvant chemotherapy (NC) in individuals with invasive breast cancer (IBC) must be monitored, and biomarkers are needed. NC can activate an anti-tumour immune response in its microenvironment, known as Tumor-infiltrating Lymphocytes (TIL). TIL components believed to have great potential as predictors are CD4+, CD8+, and FOXP3+ TIL. This study aims to explore TIL components that can potentially be predictive biomarkers of NC pathological responses. METHODS: A sample size of 40 were analyzed based on the relationship between CD4+, CD8+, and FOXP3+ TIL expression with the Miller-Payne (MP) grading system. Age, tumour grade, PR, ER, Ki-67, and HER2 were also evaluated. CD4+, CD8+, and FOXP3+ TIL expressions were analayzed by IHC staining, while other data were collected from archives. Data was analyzed using univariate and multivariate analysis. RESULTS: Univariate analysis showed a significant relationship between CD4+ TIL and MP (p<0.001), CD8+ and MP (p=0.004), and FOXP3 with MP (p<0.001). The simultaneous integration of the three biomarkers in one model was not good enough to be a predictive model. Therefore, an exploratory analysis was conducted by testing several alternative models that combined two of the three existing biomarkers. It turned out that CD4+ TIL in model 2 (CD4+CD8+) and FOXP3+ TIL in model 4 (CD8+FOXP3+) showed significant coefficient values. Moreover, all of the threshold coefficients in model 4 are significant. CONCLUSION: This study shows that CD4+, CD8+, and FOXP3+ TIL have promising potential as predictive biomarkers. In particular, FOXP3+ is dominant in predictive models of pathological response in patients with IBC.
Asunto(s)
Biomarcadores de Tumor , Neoplasias de la Mama , Linfocitos T CD8-positivos , Factores de Transcripción Forkhead , Linfocitos Infiltrantes de Tumor , Terapia Neoadyuvante , Humanos , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/metabolismo , Femenino , Factores de Transcripción Forkhead/metabolismo , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Neoplasias de la Mama/inmunología , Neoplasias de la Mama/metabolismo , Terapia Neoadyuvante/métodos , Persona de Mediana Edad , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Biomarcadores de Tumor/metabolismo , Pronóstico , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Adulto , Estudios de Seguimiento , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Microambiente Tumoral/inmunología , Invasividad Neoplásica , Anciano , Carcinoma Ductal de Mama/tratamiento farmacológico , Carcinoma Ductal de Mama/patología , Carcinoma Ductal de Mama/inmunología , Carcinoma Ductal de Mama/metabolismoRESUMEN
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.
Asunto(s)
Biomarcadores de Tumor/análisis , Neoplasias de la Mama/inmunología , Carcinoma Ductal de Mama/inmunología , Líquido Extracelular/inmunología , Interleucina-1beta/análisis , Adulto , Anciano , Biopsia con Aguja Gruesa , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Persona de Mediana Edad , Microambiente TumoralRESUMEN
Tumor immune microenvironment plays a crucial role in tumor progression. We performed immune profiling to compare immune-related gene expression between ductal carcinoma in situ (DCIS) and invasive carcinoma of the breast using nCounter PanCancer immune Profiling Panel and found that CXCL10 was the most significant gene that had the highest difference in expression between them. Effect of CXCL10 on breast cancer cell proliferation and invasion was examined in vitro, and expression of CXCL10 and its relationship with immune cell infiltration was assessed in breast cancer samples. CXCL10 induced cell proliferation, migration and epithelial-mesenchymal transition in MCF-7 and MDA-MB-231 breast cancer cell lines. We confirmed that CXCL10 mRNA expression was significantly higher in invasive carcinoma than in DCIS, especially in hormone receptor (HR)-negative tumors using a validation set. CXCL10 mRNA expression showed a positive correlation with tumor infiltrating lymphocyte (TIL) density in both DCIS and invasive carcinoma; CXCL10-positive tumors generally showed higher infiltration of CD8+ and FOXP3+TILs as well as PD-L1+ immune cells compared to CXCL10-negative tumors, albeit with different patterns according to HR status. In conclusion, our study showed that CXCL10 promotes tumor cell proliferation, invasion, and immune cell infiltration, implying its contribution in the progression of DCIS to invasive carcinoma of the breast.
Asunto(s)
Neoplasias de la Mama/genética , Carcinoma Ductal de Mama/genética , Carcinoma Intraductal no Infiltrante/genética , Quimiocina CXCL10/genética , Transición Epitelial-Mesenquimal/genética , Linfocitos Infiltrantes de Tumor/inmunología , Antígeno B7-H1/genética , Antígeno B7-H1/inmunología , Neoplasias de la Mama/inmunología , Neoplasias de la Mama/patología , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/patología , Carcinoma Ductal de Mama/inmunología , Carcinoma Ductal de Mama/patología , Carcinoma Intraductal no Infiltrante/inmunología , Carcinoma Intraductal no Infiltrante/patología , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Quimiocina CXCL10/inmunología , Progresión de la Enfermedad , Transición Epitelial-Mesenquimal/inmunología , Femenino , Factores de Transcripción Forkhead/genética , Factores de Transcripción Forkhead/inmunología , Regulación Neoplásica de la Expresión Génica , Humanos , Linfocitos Infiltrantes de Tumor/patología , Células MCF-7 , Invasividad Neoplásica , ARN Mensajero/genética , ARN Mensajero/inmunología , Microambiente Tumoral/genética , Microambiente Tumoral/inmunologíaRESUMEN
BACKGROUND: The composition of the population of immune-related long non-coding ribonucleic acid (irlncRNA) generates a signature, irrespective of expression level, with potential value in predicting the survival status of patients with invasive breast carcinoma. METHODS: The current study uses univariate analysis to identify differentially expressed irlncRNA (DEirlncRNA) pairs from RNA-Seq data from The Cancer Genome Atlas (TCGA). 36 pairs of DEirlncRNA pairs were identified. Using various algorithms to construct a model, we have compared the area under the curve and calculated the 5-year curve of Akaike information criterion (AIC) values, which allows determination of the threshold indicating the maximum value for differentiation. Through cut-off point to establish the optimal model for distinguishing high-risk or low-risk groups among breast cancer patients. We assigned individual patients with invasive breast cancer to either high risk or low risk groups depending on the cut-off point, re-evaluated the tumor immune cell infiltration, the effectiveness of chemotherapy, immunosuppressive biomarkers, and immunotherapy. RESULTS: After re-assessing patients according to the threshold, we demonstrated an effective means of distinguish the severity of the disease, and identified patients with different clinicopathological characteristics, specific tumor immune infiltration states, high sensitivity to chemotherapy,wellpredicted response to immunotherapy and thus a more favorable survival outcome. CONCLUSIONS: The current study presents novel findings regarding the use of irlncRNA without the need to predict precise expression levels in the prognosis of breast cancer patients and to indicate their suitability for anti-tumor immunotherapy.
Asunto(s)
Biomarcadores de Tumor/metabolismo , Neoplasias de la Mama/inmunología , Carcinoma Ductal de Mama/inmunología , Regulación Neoplásica de la Expresión Génica/inmunología , ARN Largo no Codificante/metabolismo , Mama/inmunología , Mama/patología , Mama/cirugía , Neoplasias de la Mama/genética , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/terapia , Carcinoma Ductal de Mama/genética , Carcinoma Ductal de Mama/mortalidad , Carcinoma Ductal de Mama/terapia , Quimioterapia Adyuvante/métodos , Resistencia a Antineoplásicos/genética , Femenino , Perfilación de la Expresión Génica , Humanos , Inhibidores de Puntos de Control Inmunológico/farmacología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Estimación de Kaplan-Meier , Mastectomía , Persona de Mediana Edad , Terapia Neoadyuvante/métodos , Pronóstico , RNA-Seq , Medición de Riesgo/métodos , Tasa de Supervivencia , Microambiente Tumoral/genética , Microambiente Tumoral/inmunologíaRESUMEN
This study was undertaken to investigate immunohistochemical expression of the senescence-associated secretory phenotype (SASP) in invasive breast cancer (IBC) tissues and to determine relationships between SASP positivity and tumor microenvironments and the clinicopathological characteristics of IBC. Immunohistochemistry for senescence markers, that is, high mobility group box-1 (HMGB1), p16, p15, and decoy receptor 2 (DCR2), was performed in tissue microarrays of 1140 IBC samples. Cases positive for at least one of these four markers were considered SASP-positive. Relations between SASP and tumor characteristics, including immune microenvironments (stromal tumor-infiltrating lymphocytes [sTILs] density and numbers of intraepithelial CD103-positive [iCD103 + ] lymphocytes) and clinical outcomes were retrospectively evaluated. HMGB1, p16, p15, or DCR2 was positive in 6.7%, 26.6%, 21.1%, and 26.5%, respectively, of the 1,140 cases. Six hundred and five (53.1%) cases were SASP positive, and SASP positivity was significantly associated with histologic grade 3, high-sTIL and iCD103 + lymphocyte counts, absence of ER or PR, and a high Ki-67 index. Although SASP did not predict breast cancer-specific survival (BCSS) or disease-free survival (DFS) in the entire cohort, SASP positivity in luminal A IBC was associated with poor BCSS and DFS. However, patients with SASP-positive TNBC showed better survival than those with SASP-negative TNBC. In multivariate analysis, SASP positivity was an independent prognostic factor in both luminal A IBC and TNBC, although the effect on prognosis was the opposite. In conclusion, SASP would be involved in the modulation of immune microenvironments and tumor progression in IBC, and its prognostic significance depends on molecular subtype.
Asunto(s)
Biomarcadores de Tumor/metabolismo , Neoplasias de la Mama/patología , Carcinoma Ductal de Mama/patología , Linfocitos Infiltrantes de Tumor/inmunología , Fenotipo Secretor Asociado a la Senescencia , Microambiente Tumoral , Neoplasias de la Mama/inmunología , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/cirugía , Carcinoma Ductal de Mama/inmunología , Carcinoma Ductal de Mama/metabolismo , Carcinoma Ductal de Mama/cirugía , Femenino , Estudios de Seguimiento , Regulación Neoplásica de la Expresión Génica , Humanos , Inmunohistoquímica , Persona de Mediana Edad , Pronóstico , Receptor ErbB-2/metabolismo , Receptores de Estrógenos/metabolismo , Receptores de Progesterona/metabolismo , Estudios Retrospectivos , Tasa de SupervivenciaRESUMEN
BACKGROUND: In silico deconvolution of invasive immune cell infiltration in bulk breast tumors helps characterize immunophenotype, expands treatment options, and influences survival endpoints. In this study, we identify the differential expression (DE) of the LM22 signature to classify immune-rich and -poor breast tumors and evaluate immune infiltration by receptor subtype and lymph node metastasis. METHODS: Using publicly available data, we applied the CIBERSORT algorithm to estimate immune cells infiltrating the tumor into immune-rich and immune-poor groups. We then tested the association of receptor subtype and nodal status with immune-rich/poor phenotype. We used DE to test individual signature genes and over-representation analysis for related pathways. RESULTS: CCL19 and CXCL9 expression differed between rich/poor signature groups regardless of subtype. Overexpression of CHI3L2 and FES was observed in triple negative breast cancers (TNBCs) relative to other subtypes in immune-rich tumors. Non-signature genes, LYZ, C1QB, CORO1A, EVI2B, GBP1, PSMB9, and CD52 were consistently overexpressed in immune-rich tumors, and SCUBE2 and GRIA2 were associated with immune-poor tumors. Immune-rich tumors had significant upregulation of genes/pathways while none were identified in immune-poor tumors. CONCLUSIONS: Overall, the proportion of immune-rich/poor tumors differed by subtype; however, a subset of 10 LM22 genes that marked immune-rich status remained the same across subtype. Non-LM22 genes differentially expressed between the phenotypes suggest that the biologic processes responsible for immune-poor phenotype are not yet well characterized.
Asunto(s)
Biomarcadores de Tumor/metabolismo , Neoplasias de la Mama/inmunología , Carcinoma Ductal de Mama/inmunología , Regulación Neoplásica de la Expresión Génica/inmunología , Linfocitos Infiltrantes de Tumor/inmunología , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Carcinoma Ductal de Mama/genética , Carcinoma Ductal de Mama/patología , Conjuntos de Datos como Asunto , Femenino , Perfilación de la Expresión Génica , Humanos , Inmunofenotipificación , Linfocitos Infiltrantes de Tumor/metabolismo , Regulación hacia Arriba/inmunologíaRESUMEN
Reduced infiltration of anti-tumor lymphocytes remains a major cause of tumor immune evasion and is correlated with poor cancer survival. Here, we found that upregulation of regulator of G protein signaling (RGS)1 in helper TH1 cells and cytotoxic T lymphocytes (CTLs) reduced their trafficking to and survival in tumors and was associated with shorter survival of patients with breast and lung cancer. RGS1 was upregulated by type II interferon (IFN)-signal transducer and activator of transcription (STAT)1 signaling and impaired trafficking of circulating T cells to tumors by inhibiting calcium influx and suppressing activation of the kinases ERK and AKT. RGS1 knockdown in adoptively transferred tumor-specific CTLs significantly increased their infiltration and survival in breast and lung tumor grafts and effectively inhibited tumor growth in vivo, which was further improved when combined with programmed death ligand (PD-L)1 checkpoint inhibition. Our findings reveal RGS1 is important for tumor immune evasion and suggest that targeting RGS1 may provide a new strategy for tumor immunotherapy.
Asunto(s)
Neoplasias de la Mama/metabolismo , Carcinoma Ductal de Mama/metabolismo , Quimiotaxis de Leucocito , Linfocitos Infiltrantes de Tumor/metabolismo , Proteínas RGS/metabolismo , Subgrupos de Linfocitos T/metabolismo , Animales , Apoptosis , Neoplasias de la Mama/inmunología , Neoplasias de la Mama/patología , Neoplasias de la Mama/terapia , Carcinoma Ductal de Mama/inmunología , Carcinoma Ductal de Mama/patología , Carcinoma Ductal de Mama/terapia , Línea Celular Tumoral , Quimiocinas/metabolismo , Técnicas de Cocultivo , Citotoxicidad Inmunológica , Femenino , Humanos , Inmunoterapia Adoptiva , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/trasplante , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Microscopía Fluorescente , Microscopía por Video , Proteínas RGS/genética , Transducción de Señal , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/trasplante , Linfocitos T Citotóxicos/inmunología , Linfocitos T Citotóxicos/metabolismo , Células TH1/inmunología , Células TH1/metabolismo , Factores de Tiempo , Imagen de Lapso de Tiempo , Células Tumorales Cultivadas , Escape del TumorRESUMEN
BACKGROUND: Mucin-associated sialyl-Tn (sTn) antigen is overexpressed and related with adverse outcome in breast cancer (BC). The role of sTn in BC has not been well defined in pathological nipple discharge (PND) cytology. The authors examined sTn immunocytochemistry (ICC) in PND to determine whether it could be a biomarker of malignancy or aggressive disease. METHODS: PND was subjected to immunocytochemical staining for sTn antigen expression and thinprep cytology test (TCT) for enhancing the sensitivity and specificity. The examination data was compared with histological findings of subsequent biopsy specimens. Logistic regression analysis was used to determine which factors were most associated with malignant breast lesions. RESULTS: PND specimens were collected including 120 cases of intraductal papilloma, 24 cases of hyperplasia, 45 cases of ductal carcinoma in situ (DCIS), and 48 cases of invasive ductal carcinoma (IDC). STn ICC differentiated BC from benign intraductal lesions with a low sensitivity of 41.9% and a high specificity of 95.8%, but increased in combination with TCT to 64.5% and 100%, respectively. A high degree of concordance was observed between the results of sTn expression in cell smears and histological specimens. Moreover, the sTn expression was strongly associated with HER2-positive IDC (p = 0.039). Multivariate logistic analysis showed that positive sTn expression (OR: 14.241, 95%CI: 2.574, 78.794, p = 0.010) and accompanying mass (OR: 3.307, 95%CI: 1.073, 10.188, p = 0.037) were statistically significant independent risk factors for malignant PND. CONCLUSIONS: Mucin-associated sTn expression in PND cytology appears to be a reliable diagnostic marker for BC patients with the chief complaint of malignant nipple discharge and indicates a more aggressive behavior in IDC.
Asunto(s)
Antígenos de Carbohidratos Asociados a Tumores/análisis , Neoplasias de la Mama/inmunología , Carcinoma Ductal de Mama/inmunología , Carcinoma Intraductal no Infiltrante/inmunología , Secreción del Pezón/inmunología , Papiloma Intraductal/inmunología , Adulto , Biomarcadores de Tumor/análisis , Biopsia , Mama/inmunología , Mama/patología , Neoplasias de la Mama/complicaciones , Neoplasias de la Mama/patología , Carcinoma Ductal de Mama/complicaciones , Carcinoma Ductal de Mama/patología , Carcinoma Intraductal no Infiltrante/complicaciones , Carcinoma Intraductal no Infiltrante/patología , Intervalos de Confianza , Femenino , Humanos , Hiperplasia/inmunología , Hiperplasia/patología , Inmunohistoquímica , Modelos Logísticos , Oportunidad Relativa , Papiloma Intraductal/complicaciones , Papiloma Intraductal/patología , Receptor ErbB-2/análisis , Factores de Riesgo , Sensibilidad y EspecificidadRESUMEN
The drivers of ductal carcinoma in situ (DCIS) to invasive ductal carcinoma (IDC) transition are poorly understood. Here, we conducted an integrated genomic, transcriptomic, and whole-slide image analysis to evaluate changes in copy-number profiles, mutational profiles, expression, neoantigen load, and topology in 6 cases of matched pure DCIS and recurrent IDC. We demonstrate through combined copy-number and mutational analysis that recurrent IDC can be genetically related to its pure DCIS despite long latency periods and therapeutic interventions. Immune "hot" and "cold" tumors can arise as early as DCIS and are subtype-specific. Topologic analysis showed a similar degree of pan-leukocyte-tumor mixing in both DCIS and IDC but differ when assessing specific immune subpopulations such as CD4 T cells and CD68 macrophages. Tumor-specific copy-number aberrations in MHC-I presentation machinery and losses in 3p, 4q, and 5p are associated with differences in immune signaling in estrogen receptor (ER)-negative IDC. Common oncogenic hotspot mutations in genes including TP53 and PIK3CA are predicted to be neoantigens yet are paradoxically conserved during the DCIS-to-IDC transition, and are associated with differences in immune signaling. We highlight both tumor and immune-specific changes in the transition of pure DCIS to IDC, including genetic changes in tumor cells that may have a role in modulating immune function and assist in immune escape, driving the transition to IDC. IMPLICATIONS: We demonstrate that the in situ to IDC evolutionary bottleneck is shaped by both tumor and immune cells.
Asunto(s)
Neoplasias de la Mama/genética , Neoplasias de la Mama/inmunología , Carcinoma Ductal de Mama/genética , Carcinoma Ductal de Mama/inmunología , Carcinoma Intraductal no Infiltrante/genética , Carcinoma Intraductal no Infiltrante/inmunología , Femenino , Genómica , Humanos , Sistema InmunológicoRESUMEN
Humoral immunity plays a substantial role in the suppression of breast cancer. We have revealed that a high serum concentration of anti-HER2 autoantibody (HER2-AAb) is associated with favorable outcomes in patients with invasive breast cancer. Thus, we aimed to clarify the association between high serum concentration of HER2-AAb and humoral immune response in the tumor microenvironment. Out of 500 consecutive patients with invasive breast cancer, we selected those whose HER2-AAb values were high (n = 33) or low (n = 20) based on the distribution of HER2-AAb values of 100 healthy individuals. Tumor and regional lymph node formalin-fixed paraffin-embedded samples prepared from the surgical specimens were subjected to immunohistochemistry. We confirmed that the recurrence-free survival of the high HER2-AAb group was significantly longer than that of the low HER2-AAb group (p = 0.015). The numbers of tumor-infiltrating CD20+ immune cells (ICs) (p < 0.001), IGKC+ICs (p = 0.023), and CXCL13+ ICs (p = 0.044) were significantly higher in the high HER2-AAb group than in the low HER2-AAb group. The number of CD4+ ICs in the B-cell follicles of the regional lymph nodes was also significantly greater in the high HER2-AAb group than in the low HER2-AAb group (p = 0.026). Our findings indicate that a high level of HER2-AAb is associated with enhanced humoral immunity against breast cancer and thus may provide a rationale for the association of HER2-AAb with favorable prognosis.
Asunto(s)
Autoanticuerpos/sangre , Biomarcadores de Tumor/sangre , Neoplasias de la Mama/inmunología , Carcinoma Ductal de Mama/inmunología , Carcinoma Lobular/inmunología , Receptor ErbB-2/inmunología , Adulto , Anciano , Autoanticuerpos/inmunología , Biomarcadores de Tumor/inmunología , Neoplasias de la Mama/sangre , Neoplasias de la Mama/patología , Neoplasias de la Mama/cirugía , Carcinoma Ductal de Mama/sangre , Carcinoma Ductal de Mama/patología , Carcinoma Ductal de Mama/cirugía , Carcinoma Lobular/sangre , Carcinoma Lobular/patología , Carcinoma Lobular/cirugía , Estudios de Casos y Controles , Femenino , Estudios de Seguimiento , Humanos , Inmunidad Humoral/inmunología , Linfocitos Infiltrantes de Tumor/inmunología , Persona de Mediana Edad , Pronóstico , Tasa de Supervivencia , Microambiente Tumoral/inmunologíaRESUMEN
Innate immune defense mechanisms play a pivotal role in antitumor responses. Recent evidence suggests that antiviral innate immunity is regulated not only by exogenous non-self-RNA but also by host-derived pseudogene RNAs. A growing body of evidence also indicates a biological role for pseudogenes as gene expression regulators or immune modulators. Here, we report an important role for BRCA1P1, the pseudogene of the BRCA1 tumor-suppressor gene, in regulating innate immune defense mechanisms in breast cancer cells. BRCA1P1 expresses a long-noncoding RNA (lncRNA) in breast cancer cells through divergent transcription. Expression of lncRNA-BRCA1P1 is increased in breast tumors compared with normal breast tissues. Depletion of BRCA1P1 induces an antiviral defense-like program, including the expression of antiviral genes in breast cancer cells. Furthermore, BRCA1P1-deficient cancer cells mimic virus-infected cells by stimulating cytokines and inducing cell apoptosis. Accordingly, depletion of BRCA1P1 increases host innate immune responses and restricts virus replication. In converse, overexpression of BRCA1P1 reduces cytokine expression in breast cancer cells. Mechanistically, lncRNA-BRCA1P1 is localized in the nucleus, binds to the NF-κB subunit RelA, and negatively regulates antiviral gene expression. Finally, in a xenograft mouse model of breast cancer, depletion of BRCA1P1 stimulates cytokine expression and local immunity, and suppresses tumor growth. Our results suggest an important role for BRCA1P1 in innate immune defense mechanisms and antitumor responses. This mechanism of antiviral immunity regulated by a host-derived pseudogene RNA may guide the development of novel therapies targeting immune responses in breast cancer. SIGNIFICANCE: This study identifies a novel mechanism of innate immunity driven by a host pseudogene RNA that inhibits innate immune defense mechanisms and antitumor responses through regulation of antiviral gene expression.
Asunto(s)
Neoplasias de la Mama/genética , Carcinoma Ductal de Mama/genética , Seudogenes/fisiología , ARN Largo no Codificante/metabolismo , Escape del Tumor/genética , Animales , Mama/patología , Mama/cirugía , Neoplasias de la Mama/inmunología , Neoplasias de la Mama/patología , Neoplasias de la Mama/cirugía , Carcinoma Ductal de Mama/inmunología , Carcinoma Ductal de Mama/patología , Carcinoma Ductal de Mama/cirugía , Línea Celular Tumoral , Núcleo Celular/genética , Citocinas/genética , Femenino , Regulación Neoplásica de la Expresión Génica/inmunología , Técnicas de Inactivación de Genes , Interacciones Microbiota-Huesped/genética , Interacciones Microbiota-Huesped/inmunología , Humanos , Inmunidad Innata/genética , Mastectomía , Ratones , Cultivo Primario de Células , ARN Largo no Codificante/genética , Infecciones por Respirovirus/inmunología , Infecciones por Respirovirus/virología , Virus Sendai/inmunología , Factor de Transcripción ReIA/genética , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Immune cells are present in normal breast tissue and in breast carcinoma. The nature and distribution of the immune cell subtypes in these tissues are reviewed to promote a better understanding of their important role in breast cancer prevention and treatment. We conducted a review of the literature to define the type, location, distribution, and role of immune cells in normal breast tissue and in in situ and invasive breast cancer. Immune cells in normal breast tissue are located predominantly within the epithelial component in breast ductal lobules. Immune cell subtypes representing innate immunity (NK, CD68+, and CD11c+ cells) and adaptive immunity (most commonly CD8+, but CD4+ and CD20+ as well) are present; CD8+ cells are the most common subtype and are primarily effector memory cells. Immune cells may recognize neoantigens and endogenous and exogenous ligands and may serve in chronic inflammation and immunosurveillance. Progression to breast cancer is characterized by increased immune cell infiltrates in tumor parenchyma and stroma, including CD4+ and CD8+ granzyme B+ cytotoxic T cells, B cells, macrophages and dendritic cells. Tumor-infiltrating lymphocytes in breast cancer may serve as prognostic indicators for response to chemotherapy and for survival. Experimental strategies of adoptive transfer of breast tumor-infiltrating lymphocyte may allow regression of metastatic breast cancer and encourage development of innovative T-cell strategies for the immunotherapy of breast cancer. In conclusion, immune cells in breast tissues play an important role throughout breast carcinogenesis. An understanding of these roles has important implications for the prevention and the treatment of breast cancer.
Asunto(s)
Neoplasias de la Mama/inmunología , Mama/inmunología , Carcinoma Ductal de Mama/inmunología , Linfocitos Infiltrantes de Tumor/inmunología , Microambiente Tumoral/inmunología , Mama/patología , Neoplasias de la Mama/patología , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Femenino , HumanosRESUMEN
To elucidate the effects of neoadjuvant chemotherapy (NAC), we conduct whole transcriptome profiling coupled with histopathology analyses of a longitudinal breast cancer cohort of 146 patients including 110 pairs of serial tumor biopsies collected before treatment, after the first cycle of treatment and at the time of surgery. Here, we show that cytotoxic chemotherapies induce dynamic changes in the tumor immune microenvironment that vary by subtype and pathologic response. Just one cycle of treatment induces an immune stimulatory microenvironment harboring more tumor infiltrating lymphocytes (TILs) and up-regulation of inflammatory signatures predictive of response to anti-PD1 therapies while residual tumors are immune suppressed at end-of-treatment compared to the baseline. Increases in TILs and CD8+ T cell proportions in response to NAC are independently associated with pathologic complete response. Further, on-treatment immune response is more predictive of treatment outcome than immune features in paired baseline samples although these are strongly correlated.
Asunto(s)
Antígeno B7-H1/genética , Neoplasias de la Mama/tratamiento farmacológico , Carcinoma Ductal de Mama/tratamiento farmacológico , Regulación Neoplásica de la Expresión Génica , Linfocitos Infiltrantes de Tumor/efectos de los fármacos , Terapia Neoadyuvante/métodos , Antraciclinas/uso terapéutico , Antígeno B7-H1/antagonistas & inhibidores , Antígeno B7-H1/inmunología , Neoplasias de la Mama/genética , Neoplasias de la Mama/inmunología , Neoplasias de la Mama/mortalidad , Linfocitos T CD8-positivos/efectos de los fármacos , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/patología , Carcinoma Ductal de Mama/genética , Carcinoma Ductal de Mama/inmunología , Carcinoma Ductal de Mama/mortalidad , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/inmunología , Ciclofosfamida/uso terapéutico , Supervivencia sin Enfermedad , Docetaxel/uso terapéutico , Receptor alfa de Estrógeno/genética , Receptor alfa de Estrógeno/inmunología , Femenino , Perfilación de la Expresión Génica , Humanos , Inmunidad Innata , Factores Reguladores del Interferón/genética , Factores Reguladores del Interferón/inmunología , Estudios Longitudinales , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/patología , Neoplasia Residual , Receptor ErbB-2/genética , Receptor ErbB-2/inmunología , Trastuzumab/uso terapéutico , Resultado del Tratamiento , Microambiente Tumoral/efectos de los fármacos , Microambiente Tumoral/genética , Microambiente Tumoral/inmunologíaRESUMEN
Triple negative breast cancer (TNBC), usually presenting with a very aggressive phenotype, is a heterogeneous entity. We aim to discuss new biomarkers, suitable for prognostic and predictive purposes. We retrospectively collected clinical variables and immunohistochemical characteristics of early TNBCs, specifically focusing on the prognostic and predictive significance of tumor infiltrating lymphocytes (TILs) and androgen receptor (AR) expression, assessing their correlation with clinical variables. Among 159 patients, TILs were significantly higher in younger patients and with lower BMI, and in tumors with higher ki-67 and greater nodal involvement; conversely, AR was significantly higher in older patients and in tumors with lower ki-67. Interestingly and in line with literature, both TILs level and ARs expression were lower within metastatic sites, in patients who developed distant metastases, compared to those found in the primary site. Small (pT1) and node negative tumors were highly represented and no correlation of either TILs or AR with prognosis could be observed. Our findings support the use of stromal TILs to identify a more aggressive, but chemo-sensitive phenotype, mostly represented in younger women, while AR may identify a less aggressive, slow-growing luminal TNBC subtype, more common among older patients. TILs and AR are worth implementing in routine clinical practice to refine prognosis even if, in our case series, we couldn't identify a significant correlation of the two variables with either disease-free and overall survival.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma Ductal de Mama/patología , Carcinoma Lobular/patología , Linfocitos Infiltrantes de Tumor/inmunología , Receptores Androgénicos/metabolismo , Neoplasias de la Mama Triple Negativas/patología , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/metabolismo , Carcinoma Ductal de Mama/tratamiento farmacológico , Carcinoma Ductal de Mama/inmunología , Carcinoma Ductal de Mama/metabolismo , Carcinoma Lobular/tratamiento farmacológico , Carcinoma Lobular/inmunología , Carcinoma Lobular/metabolismo , Femenino , Estudios de Seguimiento , Regulación Neoplásica de la Expresión Génica , Humanos , Persona de Mediana Edad , Pronóstico , Estudios Retrospectivos , Tasa de Supervivencia , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/inmunología , Neoplasias de la Mama Triple Negativas/metabolismoRESUMEN
BACKGROUND: Whether tumour-infiltrating lymphocytes (TILs) play different roles in different molecular subtypes of breast cancer remains unknown. Additionally, their prognostic and predictive value in different molecular subtypes of breast cancer is still controversial. The aim of our meta-analysis was to assess the prognostic and predictive value of TILs in different molecular subtypes of breast cancer by summarizing all relevant studies performing multivariate analysis. METHODS: PubMed, Embase, EBSCO, ScienceDirect, the Cochrane Database and Web of Science were comprehensively searched (until March 2020). Hazard ratios (HRs), odds ratios (ORs) and their 95% confidence intervals (CIs) were used as effect measures to perform our meta-analysis. A random effect model was used. Stata software, version 15 (2017) (StataCorp, College Station, TX, USA) was used to perform the statistical analysis. RESULTS: Thirty-three studies including 18,170 eligible breast cancer patients were analysed. The meta-analysis showed that high TIL expression was significantly associated with increased pathological complete response (pCR) rates after neoadjuvant chemotherapy in patients with the HER2-enriched molecular subtype (OR = 1.137, 95% CI [1.061 ~ 1.218], p < 0.001) and triple-negative breast cancer (TNBC) subtype (OR = 1.120, 95% CI [1.061 ~ 1.182], p < 0.001). However, high TIL expression was not significantly associated with high pCR rates after neoadjuvant chemotherapy in patients with the luminal molecular subtype of breast cancer (OR = 1.154, 95% CI [0.789 ~ 1.690], p = 0.460). We carried out a meta-analysis on the HRs of overall survival (OS) and disease-free survival (DFS) to assess the prognostic value of TILs in breast cancer with different molecular subtypes more deeply. Our meta-analysis confirmed that high TILs were associated with significantly improved DFS in patients with the HER2-enriched molecular subtype [HR = 0.940, 95% CI (0.903 ~ 0.979), p = 0.003] and TNBC molecular subtype [HR = 0.907, 95% CI (0.862 ~ 0.954), p < 0.001]. However, high TILs were not associated with significantly better DFS in patients with the luminal molecular subtype of breast cancer [HR = 0.998, 95% CI (0.977 ~ 1.019), p = 0.840]. Furthermore, the results confirmed that high TILs were significantly related to better OS in patients with the HER2-enriched molecular subtype [HR = 0.910, 95% CI (0.866 ~ 0.957), p < 0.001] and TNBC molecular subtype [HR = 0.869, 95% CI (0.836 ~ 0.904), p < 0.001]. Conversely, the summarized results indicated that high TILs were significantly associated with poor OS in patients with the luminal molecular subtype of breast cancer [HR = 1.077, 95% CI (1.016 ~ 1.141), p = 0.012]. CONCLUSIONS: Our meta-analysis confirms that high TILs are associated with favourable survival and predicts pCR in breast cancer patients with the TNBC and HER2-enriched molecular subtypes.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biomarcadores de Tumor/metabolismo , Neoplasias de la Mama/patología , Carcinoma Ductal de Mama/patología , Carcinoma Lobular/patología , Linfocitos Infiltrantes de Tumor/inmunología , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/inmunología , Neoplasias de la Mama/metabolismo , Carcinoma Ductal de Mama/tratamiento farmacológico , Carcinoma Ductal de Mama/inmunología , Carcinoma Ductal de Mama/metabolismo , Carcinoma Lobular/tratamiento farmacológico , Carcinoma Lobular/inmunología , Carcinoma Lobular/metabolismo , Femenino , Humanos , Terapia Neoadyuvante , Pronóstico , Receptor ErbB-2/metabolismo , Receptores de Estrógenos/metabolismo , Receptores de Progesterona/metabolismoRESUMEN
PURPOSE: Invasive lobular carcinoma (ILC) represents the second most common histologic breast cancer subtype after invasive ductal carcinoma (IDC). While primary ILC has been extensively studied, metastatic ILC has been poorly characterized at the genomic and immune level. EXPERIMENTAL DESIGN: We retrospectively assembled the multicentric EuroILC series of matched primary and metastatic samples from 94 patients with estrogen receptor (ER)-positive ILC. Stromal tumor-infiltrating lymphocytes (sTILs) were assessed by experienced pathologists. Targeted sequencing and low pass whole-genome sequencing were conducted to detect mutations and copy-number aberrations (CNAs). We compared the frequencies of the alterations in EuroILC with those from patients with ER-positive metastatic ILC (n = 135) and IDC (n = 563) from MSK-IMPACT. RESULTS: Low sTIL levels were observed in ILC metastases, with higher levels in the mixed nonclassic histology. Considering ILC metastases from EuroILC and MSK-IMPACT, we observed that >50% of tumors harbor genomic alterations that have previously been associated with endocrine resistance. A matched primary/metastasis comparison in EuroILC revealed mutations (AKT1, ARID1A, ESR1, ERBB2, or NF1) and CNAs (PTEN or NF1 deletion, CYP19A1 amplification) associated with endocrine resistance that were private to the metastasis in 22% (7/32) and 19% (4/21) of patients, respectively. An increase in CDH1, ERBB2, FOXA1, and TBX3 mutations, in CDH1 deletions and a decrease in TP53 mutations was observed in ILC as compared with IDC metastases. CONCLUSIONS: ILC metastases harbor genomic alterations that may potentially explain endocrine resistance in a large proportion of patients, and present genomic differences as compared with IDC metastases.
Asunto(s)
Biomarcadores de Tumor/genética , Neoplasias de la Mama/patología , Carcinoma Ductal de Mama/secundario , Carcinoma Lobular/secundario , Genómica/métodos , Linfocitos Infiltrantes de Tumor/inmunología , Mutación , Células del Estroma/inmunología , Neoplasias de la Mama/genética , Neoplasias de la Mama/inmunología , Neoplasias de la Mama/metabolismo , Carcinoma Ductal de Mama/genética , Carcinoma Ductal de Mama/inmunología , Carcinoma Ductal de Mama/metabolismo , Carcinoma Lobular/genética , Carcinoma Lobular/inmunología , Carcinoma Lobular/metabolismo , Femenino , Estudios de Seguimiento , Humanos , Metástasis Linfática , Persona de Mediana Edad , Pronóstico , Receptor ErbB-2/metabolismo , Receptores de Estrógenos/metabolismo , Receptores de Progesterona/metabolismo , Estudios Retrospectivos , Tasa de SupervivenciaRESUMEN
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 IFNγ 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.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Antígeno CTLA-4/antagonistas & inhibidores , Carcinoma Ductal de Mama/tratamiento farmacológico , Antígenos Específicos del Melanoma/metabolismo , Linfocitos T Citotóxicos/inmunología , Adulto , Anciano , Anciano de 80 o más Años , Antimetabolitos Antineoplásicos/administración & dosificación , Neoplasias de la Mama/inmunología , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Antígeno CTLA-4/inmunología , Carcinoma Ductal de Mama/inmunología , Carcinoma Ductal de Mama/metabolismo , Carcinoma Ductal de Mama/patología , Línea Celular Tumoral , Decitabina/administración & dosificación , Femenino , Estudios de Seguimiento , Humanos , Metástasis Linfática , Células MCF-7 , Antígenos Específicos del Melanoma/genética , Persona de Mediana Edad , Invasividad Neoplásica , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/inmunología , Recurrencia Local de Neoplasia/metabolismo , Recurrencia Local de Neoplasia/patología , Pronóstico , Tasa de Supervivencia , Linfocitos T Citotóxicos/efectos de los fármacosRESUMEN
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.