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1.
Cancer Immunol Res ; 2021 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-34580116

RESUMO

Enhancing NK cell-based cancer immunotherapy by overcoming immunosuppression is an area of intensive research. Here, we have demonstrated that the anti-CD137 agonist urelumab can overcome TGFß-mediated inhibition of human NK-cell proliferation and antitumor function. Transcriptomic, immunophenotypic and functional analyses showed that CD137 costimulation modified the transcriptional program induced by TGFß on human NK cells by rescuing their proliferation in response to IL2, preserving their expression of activating receptors (NKG2D) and effector molecules (granzyme B, IFN-γ), while allowing the acquisition of tumor-homing/retention features (CXCR3, CD103). Activated NK cells cultured in the presence of TGFß1 and CD137 agonist recovered CCL5 and IFNγ secretion and showed enhanced direct and antibody-dependent cytotoxicity upon restimulation with cancer cells. Trastuzumab treatment of fresh breast carcinoma-derived multicellular cultures induced CD137 expression on tumor-infiltrating CD16+ NK cells, enabling the action of urelumab, which fostered tumor-infiltrating NK cells and recapitulated the enhancement of CCL5 and IFNγ production. Bioinformatic analysis pointed to IFNG as the driver of the association between NK cells and clinical response to trastuzumab in HER2-positive primary breast cancer patients, highlighting the translational relevance of the CD137 costimulatory axis for enhancing IFNγ production. Our data reveals CD137 as a targetable checkpoint for overturning TGFß constraints on NK-cell antitumor responses.

2.
Theranostics ; 11(16): 7671-7684, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34335957

RESUMO

Snail1 is a transcriptional factor required for epithelial to mesenchymal transition and activation of cancer-associated fibroblasts (CAF). Apart from that, tumor endothelial cells also express Snail1. Here, we have unraveled the role of Snail1 in this tissue in a tumorigenic context. Methods: We generated transgenic mice with an endothelial-specific and inducible Snail1 depletion. This murine line was crossed with MMTV-PyMT mice that develop mammary gland tumors and the consequence of Snail1 depletion in the endothelium were investigated. We also interfere Snail1 expression in cultured endothelial cells. Results: Specific Snail1 depletion in the endothelium of adult mice does not promote an overt phenotype; however, it delays the formation of mammary gland tumors in MMTV-PyMT mice. These effects are associated to the inability of Snail1-deficient endothelial cells to undergo angiogenesis and to enhance CAF activation in a paracrine manner. Moreover, tumors generated in mice with endothelium-specific Snail1 depletion are less advanced and show a papillary phenotype. Similar changes on onset and tumor morphology are observed by pretreatment of MMTV-PyMT mice with the angiogenic inhibitor Bevacizumab. Human breast papillary carcinomas exhibit a lower angiogenesis and present lower staining of Snail1, both in endothelial and stromal cells, compared with other breast neoplasms. Furthermore, human breast tumors datasets show a strong correlation between Snail1 expression and high angiogenesis. Conclusion: These findings show a novel role for Snail1 in endothelial cell activation and demonstrate that these cells impact not only on angiogenesis, but also on tumor onset and phenotype.


Assuntos
Neoplasias da Mama/genética , Fatores de Transcrição da Família Snail/metabolismo , Animais , Neoplasias da Mama/metabolismo , Fibroblastos Associados a Câncer/metabolismo , Carcinogênese/patologia , Linhagem Celular Tumoral , Células Endoteliais/metabolismo , Transição Epitelial-Mesenquimal/genética , Transição Epitelial-Mesenquimal/fisiologia , Feminino , Fibroblastos/metabolismo , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neovascularização Patológica/patologia , Fatores de Transcrição da Família Snail/genética , Fatores de Transcrição/metabolismo
3.
Eur Radiol ; 2021 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-34156554

RESUMO

OBJECTIVES: To evaluate the mammographic features in women with benign breast disease (BBD) and the risk of subsequent breast cancer according to their mammographic findings. METHODS: We analyzed data from a Spanish cohort of women screened from 1995 to 2015 and followed up until December 2017 (median follow-up, 5.9 years). We included 10,650 women who had both histologically confirmed BBD and mammographic findings. We evaluated proliferative and nonproliferative BBD subtypes, and their mammographic features: architectural distortion, asymmetries, calcifications, masses, and multiple findings. The adjusted hazard ratios (aHR) and 95% confidence intervals (95% CI) for breast cancer were estimated using a Cox proportional hazards model. We plotted the adjusted cumulative incidence curves. RESULTS: Calcifications were more frequent in proliferative disease with atypia (43.9%) than without atypia (36.8%) or nonproliferative disease (22.2%; p value < 0.05). Masses were more frequent in nonproliferative lesions (59.1%) than in proliferative lesions without atypia (35.1%) or with atypia (30.0%; p value < 0.05). Multiple findings and architectural distortion were more likely in proliferative disease (16.1% and 4.7%) than in nonproliferative disease (12.8% and 1.9%). Subsequent breast cancer occurred in 268 (2.5%) women. Compared with women who had masses, the highest risk of subsequent breast cancer was found in those with architectural distortions (aHR, 2.21; 95% CI, 1.16-4.22), followed by those with multiple findings (aHR, 1.89; 95% CI, 1.34-2.66), asymmetries (aHR, 1.66; 95% CI, 0.84-3.28), and calcifications (aHR, 1.60; 95% CI, 1.21-2.12). CONCLUSION: BBD subtypes showed distinct mammographic findings. The risk of subsequent breast cancer was high in those who have shown architectural distortion, multiple findings, asymmetries, and calcifications than in women with masses. KEY POINTS: • The presence of mammographic findings in women attending breast cancer screening helps clinicians to assess women with benign breast disease (BBD). • Calcifications were frequent in BBDs with atypia, which are the ones with a high breast cancer risk, while masses were common in low-risk BBDs. • The excess risk of subsequent breast cancer in women with BBD was higher in those who showed architectural distortion compared to those with masses.

4.
Future Oncol ; 17(10): 1209-1218, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33289433

RESUMO

Triple-negative breast cancer (TNBC) is more aggressive than other breast cancer subtypes. TNBC is characterized by increased expression of Programmed Death-ligand 1 (PD-L1), a signal used by many tumors to escape the immune response. Expression of PD-L1 is a positive predictor of response to immunotherapy; therefore, it should be investigated in TNBC in order to select patients who may benefit from anti-PD-L1 therapies. While many PD-L1 assays are available, only the VENTANA platform with the anti-PD-L1 (SP142) antibody is licensed as a companion diagnostic device for selecting patients with metastatic/advanced TNBC who are candidates for treatment with atezolizumab. In this article, we provide a summary of an expert round-table discussion about PD-L1 testing, using the SP142 antibody in metastatic TNBC.

5.
Cancer Res ; 81(2): 438-451, 2021 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-33229340

RESUMO

Tumors are complex tissues composed of transformed epithelial cells as well as cancer-activated fibroblasts (CAF) that facilitate epithelial tumor cell invasion. We show here that CAFs and other mesenchymal cells rely much more on glutamine than epithelial tumor cells; consequently, they are more sensitive to inhibition of glutaminase. Glutamine dependence drove CAF migration toward this amino acid when cultured in low glutamine conditions. CAFs also invaded a Matrigel matrix following a glutamine concentration gradient and enhanced the invasion of tumor cells when both cells were cocultured. Accordingly, glutamine directed invasion of xenografted tumors in immunocompromised mice. Stimulation of glutamine-driven epithelial tumor invasion by fibroblasts required previous CAF activation, which involved the TGFß/Snail1 signaling axis. CAFs moving toward Gln presented a polarized Akt2 distribution that was modulated by the Gln-dependent activity of TRAF6 and p62 in the migrating front, and depletion of these proteins prevented Akt2 polarization and Gln-driven CAF invasion. Our results demonstrate that glutamine deprivation promotes CAF migration and invasion, which in turn facilitates the movement of tumor epithelial cells toward nutrient-rich territories. These results provide a novel molecular mechanism for how metabolic stress enhances invasion and metastasis. SIGNIFICANCE: Cancer-associated fibroblasts migrate and invade toward free glutamine and facilitate invasion of tumor epithelial cells, accounting for their movement away from the hostile conditions of the tumor towards nutrient-rich adjacent tissues. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/81/2/438/F1.large.jpg.


Assuntos
Neoplasias da Mama/patologia , Fibroblastos Associados a Câncer/patologia , Movimento Celular , Transição Epitelial-Mesenquimal , Glutamina/farmacologia , Neoplasias Epiteliais e Glandulares/patologia , Animais , Apoptose , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Fibroblastos Associados a Câncer/efeitos dos fármacos , Fibroblastos Associados a Câncer/metabolismo , Proliferação de Células , Feminino , Humanos , Camundongos , Camundongos Nus , Neoplasias Epiteliais e Glandulares/tratamento farmacológico , Neoplasias Epiteliais e Glandulares/metabolismo , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
6.
Breast ; 54: 343-348, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33023825

RESUMO

INTRODUCTION: We aimed to assess differences in breast cancer risk across benign breast disease diagnosed at prevalent or incident screens. MATERIALS AND METHODS: We conducted a retrospective cohort study with data from 629,087 women participating in a long-standing population-based breast cancer screening program in Spain. Each benign breast disease was classified as non-proliferative, proliferative without atypia, or proliferative with atypia, and whether it was diagnosed in a prevalent or incident screen. We used partly conditional Cox hazard regression to estimate the adjusted hazard ratios of the risk of breast cancer. RESULTS: Compared with women without benign breast disease, the risk of breast cancer was significantly higher (p-value = 0.005) in women with benign breast disease diagnosed in an incident screen (aHR, 2.67; 95%CI: 2.24-3.19) than in those with benign breast disease diagnosed in a prevalent screen (aHR, 1.87; 95%CI: 1.57-2.24). The highest risk was found in women with a proliferative benign breast disease with atypia (aHR, 4.35; 95%CI: 2.09-9.08, and 3.35; 95%CI: 1.51-7.40 for those diagnosed at incident and prevalent screens, respectively), while the lowest was found in women with non-proliferative benign breast disease (aHR, 2.39; 95%CI: 1.95-2.93, and 1.63; 95%CI: 1.32-2.02 for those diagnosed at incident and prevalent screens, respectively). CONCLUSION: Our study showed that the risk of breast cancer conferred by a benign breast disease differed according to type of screen (prevalent or incident). To our knowledge, this is the first study to analyse the impact of the screening type on benign breast disease prognosis.

7.
NPJ Breast Cancer ; 6: 16, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32411818

RESUMO

Assessment of tumor-infiltrating lymphocytes (TILs) is increasingly recognized as an integral part of the prognostic workflow in triple-negative (TNBC) and HER2-positive breast cancer, as well as many other solid tumors. This recognition has come about thanks to standardized visual reporting guidelines, which helped to reduce inter-reader variability. Now, there are ripe opportunities to employ computational methods that extract spatio-morphologic predictive features, enabling computer-aided diagnostics. We detail the benefits of computational TILs assessment, the readiness of TILs scoring for computational assessment, and outline considerations for overcoming key barriers to clinical translation in this arena. Specifically, we discuss: 1. ensuring computational workflows closely capture visual guidelines and standards; 2. challenges and thoughts standards for assessment of algorithms including training, preanalytical, analytical, and clinical validation; 3. perspectives on how to realize the potential of machine learning models and to overcome the perceptual and practical limits of visual scoring.

8.
Oncogene ; 39(13): 2835-2843, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32001817

RESUMO

Poly(ADP-ribose)-polymerase (PARP)-1 and PARP-2 play an essential role in the DNA damage response. Based on this effect of PARP in the tumor cell itself, PARP inhibitors have emerged as new therapeutic tools both approved and in clinical trials. However, the interactome of multiple other cell types, particularly T cells, within the tumor microenvironment are known to either favor or limit tumorigenesis. Here, we bypassed the embryonic lethality of dually PARP-1/PARP-2-deficient mice by using a PARP-1-deficient mouse with a Cd4-promoter-driven deletion of PARP-2 in T cells to investigate the understudied role of these PARPs in the modulation of T cell responses against AT-3-induced breast tumors. We found that dual PARP-1/PARP-2-deficiency in T cells promotes tumor growth while single deficiency of each protein limited tumor progression. Analysis of tumor-infiltrating cells in dual PARP-1/PARP-2-deficiency host-mice revealed a global change in immunological profile and impaired recruitment and activation of T cells. Conversely, single PARP-1 and PARP-2-deficiency tends to produce an environment with an active and partially upregulated immune response. Our findings pinpoint opposite effects of single and dual PARP-1 and PARP-2-deficiency in modulating the antitumor response with an impact on tumor progression, and will have implications for the development of more selective PARP-centered therapies.


Assuntos
Carcinogênese/imunologia , Neoplasias Mamárias Experimentais/imunologia , Poli(ADP-Ribose) Polimerase-1/metabolismo , Poli(ADP-Ribose) Polimerases/metabolismo , Linfócitos T/imunologia , Animais , Carcinogênese/efeitos dos fármacos , Linhagem Celular Tumoral/transplante , Progressão da Doença , Feminino , Humanos , Imunidade Celular , Glândulas Mamárias Humanas/imunologia , Glândulas Mamárias Humanas/patologia , Neoplasias Mamárias Experimentais/tratamento farmacológico , Neoplasias Mamárias Experimentais/patologia , Camundongos , Camundongos Knockout , Poli(ADP-Ribose) Polimerase-1/genética , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Poli(ADP-Ribose) Polimerases/genética , Linfócitos T/metabolismo , Evasão Tumoral , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia
9.
Ultrastruct Pathol ; 43(6): 237-247, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31810413

RESUMO

With the identification of therapeutic targets for lung adenocarcinoma, it has become mandatory to distinguish it from other entities. Some cases remain classified as non-small cell lung carcinoma, not otherwise specified (NSCLC-NOS) with immunohistochemistry. Electron microscopy (EM) can be useful, allowing the identification of glandular differentiation. The aim of this study was to determine the complementary value of immunohistochemistry and EM.Forty-eight NSCLC-NOS cases were selected (PSMAR-Biobank, Barcelona, Spain). Immunohistochemistry (TTF-1, p40) was performed. Tissue was retrieved from paraffin blocks. Results were compared to the final diagnosis, derived from combination of light microscopy, immunohistochemistry, EM, molecular studies and resection specimen.Immunohistochemistry concurred with final diagnosis in 36 cases (75%, Kappa = 0.517). EM agreed with final diagnosis in 35 (72.9%, Kappa = 0.471). Immunohistochemistry had a sensitivity = 73%, specificity = 100%, positive predictive value (PPV) = 100% and negative predictive value (NPV) = 52.4% for adenocarcinoma. All adenocarcinoma cases not solved by immunohistochemistry (n = 10) were classified by EM, and vice versa. Data from EM were identical to those of immunohistochemistry: sensitivity = 73%, specificity = 100%, PPV = 100% and NPV = 52.4%. Combining both techniques, 47 cases were coincident with final diagnosis (97.9%, Kappa = 0.943).EM can provide valuable information in subtyping NSCLC-NOS, being particularly useful when immunohistochemistry is inconclusive. EM could be considered as a complementary tool for decision-making in NSCLC-NOS.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Imuno-Histoquímica/métodos , Neoplasias Pulmonares/diagnóstico , Microscopia Eletrônica de Transmissão/métodos , Biomarcadores Tumorais/análise , Carcinoma Pulmonar de Células não Pequenas/classificação , Carcinoma Pulmonar de Células não Pequenas/patologia , Humanos , Neoplasias Pulmonares/classificação , Neoplasias Pulmonares/patologia , Terapia de Alvo Molecular
10.
Cancer Immunol Res ; 7(8): 1280-1292, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31189644

RESUMO

Natural killer (NK) cells can orchestrate effective antitumor immunity. The presence of tumor-infiltrating NK cells in diagnostic biopsies predicts pathologic complete response (pCR) to HER2-specific therapeutic antibodies in patients with primary breast cancer. Here, we analyzed whether diversity in circulating NK cells might influence tumor infiltration and HER2-specific therapeutic antibody efficacy. We found that numbers of circulating CD57+ NK cells inversely correlated with pCR to HER2-specific antibody treatment in patients with primary breast cancer independently of age, traditional clinicopathologic factors, and CD16A 158F/V genotype. This association was uncoupled from the expression of other NK-cell receptors, the presence of adaptive NK cells, or changes in major T-cell subsets, reminiscent of cytomegalovirus-induced immunomodulation. NK-cell activation against trastuzumab-coated HER2+ breast cancer cells was comparable in patients with high and low proportions of CD57+ NK cells. However, circulating CD57+ NK cells displayed decreased CXCR3 expression and CD16A-induced IL2-dependent proliferation in vitro Presence of CD57+ NK cells was reduced in breast tumor-associated infiltrates as compared with paired peripheral blood samples, suggesting deficient homing, proliferation, and/or survival of NK cells in the tumor niche. Indeed, numbers of circulating CD57+ were inversely related to tumor-infiltrating NK-cell numbers. Our data reveal that NK-cell differentiation influences their antitumor potential and that CD57+ NK cells may be a biomarker useful for tailoring HER2 antibody-based therapeutic strategies in breast cancer.


Assuntos
Antineoplásicos Imunológicos/farmacologia , Neoplasias da Mama/sangue , Neoplasias da Mama/metabolismo , Antígenos CD57/metabolismo , Resistencia a Medicamentos Antineoplásicos , Células Matadoras Naturais/metabolismo , Contagem de Linfócitos , Adulto , Idoso , Biópsia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Antígenos CD57/genética , Feminino , Genótipo , Humanos , Imunomodulação , Imunofenotipagem , Células Matadoras Naturais/imunologia , Ativação Linfocitária/imunologia , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Linfócitos do Interstício Tumoral/patologia , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Receptores de IgG/genética
11.
J Proteomics ; 204: 103372, 2019 07 30.
Artigo em Inglês | MEDLINE | ID: mdl-31051282

RESUMO

The inherent propensity to enzymatic degradation of most peptides remains a bottleneck in their therapeutic development. Efficient, early screening methods are necessary for in vitro characterization of the molecular events occurring when peptides get in contact with biological fluids such us plasma. Herein we present an affinity purification/MS approach for mapping peptide serum interactors. We have applied this methodology to identify the serum partners of antibiotic peptide Ctn [15-34], aiming to ascertain the molecular interactions underlying its unusually long half-life (~ 12 h) in human serum. From 42 proteins captured in pull-downs with biotinylated Ctn [15-34] as bait, five are of special interest for their transport/binding properties hence alleged peptide arresting potential. The subset contains two members of the albumin superfamily, two apolipoproteins and a globulin. All five share a binding ability for hydrophobic species, and also bind Ctn [15-34], presumably via its C-terminal hydrophobic section, with affinities in the µM range as shown by surface plasmon resonance. Additionally, our functional enrichment reveals several significant immune-related processes suggesting an immunomodulatory role of Ctn [15-34]. Taken together, this study exemplifies how pharmacoproteomics can be used to analyze bioavailability issues and shed light on the serum interactors ultimately conferring protection to Ctn [15-34] against proteolytic events. SIGNIFICANCE: The affinity purification/MS identification methodology reported here can be viewed as a routine pharmacoproteomic approach to investigate the serum interactome of peptide drugs, identifying proteins affecting bioavailability and thus assisting the peptide drug development process. The specific results described here enlighten the serum stability issues of peptide Ctn [15-34] and ratify its promising future as an anti-infective lead.


Assuntos
Peptídeos Catiônicos Antimicrobianos/química , Proteínas Sanguíneas/química , Proteínas de Répteis/química , Venenos de Serpentes/química , Peptídeos Catiônicos Antimicrobianos/metabolismo , Proteínas Sanguíneas/metabolismo , Meia-Vida , Humanos , Proteínas de Répteis/metabolismo
12.
Immunity ; 49(4): 709-724.e8, 2018 10 16.
Artigo em Inglês | MEDLINE | ID: mdl-30291028

RESUMO

B cells thwart antigenic aggressions by releasing immunoglobulin M (IgM), IgG, IgA, and IgE, which deploy well-understood effector functions. In contrast, the role of secreted IgD remains mysterious. We found that some B cells generated IgD-secreting plasma cells following early exposure to external soluble antigens such as food proteins. Secreted IgD targeted basophils by interacting with the CD44-binding protein galectin-9. When engaged by antigen, basophil-bound IgD increased basophil secretion of interleukin-4 (IL-4), IL-5, and IL-13, which facilitated the generation of T follicular helper type 2 cells expressing IL-4. These germinal center T cells enhanced IgG1 and IgE but not IgG2a and IgG2b responses to the antigen initially recognized by basophil-bound IgD. In addition, IgD ligation by antigen attenuated allergic basophil degranulation induced by IgE co-ligation. Thus, IgD may link B cells with basophils to optimize humoral T helper type 2-mediated immunity against common environmental soluble antigens.


Assuntos
Basófilos/imunologia , Galectinas/imunologia , Receptores de Hialuronatos/imunologia , Imunoglobulina D/imunologia , Células Th2/imunologia , Animais , Basófilos/metabolismo , Linhagem Celular Tumoral , Células Cultivadas , Galectinas/genética , Galectinas/metabolismo , Perfilação da Expressão Gênica/métodos , Humanos , Receptores de Hialuronatos/genética , Receptores de Hialuronatos/metabolismo , Imunoglobulina D/metabolismo , Imunoglobulina E/imunologia , Imunoglobulina E/metabolismo , Imunoglobulina G/imunologia , Imunoglobulina G/metabolismo , Interleucina-4/genética , Interleucina-4/imunologia , Interleucina-4/metabolismo , Camundongos Endogâmicos BALB C , Ligação Proteica , Células Th2/metabolismo
13.
Nat Commun ; 8(1): 1462, 2017 11 13.
Artigo em Inglês | MEDLINE | ID: mdl-29133782

RESUMO

Mechanistic target of rapamycin (mTOR) enhances immunity in addition to orchestrating metabolism. Here we show that mTOR coordinates immunometabolic reconfiguration of marginal zone (MZ) B cells, a pre-activated lymphocyte subset that mounts antibody responses to T-cell-independent antigens through a Toll-like receptor (TLR)-amplified pathway involving transmembrane activator and CAML interactor (TACI). This receptor interacts with mTOR via the TLR adapter MyD88. The resulting mTOR activation instigates MZ B-cell proliferation, immunoglobulin G (IgG) class switching, and plasmablast differentiation through a rapamycin-sensitive pathway that integrates metabolic and antibody-inducing transcription programs, including NF-κB. Disruption of TACI-mTOR interaction by rapamycin, truncation of the MyD88-binding domain of TACI, or B-cell-conditional mTOR deficiency interrupts TACI signaling via NF-κB and cooperation with TLRs, thereby hampering IgG production to T-cell-independent antigens but not B-cell survival. Thus, mTOR drives innate-like antibody responses by linking proximal TACI signaling events with distal immunometabolic transcription programs.


Assuntos
Linfócitos B/imunologia , Imunoglobulina G/imunologia , Alvo Mecanístico do Complexo 1 de Rapamicina/imunologia , Fator 88 de Diferenciação Mieloide/metabolismo , Serina-Treonina Quinases TOR/imunologia , Proteína Transmembrana Ativadora e Interagente do CAML/imunologia , Animais , Linhagem Celular , Proliferação de Células , Ativação Enzimática , Perfilação da Expressão Gênica , Células HEK293 , Humanos , Switching de Imunoglobulina/genética , Switching de Imunoglobulina/imunologia , Imunoglobulina G/biossíntese , Ativação Linfocitária/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , NF-kappa B/metabolismo , Transdução de Sinais/imunologia , Sirolimo/farmacologia
14.
Adv Anat Pathol ; 24(5): 235-251, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28777142

RESUMO

Assessment of tumor-infiltrating lymphocytes (TILs) in histopathologic specimens can provide important prognostic information in diverse solid tumor types, and may also be of value in predicting response to treatments. However, implementation as a routine clinical biomarker has not yet been achieved. As successful use of immune checkpoint inhibitors and other forms of immunotherapy become a clinical reality, the need for widely applicable, accessible, and reliable immunooncology biomarkers is clear. In part 1 of this review we briefly discuss the host immune response to tumors and different approaches to TIL assessment. We propose a standardized methodology to assess TILs in solid tumors on hematoxylin and eosin sections, in both primary and metastatic settings, based on the International Immuno-Oncology Biomarker Working Group guidelines for TIL assessment in invasive breast carcinoma. A review of the literature regarding the value of TIL assessment in different solid tumor types follows in part 2. The method we propose is reproducible, affordable, easily applied, and has demonstrated prognostic and predictive significance in invasive breast carcinoma. This standardized methodology may be used as a reference against which other methods are compared, and should be evaluated for clinical validity and utility. Standardization of TIL assessment will help to improve consistency and reproducibility in this field, enrich both the quality and quantity of comparable evidence, and help to thoroughly evaluate the utility of TILs assessment in this era of immunotherapy.


Assuntos
Neoplasias da Mama/patologia , Carcinoma Intraductal não Infiltrante/patologia , Linfócitos do Interstício Tumoral/patologia , Segunda Neoplasia Primária/patologia , Animais , Biomarcadores Tumorais/análise , Humanos , Patologistas
15.
Adv Anat Pathol ; 24(6): 311-335, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28777143

RESUMO

Assessment of the immune response to tumors is growing in importance as the prognostic implications of this response are increasingly recognized, and as immunotherapies are evaluated and implemented in different tumor types. However, many different approaches can be used to assess and describe the immune response, which limits efforts at implementation as a routine clinical biomarker. In part 1 of this review, we have proposed a standardized methodology to assess tumor-infiltrating lymphocytes (TILs) in solid tumors, based on the International Immuno-Oncology Biomarkers Working Group guidelines for invasive breast carcinoma. In part 2 of this review, we discuss the available evidence for the prognostic and predictive value of TILs in common solid tumors, including carcinomas of the lung, gastrointestinal tract, genitourinary system, gynecologic system, and head and neck, as well as primary brain tumors, mesothelioma and melanoma. The particularities and different emphases in TIL assessment in different tumor types are discussed. The standardized methodology we propose can be adapted to different tumor types and may be used as a standard against which other approaches can be compared. Standardization of TIL assessment will help clinicians, researchers and pathologists to conclusively evaluate the utility of this simple biomarker in the current era of immunotherapy.


Assuntos
Neoplasias Encefálicas/imunologia , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma de Células Escamosas/imunologia , Neoplasias do Endométrio/imunologia , Neoplasias Gastrointestinais/imunologia , Neoplasias de Cabeça e Pescoço/imunologia , Neoplasias Pulmonares/imunologia , Linfócitos do Interstício Tumoral/imunologia , Melanoma/imunologia , Mesotelioma/imunologia , Neoplasias Ovarianas/imunologia , Patologia/métodos , Neoplasias Cutâneas/imunologia , Neoplasias Urogenitais/imunologia , Biomarcadores Tumorais/análise , Biópsia , Neoplasias Encefálicas/patologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma de Células Escamosas/patologia , Neoplasias do Endométrio/patologia , Feminino , Neoplasias Gastrointestinais/patologia , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Imuno-Histoquímica , Neoplasias Pulmonares/patologia , Linfócitos do Interstício Tumoral/patologia , Melanoma/patologia , Mesotelioma/patologia , Neoplasias Ovarianas/patologia , Patologia/normas , Fenótipo , Valor Preditivo dos Testes , Neoplasias Cutâneas/patologia , Carcinoma de Células Escamosas de Cabeça e Pescoço , Neoplasias Urogenitais/patologia
16.
Immunity ; 47(1): 118-134.e8, 2017 07 18.
Artigo em Inglês | MEDLINE | ID: mdl-28709802

RESUMO

Secretory immunoglobulin A (SIgA) enhances host-microbiota symbiosis, whereas SIgM remains poorly understood. We found that gut IgM+ plasma cells (PCs) were more abundant in humans than mice and clonally related to a large repertoire of memory IgM+ B cells disseminated throughout the intestine but rare in systemic lymphoid organs. In addition to sharing a gut-specific gene signature with memory IgA+ B cells, memory IgM+ B cells were related to some IgA+ clonotypes and switched to IgA in response to T cell-independent or T cell-dependent signals. These signals induced abundant IgM which, together with SIgM from clonally affiliated PCs, recognized mucus-embedded commensals. Bacteria recognized by human SIgM were dually coated by SIgA and showed increased richness and diversity compared to IgA-only-coated or uncoated bacteria. Thus, SIgM may emerge from pre-existing memory rather than newly activated naive IgM+ B cells and could help SIgA to anchor highly diverse commensal communities to mucus.


Assuntos
Angiodisplasia/imunologia , Linfócitos B/imunologia , Neoplasias do Colo/imunologia , Pólipos do Colo/imunologia , Imunoglobulina M/metabolismo , Intestinos/imunologia , Plasmócitos/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Células Clonais , Feminino , Microbioma Gastrointestinal/imunologia , Humanos , Imunidade nas Mucosas , Imunoglobulina A/metabolismo , Switching de Imunoglobulina , Memória Imunológica , Intestinos/microbiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Simbiose
17.
Cancer Res ; 77(13): 3540-3550, 2017 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-28487385

RESUMO

Antibody targeting of the immune checkpoint receptor PD1 produces therapeutic activity in a variety of solid tumors, but most patients exhibit partial or complete resistance to treatment for reasons that are unclear. In this study, we evaluated tumor specimens from 65 patients with melanoma, lung nonsquamous, squamous cell lung or head and neck cancers who were treated with the approved PD1-targeting antibodies pembrolizumab or nivolumab. Tumor RNA before anti-PD1 therapy was analyzed on the nCounter system using the PanCancer 730-Immune Panel, and we identified 23 immune-related genes or signatures linked to response and progression-free survival (PFS). In addition, we evaluated intra- and interbiopsy variability of PD1, PD-L1, CD8A, and CD4 mRNAs and their relationship with tumor-infiltrating lymphocytes (TIL) and PD-L1 IHC expression. Among the biomarkers examined, PD1 gene expression along with 12 signatures tracking CD8 and CD4 T-cell activation, natural killer cells, and IFN activation associated significantly with nonprogressive disease and PFS. These associations were independent of sample timing, drug used, or cancer type. TIL correlated moderately (∼0.50) with PD1 and CD8A mRNA levels and weakly (∼0.35) with CD4 and PD-L1. IHC expression of PD-L1 correlated strongly with PD-L1 (0.90), moderately with CD4 and CD8A, and weakly with PD1. Reproducibility of gene expression in intra- and interbiopsy specimens was very high (total SD <3%). Overall, our results support the hypothesis that identification of a preexisting and stable adaptive immune response as defined by mRNA expression pattern is reproducible and sufficient to predict clinical outcome, regardless of the type of cancer or the PD1 therapeutic antibody administered to patients. Cancer Res; 77(13); 3540-50. ©2017 AACR.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma de Células Escamosas/genética , Neoplasias de Cabeça e Pescoço/genética , Neoplasias Pulmonares/genética , Melanoma/genética , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/patologia , Feminino , Expressão Gênica/efeitos dos fármacos , Expressão Gênica/imunologia , Perfilação da Expressão Gênica/métodos , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia , Masculino , Melanoma/tratamento farmacológico , Melanoma/imunologia , Melanoma/patologia , Pessoa de Meia-Idade , Nivolumabe , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/imunologia , Carcinoma de Células Escamosas de Cabeça e Pescoço
18.
Am J Surg Pathol ; 41(7): 877-886, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28288039

RESUMO

MYC translocation is a defining feature of Burkitt lymphoma (BL), and the new category of high-grade B-cell lymphomas with MYC and BCL2 and/or BCL6 translocations, and occurs in 6% to 15% of diffuse large B-cell lymphomas (DLBCLs). The low incidence of MYC translocations in DLBCL makes the genetic study of all these lymphomas cumbersome. Strategies based on an initial immunophenotypic screening to select cases with a high probability of carrying the translocation may be useful. LMO2 is a germinal center marker expressed in most lymphomas originated in these cells. Mining gene expression profiling studies, we observed LMO2 downregulation in BL and large B-cell lymphoma (LBCL) with MYC translocations, and postulated that LMO2 protein expression could assist to identify such cases. We analyzed LMO2 protein expression in 46 BLs and 284 LBCL. LMO2 was expressed in 1/46 (2%) BL cases, 146/268 (54.5%) DLBCL cases, and 2/16 (12.5%) high-grade B-cell lymphoma cases with MYC and BCL2 and/or BCL6 translocations. All BLs carried MYC translocation (P<0.001), whereas LMO2 was only positive in 6/42 (14%) LBCL with MYC translocation (P<0.001). The relationship between LMO2 negativity and MYC translocation was further analyzed in different subsets of tumors according to CD10 expression and cell of origin. Lack of LMO2 expression was associated with the detection of MYC translocations with high sensitivity (87%), specificity (87%), positive predictive value and negative predictive value (74% and 94%, respectively), and accuracy (87%) in CD10 LBCL. Comparing LMO2 and MYC protein expression, all statistic measures of performance of LMO2 surpassed MYC in CD10 LBCL. These findings suggest that LMO2 loss may be a good predictor for the presence of MYC translocation in CD10 LBCL.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Biomarcadores Tumorais/metabolismo , Linfoma de Burkitt/metabolismo , Genes myc , Proteínas com Domínio LIM/metabolismo , Linfoma Difuso de Grandes Células B/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Translocação Genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Linfoma de Burkitt/genética , Linfoma de Burkitt/patologia , Criança , Pré-Escolar , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Imuno-Histoquímica , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/patologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Adulto Jovem
19.
Nat Immunol ; 15(4): 354-364, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24562309

RESUMO

Innate lymphoid cells (ILCs) regulate stromal cells, epithelial cells and cells of the immune system, but their effect on B cells remains unclear. Here we identified RORγt(+) ILCs near the marginal zone (MZ), a splenic compartment that contains innate-like B cells highly responsive to circulating T cell-independent (TI) antigens. Splenic ILCs established bidirectional crosstalk with MAdCAM-1(+) marginal reticular cells by providing tumor-necrosis factor (TNF) and lymphotoxin, and they stimulated MZ B cells via B cell-activation factor (BAFF), the ligand of the costimulatory receptor CD40 (CD40L) and the Notch ligand Delta-like 1 (DLL1). Splenic ILCs further helped MZ B cells and their plasma-cell progeny by coopting neutrophils through release of the cytokine GM-CSF. Consequently, depletion of ILCs impaired both pre- and post-immune TI antibody responses. Thus, ILCs integrate stromal and myeloid signals to orchestrate innate-like antibody production at the interface between the immune system and circulatory system.


Assuntos
Formação de Anticorpos , Linfócitos B/imunologia , Linfócitos/imunologia , Plasmócitos/imunologia , Baço/imunologia , Animais , Anticorpos/sangue , Antígenos T-Independentes/imunologia , Proteínas Sanguíneas/imunologia , Moléculas de Adesão Celular , Comunicação Celular/imunologia , Diferenciação Celular , Células Cultivadas , Fator Estimulador de Colônias de Granulócitos e Macrófagos/metabolismo , Humanos , Imunidade Inata , Imunoglobulinas/metabolismo , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos C57BL , Mucoproteínas/metabolismo , Neutrófilos/imunologia , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Picratos/imunologia , Transdução de Sinais/imunologia , Células Estromais/imunologia
20.
Science ; 342(6157): 447-53, 2013 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-24072822

RESUMO

A dense mucus layer in the large intestine prevents inflammation by shielding the underlying epithelium from luminal bacteria and food antigens. This mucus barrier is organized around the hyperglycosylated mucin MUC2. Here we show that the small intestine has a porous mucus layer, which permitted the uptake of MUC2 by antigen-sampling dendritic cells (DCs). Glycans associated with MUC2 imprinted DCs with anti-inflammatory properties by assembling a galectin-3-Dectin-1-FcγRIIB receptor complex that activated ß-catenin. This transcription factor interfered with DC expression of inflammatory but not tolerogenic cytokines by inhibiting gene transcription through nuclear factor κB. MUC2 induced additional conditioning signals in intestinal epithelial cells. Thus, mucus does not merely form a nonspecific physical barrier, but also constrains the immunogenicity of gut antigens by delivering tolerogenic signals.


Assuntos
Homeostase , Tolerância Imunológica/imunologia , Intestino Delgado/imunologia , Boca/imunologia , Muco/imunologia , Animais , Células Cultivadas , Células Dendríticas/imunologia , Galectina 3/genética , Galectina 3/metabolismo , Glicosilação , Humanos , Tolerância Imunológica/genética , Inflamação/imunologia , Mucosa Intestinal/imunologia , Lectinas Tipo C/genética , Lectinas Tipo C/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Mucina-2/genética , Mucina-2/fisiologia , NF-kappa B/metabolismo , Receptores de IgG/genética , Receptores de IgG/metabolismo , Transcrição Genética , beta Catenina/metabolismo
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