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1.
Mod Pathol ; 37(9): 100551, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-38936478

RESUMO

As around 25% to 30% of classical Hodgkin lymphoma (cHL) patients with advanced stages do not respond to standard therapies, the tumor microenvironment of cHL is one avenue that may be explored with the aim of improving risk stratification. CD4+ T cells are thought to be one of the main cell types in the tumor microenvironment. However, few immune signatures have been studied, and many of these lack related spatial data. Thus, our aim is to spatially resolve the CD4+ T cell subtypes that influence cHL outcome, depicting new immune signatures or transcriptional patterns that are in crosstalk with the tumor cells. This study was conducted using the NanoString GeoMx digital spatial profiling technology, based on the selection of distinct functional areas of patients' tissues followed by gene-expression profiling. The goals were to assess the differences in CD4+ T cell populations between tumor-rich and immune-predominant areas defined by different CD30 and PD-L1 expression levels and seek correlations with clinical metadata. Our results depict a complex map of CD4+ T cells with different functions and differentiation states that are enriched at distinct locations, the flux of cytokines and chemokines that could be related to these, and the specific relationships with the clinical outcome.


Assuntos
Linfócitos T CD4-Positivos , Doença de Hodgkin , Microambiente Tumoral , Humanos , Doença de Hodgkin/patologia , Doença de Hodgkin/imunologia , Linfócitos T CD4-Positivos/imunologia , Microambiente Tumoral/imunologia , Masculino , Adulto , Feminino , Pessoa de Meia-Idade , Perfilação da Expressão Gênica , Idoso , Adulto Jovem , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/patologia
2.
Int J Cancer ; 153(6): 1300-1312, 2023 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-37260183

RESUMO

Mammalian target of rapamycin (mTOR) is a central regulator of mammalian metabolism and physiology. Aberrant hyperactivation of the mTOR pathway promotes tumor growth and metastasis, and can also promote tumor resistance to chemotherapy and cancer drugs; this makes mTOR an attractive cancer therapeutic target. mTOR inhibitors have been approved to treat cancer; however, the mechanisms underlying drug sensitivity remain poorly understood. Here, whole exome sequencing of three chromophobe renal cell carcinoma (chRCC) patients with exceptional mTOR inhibitor sensitivity revealed that all three patients shared somatic mutations in the deubiquitinase gene USP9X. The clonal characteristics of the mutations, which were amassed by studying multiple patients' primary and metastatic samples from various years, together with the low USP9X mutation rate in unselected chRCC series, reinforced a causal link between USP9X and mTOR inhibitor sensitivity. Rapamycin treatment of USP9X-depleted HeLa and renal cancer 786-O cells, along with the pharmacological inhibition of USP9X, confirmed that this protein plays a role in patients' sensitivity to mTOR inhibitors. USP9X was not found to exert a direct effect on mTORC1, but subsequent ubiquitylome analyses identified p62 as a direct USP9X target. Increased p62 ubiquitination and the augmented rapamycin effect upon bortezomib treatment, together with the results of p62 and LC3 immunofluorescence assays, suggested that dysregulated autophagy in USP9X-depleted cells can have a synergistic effect with mTOR inhibitors. In summary, we show that USP9X constitutes a potential novel marker of sensitivity to mTOR inhibitors in chRCC patients, and represents a clinical strategy for increasing the sensitivity to these drugs.


Assuntos
Carcinoma de Células Renais , Neoplasias Renais , Humanos , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/patologia , Linhagem Celular Tumoral , Enzimas Desubiquitinantes , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/genética , Inibidores de MTOR , Sirolimo/farmacologia , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo , Ubiquitina Tiolesterase/genética
3.
Cancer Sci ; 113(1): 334-348, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34706126

RESUMO

Tumor-associated macrophages (TAMs) are associated with a poor prognosis of diffuse large B-cell lymphoma (DLBCL). As macrophages are heterogeneous, the immune polarization and their pathological role warrant further study. We characterized the microenvironment of DLBCL by immunohistochemistry in a training set of 132 cases, which included 10 Epstein-Barr virus-encoded small RNA (EBER)-positive and five high-grade B-cell lymphomas, with gene expression profiling in a representative subset of 37 cases. Diffuse large B-cell lymphoma had a differential infiltration of TAMs. The high infiltration of CD68 (pan-macrophages), CD16 (M1-like), CD163, pentraxin 3 (PTX3), and interleukin (IL)-10-positive macrophages (M2c-like) and low infiltration of FOXP3-positive regulatory T lymphocytes (Tregs) correlated with poor survival. Activated B cell-like DLBCL was associated with high CD16, CD163, PTX3, and IL-10, and EBER-positive DLBCL with high CD163 and PTX3. Programmed cell death-ligand 1 positively correlated with CD16, CD163, IL-10, and RGS1. In a multivariate analysis of overall survival, PTX3 and International Prognostic Index were identified as the most relevant variables. The gene expression analysis showed upregulation of genes involved in innate and adaptive immune responses and macrophage and Toll-like receptor pathways in high PTX3 cases. The prognostic relevance of PTX3 was confirmed in a validation set of 159 cases. Finally, in a series from Europe and North America (GSE10846, R-CHOP-like treatment, n = 233) high gene expression of PTX3 correlated with poor survival, and moderately with CSF1R, CD16, MITF, CD163, MYC, and RGS1. Therefore, the high infiltration of M2c-like immune regulatory macrophages and low infiltration of FOXP3-positive Tregs is associated with a poor prognosis in DLBCL, for which PTX3 is a new prognostic biomarker.


Assuntos
Proteína C-Reativa/genética , Infecções por Vírus Epstein-Barr/genética , Herpesvirus Humano 4/genética , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/virologia , Componente Amiloide P Sérico/genética , Regulação para Cima , Imunidade Adaptativa , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Infecções por Vírus Epstein-Barr/imunologia , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Imunidade Inata , Linfoma Difuso de Grandes Células B/imunologia , Masculino , Pessoa de Meia-Idade , Prognóstico , RNA Viral/genética , Análise de Sobrevida , Microambiente Tumoral , Macrófagos Associados a Tumor/imunologia , Adulto Jovem
4.
Pharmacol Res ; 179: 105918, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35031477

RESUMO

PD-L1-mediated signaling is one of the major processes that regulate local inflammatory responses in the gut. To date, protective effects against colitis through direct Fc-fused PD-L1 administration or indirect PD-L1 induction by probiotics have been reported. We have previously shown that the anti-HBV drug entecavir (ETV) induces PD-L1 expression in human hepatocytes. In the present study, we investigated whether ETV induces PD-L1 expression in intestinal cells and provides a protective effect against DSS-induced colitis. ETV induced PD-L1 expression in epithelial cells, rather than T and B cells, improving the symptoms of colitis. In the mechanistic analysis, Th17 cell differentiation was inhibited and B cell infiltration into the lamina propria was reduced. In addition, PD-L1 expression was positively correlated with Foxp3 or CSF1-R. In conclusion, ETV upregulated PD-L1 expression in epithelial cells and ameliorated inflammation in DSS-induced colitis. These results suggest that ETV may be a potential therapeutic agent as a PD-L1 enhancer for the treatment of human IBD.


Assuntos
Antígeno B7-H1 , Colite , Animais , Antígeno B7-H1/metabolismo , Colite/induzido quimicamente , Colite/tratamento farmacológico , Colite/metabolismo , Sulfato de Dextrana/farmacologia , Guanina/análogos & derivados , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Preparações Farmacêuticas/metabolismo , Linfócitos T Reguladores , Células Th17
5.
Pathol Int ; 69(5): 260-271, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30990953

RESUMO

We aimed to characterize the mucosal immune microenvironment and immune checkpoint of Ulcerative colitis (UC) by immunohistochemistry with correlation to prognosis: requirement of second-line steroid-therapy within the 2-years after diagnosis (SR). A series of 72 cases included 56 UC, 43 non-SR (with first-line treatment 5-ASA) and 13 SR, 11 infectious colitis and 5 normal colonic biopsies. Normal mucosa was characterized by low infiltrates but high BTLA and TNFRSF14. Compared to normal, UC had increased pan-immune-markers of CD3, CD8, FOXP3, PD-1, CD68, CD16, CD163, PTX3 and CD11C but had decreased BTLA (P < 0.05); by GSEA analysis comparable results were found in an independent UC gene-expression-data set (GSE38713). Compared to infectious, UC had higher CD4, CD8, PTX3 and CD11C but lower BTLA (P < 0.05). Compared to non-SR, SR had lower FOXP3 + Tregs (Odds-Ratio = 0.114, P = 0.002), PD-1 (OR = 0.176, P = 0.002) and CD163/CD68 M2-ratio (OR, 0.019, P = 0.019) but higher CD68 + pan-macrophages (OR = 6.034, P = 0.002). Higher Baron endoscopic and Geboes histologic disease activity scores also correlated with SR. In summary, UC was characterized by increased pan-immune-markers, normal TNFRSF14 and low BTLA. SR had increased CD68 + pan-macrophages but lower immune inhibitors of FOXP3 + Tregs, PD-1 and CD163/CD68 M2-macrophage ratio. In conclusion, alterations of the immune homeostasis mechanisms are relevant in the UC pathogenesis and steroid-requiring situation.


Assuntos
Colite Ulcerativa/patologia , Colite Ulcerativa/terapia , Macrófagos/imunologia , Mucosa/imunologia , Esteroides/uso terapêutico , Adulto , Antígenos CD/metabolismo , Antígenos de Diferenciação Mielomonocítica/metabolismo , Biomarcadores , Proteína C-Reativa/metabolismo , Colite Ulcerativa/imunologia , Feminino , Fatores de Transcrição Forkhead/metabolismo , Humanos , Imuno-Histoquímica , Imunomodulação/fisiologia , Macrófagos/patologia , Masculino , Pessoa de Meia-Idade , Mucosa/patologia , Receptor de Morte Celular Programada 1/metabolismo , Receptores de Superfície Celular/metabolismo , Receptores Imunológicos/metabolismo , Membro 14 de Receptores do Fator de Necrose Tumoral/metabolismo , Componente Amiloide P Sérico/metabolismo
6.
Histopathology ; 70(4): 595-621, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-27775850

RESUMO

AIMS: We aimed to define the clinicopathological characteristics of 29 primary sinonasal diffuse large B cell lymphoma (DLBCLsn ) in a series of 240 cases of DLBCL not otherwise specified [DLBCLall (NOS) ], including DLBCLsn training set (n = 11) and validation set (n = 18), and DLBCLnon-sn (n = 211). METHODS AND RESULTS: In the training set, 82% had a non-germinal center B-cell-like (Hans' Classifier) (non-GCB) phenotype and 18% were Epstein-Barr virus-encoded small RNAs (EBER)+ . The genomic profile showed gains(+) of 1q21.3q31.2 (55%), 10q24.1 (46%), 11q14.1 (46%) and 18q12.1q23 (46%); losses(-) of 6q26q27 (55%) and 9p21.3 (64%); and copy number neutral loss of heterozygosity (LOH) (acquired uniparental disomy, UPD) at 6p25.3p21.31 (36%). This profile is comparable to DLBCLNOS (GSE11318, n = 203.) and closer to non-GCB/activated B-cell-like subtype (ABC). Nevertheless, +1q31, -9p21.3 and -10q11.1q26.2 were more characteristic of DLBCLsn (P < 0.001). Array results were verified successfully by fluorescence in situ hybridization (FISH) on +1q21.3 (CKS1B), -6q26 (PARK2), +8q24.21 (MYC), -9p21.3 (MTAP, CDKN2A/B), -17p13.1 (TP53) and +18q21.33 (BCL2) with 82-91% agreement. Minimal common regions included biologically relevant genes of MNDA (+1q23.1), RGS1 and RGS13 (+1q31.2), FOXP1 (+3p13), PRDM1 (BLIMP1) and PARK2 (-6q21q26), MYC (+8q24.21), CDKN2A (-9p21.3), PTEN (-10q23.31), MDM2 (+12q15), TP53 (-17p13.1) and BCL2 (+18q21.33). Correlation between DNA copy number and protein immunohistochemistry was confirmed for RGS1, RGS13, FOXP1, PARK2 and BCL2. The microenvironment had high infiltration of M2-like tumour associated macrophages (TAMs) and CD8+ T lymphocytes that associated with higher genomic instability. The DLBCLsn validation set confirmed the clinicopathological characteristics, all FISH loci and immunohistochemistry (IHC) for RGS1. RGS1, one of the most frequently altered genes, was analysed by IHC in DLBCLall and high RGS1 expression associated with non-GCB, EBER+ and unfavourable overall survival (hazard ratio = 1.794; P = 0.016). CONCLUSIONS: DLBCLsn has a characteristic genomic profile. High RGS1 IHC expression associates with poor overall survival in DLBCLall (NOS) .


Assuntos
Cromossomos Humanos Par 1/genética , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/patologia , Proteínas RGS/genética , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/análise , Feminino , Dosagem de Genes , Perfilação da Expressão Gênica , Humanos , Processamento de Imagem Assistida por Computador , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Estimativa de Kaplan-Meier , Perda de Heterozigosidade , Linfoma Difuso de Grandes Células B/mortalidade , Masculino , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos , Prognóstico , Transcriptoma
7.
Blood ; 121(4): 643-7, 2013 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-23165482

RESUMO

SPIB is an Ets transcription factor that is expressed exclusively in mature B cells, T-cell progenitors, and plasmacytoid dendritic cells. In the present study, we developed a novel mAb against the SPIB protein and characterized its expression in major hematolymphoid neoplasms, including a series of 45 cases of blastic plasmacytoid dendritic cell (BPDC) neoplasms and their potential cutaneous mimics. We found that SPIB is expressed heterogeneously among B- and T-cell lymphoma types. Interestingly, SPIB is expressed in a large proportion of nongerminal center type DLBCLs. In cutaneous neoplasms, SPIB is overexpressed in all BPDC neoplasms, but none of its cutaneous mimics. SPIB remains overexpressed in all cases that lack 1 or 2 of the markers used for BPDC neoplasms (ie, CD4, CD56, TCL1, and CD123). We conclude that SPIB expression can be used as a tool for diagnosing BPDC neoplasms, but it needs to be tested in conjunction with the growing arsenal of markers for human plasmacytoid dendritic cells.


Assuntos
Biomarcadores Tumorais/metabolismo , Proteínas de Ligação a DNA/metabolismo , Células Dendríticas/metabolismo , Neoplasias Hematológicas/metabolismo , Fatores de Transcrição/metabolismo , Biomarcadores Tumorais/genética , Linhagem Celular Tumoral , Proteínas de Ligação a DNA/genética , Células Dendríticas/patologia , Neoplasias Hematológicas/diagnóstico , Neoplasias Hematológicas/genética , Humanos , Tecido Linfoide/metabolismo , Tecido Linfoide/patologia , Linfoma/diagnóstico , Linfoma/genética , Linfoma/metabolismo , Fatores de Transcrição/genética
8.
Virchows Arch ; 484(4): 657-676, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38462571

RESUMO

BCL6-rearrangement (BCL6-R) is associated with a favorable prognosis of follicular lymphoma (FL), but the mechanism is unknown. We analyzed the clinicopathological, immune microenvironment (immune checkpoint, immuno-oncology markers), and mutational profiles of 10 BCL6-R-positive FL, and 19 BCL6-R-positive diffuse large B-cell lymphoma (DLBCL) cases (both BCL2-R and MYC-R negative). A custom-made panel included 168 genes related to aggressive B-cell lymphomas and FL. FL cases were nodal, histological grade 3A in 70%, low Ki67; and had a favorable overall and progression-free survival. DLBCL cases were extranodal in 60%, IPI high in 63%, non-GCB in 60%, EBER-negative; and had a progression-free survival comparable to that of DLBCL NOS. The microenvironment had variable infiltration of M2-like tumor-associated macrophages (TAMs) that were CD163, CSF1R, LAIR1, PD-L1, and CD85A (LILRB3) positive; but had low IL10 and PTX3 expression. In comparison to FL, DLBCL had higher TAMs, IL10, and PTX3 expression. Both lymphoma subtypes shared a common mutational profile with mutations in relevant pathogenic genes such as KMT2D, OSBPL10, CREBBP, and HLA-B (related to chromatin remodeling, metabolism, epigenetic modification, and antigen presentation). FL cases were characterized by a higher frequency of mutations of ARID1B, ATM, CD36, RHOA, PLOD2, and PRPRD (p < 0.05). DLBCL cases were characterized by mutations of BTG2, and PIM1; and mutations of HIST1H1E and MFHAS1 to disease progression (p < 0.05). Interestingly, mutations of genes usually associated with poor prognosis, such as NOTCH1/2 and CDKN2A, were infrequent in both lymphoma subtypes. Some high-confidence variant calls were likely oncogenic, loss-of-function. MYD88 L265P gain-of-function was found in 32% of DLBCL. In conclusion, both BCL6-R-positive FL and BCL6-R-positive DLBCL had a common mutational profile; but also, differences. DLBCL cases had a higher density of microenvironment markers.


Assuntos
Biomarcadores Tumorais , Linfoma Folicular , Linfoma Difuso de Grandes Células B , Mutação , Proteínas Proto-Oncogênicas c-bcl-6 , Microambiente Tumoral , Humanos , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/patologia , Linfoma Difuso de Grandes Células B/imunologia , Microambiente Tumoral/imunologia , Microambiente Tumoral/genética , Linfoma Folicular/genética , Linfoma Folicular/patologia , Linfoma Folicular/imunologia , Proteínas Proto-Oncogênicas c-bcl-6/genética , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Adulto , Biomarcadores Tumorais/genética , Idoso de 80 Anos ou mais , Rearranjo Gênico , Análise Mutacional de DNA , Intervalo Livre de Progressão
9.
bioRxiv ; 2024 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-38405949

RESUMO

The nucleosome remodeling factor BPTF is required for the deployment of the MYC-driven transcriptional program. Deletion of one Bptf allele delays tumor progression in mouse models of pancreatic cancer and lymphoma. In neuroblastoma, MYCN cooperates with the transcriptional core regulatory circuitry (CRC). High BPTF levels are associated with high-risk features and decreased survival. BPTF depletion results in a dramatic decrease of cell proliferation. Bulk RNA-seq, single-cell sequencing, and tissue microarrays reveal a positive correlation of BPTF and CRC transcription factor expression. Immunoprecipitation/mass spectrometry shows that BPTF interacts with MYCN and the CRC proteins. Genome-wide distribution analysis of BPTF and CRC in neuroblastoma reveals a dual role for BPTF: 1) it co-localizes with MYCN/MYC at the promoter of genes involved in cell cycle and 2) it co-localizes with the CRC at super-enhancers to regulate cell identity. The critical role of BPTF across neuroblastoma subtypes supports its relevance as a therapeutic target.

10.
Artigo em Inglês | MEDLINE | ID: mdl-39218714

RESUMO

Pheochromocytomas and paragangliomas are rare neuroendocrine tumours. Around 20-25 % of patients develop metastases, for which there is an urgent need of prognostic markers and therapeutic stratification strategies. The presence of a MAML3-fusion is associated with increased metastatic risk, but neither the processes underlying disease progression, nor targetable vulnerabilities have been addressed. We have compiled a cohort of 850 patients, which has shown a 3.65 % fusion prevalence and represents the largest MAML3-positive series reported to date. While MAML3-fusions mainly cause single pheochromocytomas, we also observed somatic post-zygotic events, resulting in multiple tumours in the same patient. MAML3-tumours show increased expression of neuroendocrine-to-mesenchymal transition markers, MYC-targets, and angiogenesis-related genes, leading to a distinct tumour microenvironment with unique vascular and immune profiles. Importantly, our findings have identified MAML3-tumours specific vulnerabilities beyond Wnt-pathway dysregulation, such as a rich vascular network, and overexpression of PD-L1 and CD40, suggesting potential therapeutic targets.

11.
Blood ; 118(20): 5517-27, 2011 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-21937691

RESUMO

PIM serine/threonine kinases are overexpressed, translocated, or amplified in multiple B-cell lymphoma types. We have explored the frequency and relevance of PIM expression in different B-cell lymphoma types and investigated whether PIM inhibition could be a rational therapeutic approach. Increased expression of PIM2 was detected in subsets of mantle cell lymphoma, diffuse large B-cell lymphoma (DLBLC), follicular lymphoma, marginal zone lymphoma-mucosa-associated lymphoid tissue type, chronic lymphocytic leukemia, and nodal marginal zone lymphoma cases. Increased PIM2 protein expression was associated with an aggressive clinical course in activated B-like-DLBCL patients. Pharmacologic and genetic inhibition of PIM2 revealed p4E-BP1(Thr37/46) and p4E-BP1(Ser65) as molecular biomarkers characteristic of PIM2 activity and indicated the involvement of PIM2 kinase in regulating mammalian target of rapamycin complex 1. The simultaneous genetic inhibition of all 3 PIM kinases induced changes in apoptosis and cell cycle. In conclusion, we show that PIM2 kinase inhibition is a rational approach in DLBCL treatment, identify appropriate biomarkers for pharmacodynamic studies, and provide a new marker for patient stratification.


Assuntos
Inibidores Enzimáticos/farmacologia , Terapia Genética/métodos , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/genética , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/genética , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Proteínas Proto-Oncogênicas/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Apoptose/efeitos dos fármacos , Apoptose/fisiologia , Biomarcadores Tumorais/metabolismo , Proteínas de Ciclo Celular , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Linfonodos/patologia , Linfoma Folicular/genética , Linfoma Folicular/patologia , Linfoma Folicular/terapia , Linfoma Difuso de Grandes Células B/patologia , Linfoma de Célula do Manto/genética , Linfoma de Célula do Manto/patologia , Linfoma de Célula do Manto/terapia , Tonsila Palatina/patologia , Fosfoproteínas/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/farmacologia , Proteína de Morte Celular Associada a bcl/metabolismo
12.
Front Immunol ; 14: 1113858, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37033927

RESUMO

Introduction: A high frequency of mutations affecting the gene encoding Herpes Virus Entry Mediator (HVEM, TNFRSF14) is a common clinical finding in a wide variety of human tumors, including those of hematological origin. Methods: We have addressed how HVEM expression on A20 leukemia cells influences tumor survival and its involvement in the modulation of the anti-tumor immune responses in a parental into F1 mouse tumor model of hybrid resistance by knocking-out HVEM expression. HVEM WT or HVEM KO leukemia cells were then injected intravenously into semiallogeneic F1 recipients and the extent of tumor dissemination was evaluated. Results: The loss of HVEM expression on A20 leukemia cells led to a significant increase of lymphoid and myeloid tumor cell infiltration curbing tumor progression. NK cells and to a lesser extent NKT cells and monocytes were the predominant innate populations contributing to the global increase of immune infiltrates in HVEM KO tumors compared to that present in HVEM KO tumors. In the overall increase of the adaptive T cell immune infiltrates, the stem cell-like PD-1- T cells progenitors and the effector T cell populations derived from them were more prominently present than terminally differentiated PD-1+ T cells. Conclusions: These results suggest that the PD-1- T cell subpopulation is likely to be a more relevant contributor to tumor rejection than the PD-1+ T cell subpopulation. These findings highlight the role of co-inhibitory signals delivered by HVEM upon engagement of BTLA on T cells and NK cells, placing HVEM/BTLA interaction in the spotlight as a novel immune checkpoint for the reinforcement of the anti-tumor responses in malignancies of hematopoietic origin.


Assuntos
Leucemia Linfocítica Crônica de Células B , Receptor de Morte Celular Programada 1 , Animais , Humanos , Camundongos , Linhagem Celular , Células Matadoras Naturais/metabolismo , Receptor de Morte Celular Programada 1/genética , Receptores Imunológicos/metabolismo
13.
Blood Adv ; 7(15): 4135-4147, 2023 08 08.
Artigo em Inglês | MEDLINE | ID: mdl-36459489

RESUMO

Constitutive activation of the JAK/STAT pathway is a common phenomenon in classic Hodgkin lymphoma (cHL). The clinical potential of anti-JAK/STAT therapy is being explored in early-stage clinical trials. Notwithstanding, very little information is available about the complex biological consequences of this blockade. Here, we investigated the effects of JAK/STAT pharmacological inhibition on cHL cell models using ruxolitinib, a JAK 1/2 inhibitor that induces apoptosis by concentration- and time-dependent mechanisms. An unbiased whole-transcriptome approach identified expression of the anti-GCSF receptor (CSF3R) as a potential surrogate biomarker of JAK/STAT overactivation. In addition, longitudinal gene expression analyses provided further mechanistic information about pertinent biological pathways involved, including 37 gene pathways distributed in 3 main clusters: cluster 1 was characterized by upregulation of the G2/M checkpoint and major histocompatibility complex-related clusters; 2 additional clusters (2 and 3) showed a progressive downregulation of the tumor-promoting inflammation signatures: JAK/STAT and interleukin 1 (IL-1)/IL-4/IL-13/IL-17. Together, our results confirm the therapeutic potential of JAK/STAT inhibitors in cHL, identify CSF3R as a new biomarker, and provide supporting genetic data and mechanistic understanding.


Assuntos
Doença de Hodgkin , Células de Reed-Sternberg , Humanos , Transdução de Sinais , Janus Quinases , Fatores de Transcrição STAT/metabolismo , Doença de Hodgkin/genética , Fenótipo
14.
Hematol Rep ; 15(1): 188-200, 2023 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-36975733

RESUMO

Diffuse large B-cell lymphoma with spindle cell morphology is a rare variant. We present the case of a 74-year-old male who initially presented with a right supraclavicular (lymph) node enlargement. Histological analysis showed a proliferation of spindle-shaped cells with narrow cytoplasms. An immunohistochemical panel was used to exclude other tumors, such as melanoma, carcinoma, and sarcoma. The lymphoma was characterized by a cell-of-origin subtype of germinal center B-cell-like (GCB) based on Hans' classifier (CD10-negative, BCL6-positive, and MUM1-negative); EBER negativity, and the absence of BCL2, BCL6, and MYC rearrangements. Mutational profiling using a custom panel of 168 genes associated with aggressive B-cell lymphomas confirmed mutations in ACTB, ARID1B, DUSP2, DTX1, HLA-B, PTEN, and TNFRSF14. Based on the LymphGen 1.0 classification tool, this case had an ST2 subtype prediction. The immune microenvironment was characterized by moderate infiltration of M2-like tumor-associated macrophages (TMAs) with positivity of CD163, CSF1R, CD85A (LILRB3), and PD-L1; moderate PD-1 positive T cells, and low FOXP3 regulatory T lymphocytes (Tregs). Immunohistochemical expression of PTX3 and TNFRSF14 was absent. Interestingly, the lymphoma cells were positive for HLA-DP-DR, IL-10, and RGS1, which are markers associated with poor prognosis in DLBCL. The patient was treated with R-CHOP therapy, and achieved a metabolically complete response.

15.
Nat Commun ; 14(1): 1122, 2023 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-36854674

RESUMO

The mechanisms triggering metastasis in pheochromocytoma/paraganglioma are unknown, hindering therapeutic options for patients with metastatic tumors (mPPGL). Herein we show by genomic profiling of a large cohort of mPPGLs that high mutational load, microsatellite instability and somatic copy-number alteration burden are associated with ATRX/TERT alterations and are suitable prognostic markers. Transcriptomic analysis defines the signaling networks involved in the acquisition of metastatic competence and establishes a gene signature related to mPPGLs, highlighting CDK1 as an additional mPPGL marker. Immunogenomics accompanied by immunohistochemistry identifies a heterogeneous ecosystem at the tumor microenvironment level, linked to the genomic subtype and tumor behavior. Specifically, we define a general immunosuppressive microenvironment in mPPGLs, the exception being PD-L1 expressing MAML3-related tumors. Our study reveals canonical markers for risk of metastasis, and suggests the usefulness of including immune parameters in clinical management for PPGL prognostication and identification of patients who might benefit from immunotherapy.


Assuntos
Neoplasias das Glândulas Suprarrenais , Segunda Neoplasia Primária , Paraganglioma , Feocromocitoma , Humanos , Neoplasias das Glândulas Suprarrenais/genética , Genômica , Paraganglioma/genética , Paraganglioma/imunologia , Feocromocitoma/genética , Feocromocitoma/imunologia , Microambiente Tumoral/genética
16.
Nat Med ; 29(3): 632-645, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36928817

RESUMO

The historical lack of preclinical models reflecting the genetic heterogeneity of multiple myeloma (MM) hampers the advance of therapeutic discoveries. To circumvent this limitation, we screened mice engineered to carry eight MM lesions (NF-κB, KRAS, MYC, TP53, BCL2, cyclin D1, MMSET/NSD2 and c-MAF) combinatorially activated in B lymphocytes following T cell-driven immunization. Fifteen genetically diverse models developed bone marrow (BM) tumors fulfilling MM pathogenesis. Integrative analyses of ∼500 mice and ∼1,000 patients revealed a common MAPK-MYC genetic pathway that accelerated time to progression from precursor states across genetically heterogeneous MM. MYC-dependent time to progression conditioned immune evasion mechanisms that remodeled the BM microenvironment differently. Rapid MYC-driven progressors exhibited a high number of activated/exhausted CD8+ T cells with reduced immunosuppressive regulatory T (Treg) cells, while late MYC acquisition in slow progressors was associated with lower CD8+ T cell infiltration and more abundant Treg cells. Single-cell transcriptomics and functional assays defined a high ratio of CD8+ T cells versus Treg cells as a predictor of response to immune checkpoint blockade (ICB). In clinical series, high CD8+ T/Treg cell ratios underlie early progression in untreated smoldering MM, and correlated with early relapse in newly diagnosed patients with MM under Len/Dex therapy. In ICB-refractory MM models, increasing CD8+ T cell cytotoxicity or depleting Treg cells reversed immunotherapy resistance and yielded prolonged MM control. Our experimental models enable the correlation of MM genetic and immunological traits with preclinical therapy responses, which may inform the next-generation immunotherapy trials.


Assuntos
Mieloma Múltiplo , Camundongos , Animais , Mieloma Múltiplo/terapia , Mieloma Múltiplo/tratamento farmacológico , Linfócitos T CD8-Positivos , Evasão da Resposta Imune , Linfócitos T Reguladores , Imunoterapia/efeitos adversos , Microambiente Tumoral/genética
18.
Histopathology ; 60(5): 785-92, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22321048

RESUMO

AIMS: Previous studies have identified clinicopathological and immunohistochemical differences among diffuse large B cell lymphomas (DLBCL) as a function of disease location. Nevertheless, there is a continuing tendency to generalize the prognostic value of various identified markers without taking into account tumour site. Accordingly, we analysed the prognostic value of several of the immunohistochemical markers that have been proposed for nodal DLBCL in a group of patients with gastric DLBCL. METHODS AND RESULTS: Using histochemical methods, CD10, Bcl-6, Gcet1, MUM-1, Bcl-2 and BLIMP-1 expression was investigated in 43 cases of gastric DBLCL. As in nodal DLBCLs, expression of BLIMP-1, and of Bcl-2 in non-germinal centre B cell-like (non-GCB) patients, was associated with a worse prognosis. However, unlike nodal DBLCL, there was no significant association of prognosis with expression of CD10, Bcl-6, Gcet1 or MUM-1, or with categorization according to Hans or Muris algorithms. CONCLUSIONS: Although most markers of prognosis in nodal DLBCL are not useful indicators for gastric DLBCL, Bcl-2 or BLIMP-1 expression does correlate with worse prognosis. These data support the notion that clinicopathological features in DLBCL vary according to the disease location.


Assuntos
Linfoma Difuso de Grandes Células B/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Proteínas Repressoras/metabolismo , Neoplasias Gástricas/metabolismo , Biomarcadores Tumorais/metabolismo , Terapia Combinada , Feminino , Humanos , Linfoma Difuso de Grandes Células B/diagnóstico , Linfoma Difuso de Grandes Células B/mortalidade , Linfoma Difuso de Grandes Células B/terapia , Masculino , Pessoa de Meia-Idade , Fator 1 de Ligação ao Domínio I Regulador Positivo , Prognóstico , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/mortalidade , Neoplasias Gástricas/terapia , Taxa de Sobrevida
19.
Am J Dermatopathol ; 34(7): 757-61, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22722467

RESUMO

CD4/CD8 double negative mycosis fungoides (MF) is a rare phenotypic variant of this epidermotropic cutaneous T-cell lymphoma. Clinically, this MF form manifests with unusual appearances such as annular lesions confined to one body region as in our patient in whom the lesions were found on the left lower leg. The cellular origin of CD4/CD8 double negative MF is unknown. In our case, the intraepidermal CD4/CD8 double negative clonal T-lymphocytes (CD2+, CD4-, CD8-, CD30-, beta-F1+) expressed programmed death-1 but were negative for CXCL-13 and cytotoxic molecules (TIA-1, granzyme B, perforin). Our observation may give an insight into the histogenesis of this unique MF variant and may also be of therapeutic significance because programmed death-1 may serve as a target for therapeutic intervention.


Assuntos
Biomarcadores Tumorais/análise , Antígenos CD4/análise , Antígenos CD8/análise , Micose Fungoide/imunologia , Receptor de Morte Celular Programada 1/análise , Neoplasias Cutâneas/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Idoso , Biópsia , Feminino , Rearranjo Gênico da Cadeia gama dos Receptores de Antígenos dos Linfócitos T , Humanos , Imuno-Histoquímica , Imunofenotipagem , Micose Fungoide/genética , Micose Fungoide/patologia , Micose Fungoide/terapia , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/terapia , Linfócitos T Auxiliares-Indutores/patologia
20.
Cancers (Basel) ; 14(21)2022 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-36358737

RESUMO

Artificial intelligence (AI) can identify actionable oncology biomarkers. This research integrates our previous analyses of non-Hodgkin lymphoma. We used gene expression and immunohistochemical data, focusing on the immune checkpoint, and added a new analysis of macrophages, including 3D rendering. The AI comprised machine learning (C5, Bayesian network, C&R, CHAID, discriminant analysis, KNN, logistic regression, LSVM, Quest, random forest, random trees, SVM, tree-AS, and XGBoost linear and tree) and artificial neural networks (multilayer perceptron and radial basis function). The series included chronic lymphocytic leukemia, mantle cell lymphoma, follicular lymphoma, Burkitt, diffuse large B-cell lymphoma, marginal zone lymphoma, and multiple myeloma, as well as acute myeloid leukemia and pan-cancer series. AI classified lymphoma subtypes and predicted overall survival accurately. Oncogenes and tumor suppressor genes were highlighted (MYC, BCL2, and TP53), along with immune microenvironment markers of tumor-associated macrophages (M2-like TAMs), T-cells and regulatory T lymphocytes (Tregs) (CD68, CD163, MARCO, CSF1R, CSF1, PD-L1/CD274, SIRPA, CD85A/LILRB3, CD47, IL10, TNFRSF14/HVEM, TNFAIP8, IKAROS, STAT3, NFKB, MAPK, PD-1/PDCD1, BTLA, and FOXP3), apoptosis (BCL2, CASP3, CASP8, PARP, and pathway-related MDM2, E2F1, CDK6, MYB, and LMO2), and metabolism (ENO3, GGA3). In conclusion, AI with immuno-oncology markers is a powerful predictive tool. Additionally, a review of recent literature was made.

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