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1.
Oxid Med Cell Longev ; 2021: 5633514, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34457116

RESUMO

This study sought to perform integrative analysis of the immune/methylation/autophagy landscape on breast cancer prognosis and single-cell genotypes. Breast Cancer Recurrence Risk Score (BCRRS) and Breast Cancer Prognostic Risk Score (BCPRS) were determined based on 6 prognostic IMAAGs obtained from the TCGA-BRCA cohort. BCRRS and BCPRS, respectively, were used to construct a risk prediction model of overall survival and progression-free survival. Predictive capacity of the model was evaluated using clinical data. Analysis showed that BCRRS is associated with a high risk of stroke. In addition, PPI and drug-ceRNA networks based on differences in BCPRS were constructed. Single cells were genotyped through integrated scRNA-seq of the TNBC samples based on clustering results of BCPRS-related genes. The findings of this study show the potential regulatory effects of IMAAGs on breast cancer tumor microenvironment. High AUCs of 0.856 and 0.842 were obtained for the OS and PFS prognostic models, respectively. scRNA-seq analysis showed high expression levels of adipocytes and adipose tissue macrophages (ATMs) in high BCPRS clusters. Moreover, analysis of ligand-receptor interactions and potential regulatory mechanisms were performed. The LINC00276&MALAT1/miR-206/FZD4-Wnt7b pathway was also identified which may be useful in future research on targets against breast cancer metastasis and recurrence. Neural network-based deep learning models using BCPRS-related genes showed that these genes can be used to map the tumor microenvironment. In summary, analysis of IMAAGs, BCPRS, and BCRRS provides information on the breast cancer microenvironment at both the macro- and microlevels and provides a basis for development of personalized treatment therapy.


Assuntos
Autofagia , Biomarcadores Tumorais/análise , Neoplasias da Mama/patologia , Metilação de DNA , Análise de Célula Única/métodos , Acidente Vascular Cerebral/patologia , Microambiente Tumoral/imunologia , Neoplasias da Mama/genética , Neoplasias da Mama/imunologia , Neoplasias da Mama/terapia , Terapia Combinada , Feminino , Seguimentos , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes , Genótipo , Humanos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/imunologia , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/terapia , Prognóstico , Medição de Risco/métodos , Acidente Vascular Cerebral/genética , Acidente Vascular Cerebral/imunologia , Acidente Vascular Cerebral/terapia , Taxa de Sobrevida , Transcriptoma
2.
Int J Mol Sci ; 22(16)2021 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-34445415

RESUMO

Chimeric antigen receptor (CAR)-T cells are effective in the treatment of hematologic malignancies but have shown limited efficacy against solid tumors. Here, we demonstrated an approach to inhibit recurrence of B cell lymphoma by co-expressing both a human anti-CD19-specific single-chain variable fragment (scFv) CAR (CD19 CAR) and a TGF-ß/IL-7 chimeric switch receptor (tTRII-I7R) in T cells (CD19 CAR-tTRII-I7R-T cells). The tTRII-I7R was designed to convert immunosuppressive TGF-ß signaling into immune-activating IL-7 signaling. The effect of TGF-ß on CD19 CAR-tTRII-I7R-T cells was assessed by western blotting. Target-specific killing by CD19 CAR-tTRII-I7R-T cells was evaluated by Eu-TDA assay. Daudi tumor-bearing NSG (NOD/SCID/IL2Rγ-/-) mice were treated with CD19 CAR-tTRII-I7R-T cells to analyze the in vivo anti-tumor effect. In vitro, CD19 CAR-tTRII-I7R-T cells had a lower level of phosphorylated SMAD2 and a higher level of target-specific cytotoxicity than controls in the presence of rhTGF-ß1. In the animal model, the overall survival and recurrence-free survival of mice that received CD19 CAR-tTRII-I7R-T cells were significantly longer than in control mice. These findings strongly suggest that CD19 CAR-tTRII-I7R-T cell therapy provides a new strategy for long-lasting, TGF-ß-resistant anti-tumor effects against B cell lymphoma, which may lead ultimately to increased clinical efficacy.


Assuntos
Antígenos CD19/imunologia , Interleucina-7/genética , Linfoma de Células B/terapia , Recidiva Local de Neoplasia/terapia , Anticorpos de Cadeia Única/metabolismo , Fator de Crescimento Transformador beta/genética , Animais , Células Cultivadas , Feminino , Humanos , Imunoterapia Adotiva , Interleucina-7/metabolismo , Células K562 , Linfoma de Células B/imunologia , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Recidiva Local de Neoplasia/imunologia , Receptores de Antígenos Quiméricos/metabolismo , Transdução de Sinais , Fator de Crescimento Transformador beta/metabolismo , Resultado do Tratamento , Ensaios Antitumorais Modelo de Xenoenxerto
3.
Nat Med ; 27(9): 1536-1543, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34341578

RESUMO

Gemcitabine-cisplatin (GP) chemotherapy is the standard first-line systemic treatment for recurrent or metastatic nasopharyngeal carcinoma (RM-NPC). In this international, double-blind, phase 3 trial (ClinicalTrials.gov identifier: NCT03581786), 289 patients with RM-NPC and no previous chemotherapy for recurrent or metastatic disease were randomized (1/1) to receive either toripalimab, a monoclonal antibody against human programmed death-1 (PD-1), or placebo in combination with GP every 3 weeks for up to six cycles, followed by monotherapy with toripalimab or placebo. The primary endpoint was progression-free survival (PFS) as assessed by a blinded independent review committee according to RECIST v.1.1. At the prespecified interim PFS analysis, a significant improvement in PFS was detected in the toripalimab arm compared to the placebo arm: median PFS of 11.7 versus 8.0 months, hazard ratio (HR) = 0.52 (95% confidence interval (CI): 0.36-0.74), P = 0.0003. An improvement in PFS was observed across key subgroups, including PD-L1 expression. As of 18 February 2021, a 40% reduction in risk of death was observed in the toripalimab arm compared to the placebo arm (HR = 0.603 (95% CI: 0.364-0.997)). The incidence of grade ≥3 adverse events (AEs) (89.0 versus 89.5%), AEs leading to discontinuation of toripalimab/placebo (7.5 versus 4.9%) and fatal AEs (2.7 versus 2.8%) was similar between the two arms; however, immune-related AEs (39.7 versus 18.9%) and grade ≥3 infusion reactions (7.5 versus 0.7%) were more frequent in the toripalimab arm. In conclusion, the addition of toripalimab to GP chemotherapy as a first-line treatment for patients with RM-NPC provided superior PFS compared to GP alone, and with a manageable safety profile.


Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Carcinoma Nasofaríngeo/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Adulto , Idoso , Anticorpos Monoclonais Humanizados/efeitos adversos , Antineoplásicos Imunológicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/genética , Cisplatino/administração & dosagem , Cisplatino/efeitos adversos , Desoxicitidina/administração & dosagem , Desoxicitidina/efeitos adversos , Desoxicitidina/análogos & derivados , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Carcinoma Nasofaríngeo/imunologia , Carcinoma Nasofaríngeo/patologia , Recidiva Local de Neoplasia/imunologia , Recidiva Local de Neoplasia/patologia , Intervalo Livre de Progressão
4.
Front Immunol ; 12: 652054, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34305889

RESUMO

Head and neck cancer (HNC) is the sixth most common malignancy worldwide; head and neck squamous cell carcinoma (HNSCC) account for the most cases of HNC. Past smoking and alcohol consumption are common risk factors of HNSCC; however, an increasing number of cases associated with human papillomavirus (HPV) infection have been reported in recent years. The treatment of HNSCC is integrated and multimodal including traditional surgery, radiotherapy, chemotherapy, and targeted therapy. Since pembrolizumab was approved in 2016, an increasing number of studies have focused on immunotherapy. However, not all of HNSCC patients have a better outcome on immunotherapy. Immunotherapy has been reported to be more effective in HPV-positive patients, but its molecular mechanism is still unclear. Some researchers have proposed that the high proportion of infiltrating immune cells in HPV-positive tumors and the difference in immune checkpoint expression level may be the reasons for their better response. As a result, a series of individualized immunotherapy trials have also been conducted in HPV-positive patients. This paper summarizes the current status of HNSCC immunotherapy, individualized immunotherapy in HPV-positive patients, and immune differences in HPV-positive tumors to provide new insights into HNSCC immunotherapy and try to identify patients who may benefit from immunotherapy.


Assuntos
Neoplasias de Cabeça e Pescoço/terapia , Imunoterapia/métodos , Recidiva Local de Neoplasia/terapia , Infecções por Papillomavirus/terapia , Carcinoma de Células Escamosas de Cabeça e Pescoço/terapia , Alphapapillomavirus/imunologia , Antineoplásicos Imunológicos/uso terapêutico , Quimiorradioterapia Adjuvante/métodos , Quimioterapia Adjuvante/métodos , Neoplasias de Cabeça e Pescoço/imunologia , Neoplasias de Cabeça e Pescoço/mortalidade , Neoplasias de Cabeça e Pescoço/virologia , Humanos , Inibidores de Checkpoint Imunológico/uso terapêutico , Terapia Neoadjuvante/métodos , Recidiva Local de Neoplasia/imunologia , Recidiva Local de Neoplasia/mortalidade , Recidiva Local de Neoplasia/virologia , Estadiamento de Neoplasias , Infecções por Papillomavirus/imunologia , Infecções por Papillomavirus/mortalidade , Infecções por Papillomavirus/virologia , Intervalo Livre de Progressão , Ensaios Clínicos Controlados Aleatórios como Assunto , Carcinoma de Células Escamosas de Cabeça e Pescoço/imunologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/mortalidade , Carcinoma de Células Escamosas de Cabeça e Pescoço/virologia
5.
Nat Med ; 27(9): 1544-1552, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34253928

RESUMO

Locoregional delivery of chimeric antigen receptor (CAR) T cells has resulted in objective responses in adults with glioblastoma, but the feasibility and tolerability of this approach is yet to be evaluated for pediatric central nervous system (CNS) tumors. Here we show that engineering of a medium-length CAR spacer enhances the therapeutic efficacy of human erb-b2 receptor tyrosine kinase 2 (HER2)-specific CAR T cells in an orthotopic xenograft medulloblastoma model. We translated these findings into BrainChild-01 ( NCT03500991 ), an ongoing phase 1 clinical trial at Seattle Children's evaluating repetitive locoregional dosing of these HER2-specific CAR T cells to children and young adults with recurrent/refractory CNS tumors, including diffuse midline glioma. Primary objectives are assessing feasibility, safety and tolerability; secondary objectives include assessing CAR T cell distribution and disease response. In the outpatient setting, patients receive infusions via CNS catheter into either the tumor cavity or the ventricular system. The initial three patients experienced no dose-limiting toxicity and exhibited clinical, as well as correlative laboratory, evidence of local CNS immune activation, including high concentrations of CXCL10 and CCL2 in the cerebrospinal fluid. This interim report supports the feasibility of generating HER2-specific CAR T cells for repeated dosing regimens and suggests that their repeated intra-CNS delivery might be well tolerated and activate a localized immune response in pediatric and young adult patients.


Assuntos
Glioblastoma/terapia , Imunoterapia Adotiva/efeitos adversos , Receptor ErbB-2/genética , Receptores de Antígenos Quiméricos/genética , Antígenos CD19/imunologia , Quimiocina CCL2/genética , Quimiocina CXCL10/genética , Feminino , Glioblastoma/líquido cefalorraquidiano , Glioblastoma/genética , Glioblastoma/imunologia , Humanos , Imunidade/genética , Imunidade/imunologia , Estimativa de Kaplan-Meier , Masculino , Recidiva Local de Neoplasia/líquido cefalorraquidiano , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/imunologia , Recidiva Local de Neoplasia/terapia , Receptor ErbB-2/antagonistas & inibidores , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/imunologia , Receptores de Antígenos de Linfócitos T/uso terapêutico , Receptores de Antígenos Quiméricos/imunologia , Linfócitos T/imunologia , Ensaios Antitumorais Modelo de Xenoenxerto
6.
Nat Immunol ; 22(8): 983-995, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34282330

RESUMO

The transcription factors nuclear factor of activated T cells (NFAT) and activator protein 1 (AP-1; Fos-Jun) cooperate to promote the effector functions of T cells, but NFAT in the absence of AP-1 imposes a negative feedback program of T cell hyporesponsiveness (exhaustion). Here, we show that basic leucine zipper ATF-like transcription factor (BATF) and interferon regulatory factor 4 (IRF4) cooperate to counter T cell exhaustion in mouse tumor models. Overexpression of BATF in CD8+ T cells expressing a chimeric antigen receptor (CAR) promoted the survival and expansion of tumor-infiltrating CAR T cells, increased the production of effector cytokines, decreased the expression of inhibitory receptors and the exhaustion-associated transcription factor TOX and supported the generation of long-lived memory T cells that controlled tumor recurrence. These responses were dependent on BATF-IRF interaction, since cells expressing a BATF variant unable to interact with IRF4 did not survive in tumors and did not effectively delay tumor growth. BATF may improve the antitumor responses of CAR T cells by skewing their phenotypes and transcriptional profiles away from exhaustion and towards increased effector function.


Assuntos
Fatores de Transcrição de Zíper de Leucina Básica/metabolismo , Linfócitos T CD8-Positivos/imunologia , Fatores Reguladores de Interferon/metabolismo , Linfócitos do Interstício Tumoral/imunologia , Neoplasias/imunologia , Receptores de Antígenos Quiméricos/imunologia , Animais , Linhagem Celular Tumoral , Modelos Animais de Doenças , Feminino , Humanos , Masculino , Melanoma Experimental , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Fatores de Transcrição NFATC/metabolismo , Recidiva Local de Neoplasia/imunologia , Fator de Transcrição AP-1/metabolismo
7.
Immunity ; 54(8): 1825-1840.e7, 2021 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-34270940

RESUMO

Hepatocellular carcinoma (HCC) often develops following chronic hepatitis B virus (HBV) infection and responds poorly to immune checkpoint blockade. Here, we examined the antigen specificities of HCC-infiltrating T cells and their relevance to tumor control. Using highly multiplexed peptide-MHC tetramer staining of unexpanded cells from blood, liver, and tumor tissues from 46 HCC patients, we detected 91 different antigen-specific CD8+ T cell populations targeting HBV, neoantigen, tumor-associated, and disease-unrelated antigens. Parallel high-dimensional analysis delineated five distinct antigen-specific tissue-resident memory T (Trm) cell populations. Intratumoral and intrahepatic HBV-specific T cells were enriched for two Trm cell subsets that were PD-1loTOXlo, despite being clonally expanded. High frequencies of intratumoral terminally exhausted T cells were uncommon. Patients with tumor-infiltrating HBV-specific CD8+ Trm cells exhibited longer-term relapse-free survival. Thus, non-terminally exhausted HBV-specific CD8+ Trm cells show hallmarks of active involvement and effective antitumor response, implying that these cells could be harnessed for therapeutic purposes.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Carcinoma Hepatocelular/imunologia , Memória Imunológica/imunologia , Neoplasias Hepáticas/imunologia , Linfócitos do Interstício Tumoral/imunologia , Antígenos de Neoplasias/imunologia , Carcinoma Hepatocelular/patologia , Vírus da Hepatite B/imunologia , Hepatite B Crônica/imunologia , Proteínas de Grupo de Alta Mobilidade/metabolismo , Humanos , Neoplasias Hepáticas/patologia , Recidiva Local de Neoplasia/imunologia , Recidiva Local de Neoplasia/prevenção & controle , Receptor de Morte Celular Programada 1/metabolismo , Células Tumorais Cultivadas
8.
J Cancer Res Clin Oncol ; 147(9): 2609-2619, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34115241

RESUMO

BACKGROUND: Intra-abdominal infection after curative surgery for colorectal cancer is a serious complication associated with an increased risk of recurrence. Lipopolysaccharides (LPS)-an essential component of the cell wall of Gram-negative bacteria-were found to exert a protumorigenic effect by stimulating the inflammatory pathology and formation of neutrophil extracellular traps (NETs). This study was conducted to test whether LPS-induced formation of NETs promotes the development of cancer and metastasis. METHODS: The clinical characteristics, incidence of relapse, and serum myeloperoxidase-DNA complexes of 40 patients with infection and 40 patients without infection after curative surgery were analyzed. The effects of LPS on the induction of NETs were evaluated in a mouse model of colorectal cancer and liver metastasis. The toll-like receptor 9 (TLR9)-a DNA receptor-was knocked down to assess its effect on the mitogen-activated protein kinase pathway and activities implicated in the formation of NETs. RESULTS: Analysis of the clinical data obtained from these patients showed the significant relation of the formation of NETs and incidence of metastasis and survival rates. Subsequent in vitro experiments revealed an increased level of citrullinated-histone H3 and myeloperoxidase-DNA in LPS-injected mice with colorectal cancer. In the mimic metastatic model, injection of LPS enhanced the metastatic capacity, which was then attenuated by DNase I. This suggested that the formation of NETs was activated by LPS. Injection of TLR9-knockdown HCT116 cells in mice, followed by induction through LPS, mitigated the level of citrullinated-histone H3 and myeloperoxidase-DNA. This finding implied that the formation of NETs was suppressed. CONCLUSION: These findings shed light on the mechanism underlying the relationship between the elevated rate of colorectal cancer recurrence in patients who underwent surgery and the incidence of infection. This mechanism involves the protumorigenic activities of LPS-induced formation of NETs. The NETs which could be mediated by the TLR9 and the mitogen-activated protein kinase signaling pathway.


Assuntos
Neoplasias Colorretais/patologia , Modelos Animais de Doenças , Armadilhas Extracelulares , Lipopolissacarídeos/efeitos adversos , Neoplasias Hepáticas/secundário , Recidiva Local de Neoplasia/patologia , Neutrófilos/imunologia , Idoso , Animais , Apoptose , Estudos de Casos e Controles , Movimento Celular , Proliferação de Células , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/cirurgia , Feminino , Seguimentos , Humanos , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/cirurgia , Masculino , Recidiva Local de Neoplasia/imunologia , Recidiva Local de Neoplasia/cirurgia , Prognóstico , Taxa de Sobrevida , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
10.
Medicine (Baltimore) ; 100(25): e26214, 2021 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-34160385

RESUMO

ABSTRACT: To investigate the relationship between the changes in circulating CD45RO+T lymphocyte subsets following neoadjuvant therapy for rectal cancer in patients with locally advanced rectal cancer.The clinicopathological data of 185 patients with rectal cancer who received neoadjuvant therapy in the General Surgery Department of Beijing Chaoyang Hospital affiliated to Capital Medical University from June 2015 to June 2017 were analyzed. Venous blood samples were collected 1 week before neoadjuvant therapy and 1 week before surgery, and the expression of CD45RO+T was detected by flow cytometry. The receiver operating characteristic curve analysis was used to determine the optimal cut-off point of CD45RO+ratio. Log-rank test and multivariate Cox regression were used to analyze the overall survival rate (OS) and disease-free survival rate (DFS) associated with CD45RO+ratio.Circulating CD45RO+ratio of 1.07 was determined as the optimal cut-off point and CD45RO+ratio-high was associated with lower tumor regression grade grading (P = .031), T stage (P = .001), and tumor node metastasis (TNM) stage (P = .012). The 3-year DFS and OS rate in the CD45RO+ratio-high group was significantly higher than that in the CD45RO+ratio-low group (89.2% vs 60.1%, P<.001; 94.4% vs 73.2%, P<.001). The multivariate Cox analysis revealed that elevated CD45RO+ratio was an independent factor for better DFS (OR, 0.339; 95% CI, 0.153-0.752; P = .008) and OS (OR, 0.244; 95% CI,0.082-0.726; P = .011).Circulating CD45RO+ratio could predict the tumor regression grade of neoadjuvant therapy for rectal cancer, as well as long-term prognosis. These findings could be used to stratify patients and develop alternative strategies for adjuvant therapy.


Assuntos
Quimiorradioterapia Adjuvante/métodos , Terapia Neoadjuvante/métodos , Recidiva Local de Neoplasia/epidemiologia , Neoplasias Retais/terapia , Subpopulações de Linfócitos T/imunologia , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Separação Celular , Colonoscopia , Ciclofosfamida/uso terapêutico , Intervalo Livre de Doença , Doxorrubicina/uso terapêutico , Citometria de Fluxo , Seguimentos , Humanos , Antígenos Comuns de Leucócito/metabolismo , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/diagnóstico , Recidiva Local de Neoplasia/imunologia , Estadiamento de Neoplasias , Oxaliplatina/uso terapêutico , Prednisona/uso terapêutico , Período Pré-Operatório , Protectomia , Prognóstico , Radioterapia de Intensidade Modulada , Neoplasias Retais/sangue , Neoplasias Retais/imunologia , Neoplasias Retais/mortalidade , Reto/diagnóstico por imagem , Reto/patologia , Reto/cirurgia , Estudos Retrospectivos , Taxa de Sobrevida , Subpopulações de Linfócitos T/metabolismo , Vindesina/uso terapêutico
11.
Front Immunol ; 12: 652105, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33968052

RESUMO

Transplantation of allogeneic hematopoietic cells faces two barriers: failure of engraftment due to a host versus graft reaction, and the attack of donor cells against the patient, the graft versus host (GVH) reaction. This reaction may lead to GVH disease (GVHD), but in patients transplanted due to leukemia or other malignant disorders, this may also convey the benefit of a graft versus leukemia (GVL) effect. The interplay of transplant conditioning with donor and host cells and the environment in the patient is complex. The microbiome, particularly in the intestinal tract, profoundly affects these interactions, directly and via soluble mediators, which also reach other host organs. The microenvironment is further altered by the modifying effect of malignant cells on marrow niches, favoring the propagation of the malignant cells. The development of stable mixed donor/host chimerism has the potential of GVHD prevention without necessarily increasing the risk of relapse. There has been remarkable progress with novel conditioning regimens and selective T-cell manipulation aimed at securing engraftment while preventing GVHD without ablating the GVL effect. Interventions to alter the microenvironment and change the composition of the microbiome and its metabolic products may modify graft/host interactions, thereby further reducing GVHD, while enhancing the GVL effect. The result should be improved transplant outcome.


Assuntos
Quimerismo , Doença Enxerto-Hospedeiro/prevenção & controle , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Leucemia/terapia , Recidiva Local de Neoplasia/prevenção & controle , Intervalo Livre de Doença , Doença Enxerto-Hospedeiro/genética , Doença Enxerto-Hospedeiro/imunologia , Reação Enxerto-Hospedeiro/efeitos dos fármacos , Reação Enxerto-Hospedeiro/genética , Reação Enxerto-Hospedeiro/imunologia , Efeito Enxerto vs Leucemia/genética , Efeito Enxerto vs Leucemia/imunologia , Humanos , Leucemia/genética , Leucemia/imunologia , Leucemia/mortalidade , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/imunologia , Condicionamento Pré-Transplante/métodos , Transplante Homólogo/efeitos adversos , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia
12.
J Cell Mol Med ; 25(12): 5534-5546, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33960636

RESUMO

Glioblastoma (GBM) is the most common malignant intracranial tumour with intrinsic infiltrative characteristics, which could lead to most patients eventually relapse. The prognosis of recurrent GBM patients remains unsatisfactory. Cancer cell infiltration and their interaction with the tumour microenvironment (TME) could promote tumour recurrence and treatment resistance. In our study, we aimed to identify potential tumour target correlated with rGBM microenvironment based on the gene expression profiles and clinical information of rGBM patients from The Cancer Genome Atlas (TCGA) database. LRRC15 gene with prognostic value was screened by univariate and multivariate analysis, and the correlation between macrophages and LRRC15 was identified as well. Furthermore, the prognosis correlation and immune characteristics of LRRC15 were validated using the Chinese Glioma Genome Atlas (CGGA) database and our clinical tissues by immunochemistry assay. Additionally, we utilized the transwell assay and carboxy fluorescein succinimidyl ester (CFSE) tracking to further confirm the effects of LRRC15 on attracting microglia/macrophages and tumour cell proliferation in the TME. Gene profiles-based rGBM microenvironment identified that LRRC15 could act in collusion with microglia/macrophages in the rGBM microenvironment to promote the poor prognosis, especially in mesenchymal subtype, indicating the strategies of targeting LRRC15 to improve macrophages-based immunosuppressive effects could be promising for rGBM treatments.


Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias Encefálicas/patologia , Regulação Neoplásica da Expressão Gênica , Glioblastoma/patologia , Macrófagos/imunologia , Proteínas de Membrana/metabolismo , Recidiva Local de Neoplasia/patologia , Microambiente Tumoral/imunologia , Biomarcadores Tumorais/genética , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/imunologia , Perfilação da Expressão Gênica , Glioblastoma/genética , Glioblastoma/imunologia , Humanos , Proteínas de Membrana/genética , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/imunologia , Prognóstico , Taxa de Sobrevida
13.
Int J Biochem Cell Biol ; 136: 106002, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33962022

RESUMO

Preclinical data suggest that head and neck cancer is an intrinsically immunosuppressive disease with abnormal inflammatory components in the tumor microenvironment. The development of immune checkpoint inhibitors, which are monoclonal antibodies capable of inhibiting immune suppressive signals to prime anticancer immunity, has revolutionized the therapeutic landscape in recurrent/metastatic head and neck cancer. However, patients with head and neck cancer present primary resistance to immunotherapy. Many ongoing trials include combinations of immunotherapy with different therapeutic interventions, aiming to improve response rates and overall survival. As novel therapy strategies are leveraged, the significance of immunotherapy in recurrent/metastatic head and neck cancer continues to be revealed. This review aims to summarize combinational immunotherapy in head and neck cancer.


Assuntos
Neoplasias de Cabeça e Pescoço/terapia , Imunoterapia/métodos , Recidiva Local de Neoplasia/terapia , Carcinoma de Células Escamosas de Cabeça e Pescoço/terapia , Animais , Neoplasias de Cabeça e Pescoço/imunologia , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Recidiva Local de Neoplasia/imunologia , Recidiva Local de Neoplasia/patologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/imunologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/secundário , Microambiente Tumoral
14.
Nat Med ; 27(6): 985-992, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33941922

RESUMO

Despite initial responses1-3, most melanoma patients develop resistance4 to immune checkpoint blockade (ICB). To understand the evolution of resistance, we studied 37 tumor samples over 9 years from a patient with metastatic melanoma with complete clinical response to ICB followed by delayed recurrence and death. Phylogenetic analysis revealed co-evolution of seven lineages with multiple convergent, but independent resistance-associated alterations. All recurrent tumors emerged from a lineage characterized by loss of chromosome 15q, with post-treatment clones acquiring additional genomic driver events. Deconvolution of bulk RNA sequencing and highly multiplexed immunofluorescence (t-CyCIF) revealed differences in immune composition among different lineages. Imaging revealed a vasculogenic mimicry phenotype in NGFRhi tumor cells with high PD-L1 expression in close proximity to immune cells. Rapid autopsy demonstrated two distinct NGFR spatial patterns with high polarity and proximity to immune cells in subcutaneous tumors versus a diffuse spatial pattern in lung tumors, suggesting different roles of this neural-crest-like program in different tumor microenvironments. Broadly, this study establishes a high-resolution map of the evolutionary dynamics of resistance to ICB, characterizes a de-differentiated neural-crest tumor population in melanoma immunotherapy resistance and describes site-specific differences in tumor-immune interactions via longitudinal analysis of a patient with melanoma with an unusual clinical course.


Assuntos
Antígeno B7-H1/genética , Inibidores de Checkpoint Imunológico/uso terapêutico , Melanoma/terapia , Proteínas do Tecido Nervoso/genética , Receptores de Fator de Crescimento Neural/genética , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/imunologia , Cromossomos Humanos Par 15/genética , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Inibidores de Checkpoint Imunológico/efeitos adversos , Imunoterapia/efeitos adversos , Masculino , Melanoma/genética , Melanoma/imunologia , Melanoma/patologia , Metástase Neoplásica , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/imunologia , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/terapia , Proteínas do Tecido Nervoso/imunologia , Filogenia , Receptores de Fator de Crescimento Neural/imunologia , Microambiente Tumoral/efeitos dos fármacos
15.
Nat Commun ; 12(1): 2559, 2021 05 07.
Artigo em Inglês | MEDLINE | ID: mdl-33963182

RESUMO

Multiple myeloma (MM) is characterized by the uncontrolled proliferation of plasma cells. Despite recent treatment advances, it is still incurable as disease progression is not fully understood. To investigate MM and its immune environment, we apply single cell RNA and linked-read whole genome sequencing to profile 29 longitudinal samples at different disease stages from 14 patients. Here, we collect 17,267 plasma cells and 57,719 immune cells, discovering patient-specific plasma cell profiles and immune cell expression changes. Patients with the same genetic alterations tend to have both plasma cells and immune cells clustered together. By integrating bulk genomics and single cell mapping, we track plasma cell subpopulations across disease stages and find three patterns: stability (from precancer to diagnosis), and gain or loss (from diagnosis to relapse). In multiple patients, we detect "B cell-featured" plasma cell subpopulations that cluster closely with B cells, implicating their cell of origin. We validate AP-1 complex differential expression (JUN and FOS) in plasma cell subpopulations using CyTOF-based protein assays, and integrated analysis of single-cell RNA and CyTOF data reveals AP-1 downstream targets (IL6 and IL1B) potentially leading to inflammation regulation. Our work represents a longitudinal investigation for tumor and microenvironment during MM progression and paves the way for expanding treatment options.


Assuntos
Linfócitos B/metabolismo , Regulação Neoplásica da Expressão Gênica/genética , Mieloma Múltiplo/genética , Mieloma Múltiplo/imunologia , Recidiva Local de Neoplasia/genética , Microambiente Tumoral/imunologia , Idoso , Linfócitos B/citologia , Linfócitos B/imunologia , Linhagem da Célula , Evolução Clonal/genética , Estudos de Coortes , Progressão da Doença , Feminino , Regulação Neoplásica da Expressão Gênica/imunologia , Haplótipos , Humanos , Interleucina-1beta/sangue , Interleucina-6/sangue , Masculino , Espectrometria de Massas , Pessoa de Meia-Idade , Família Multigênica , Mieloma Múltiplo/sangue , Mieloma Múltiplo/patologia , Mutação , Recidiva Local de Neoplasia/sangue , Recidiva Local de Neoplasia/imunologia , Proteínas Proto-Oncogênicas c-fos/sangue , Proteínas Proto-Oncogênicas c-jun/sangue , RNA-Seq , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Análise de Célula Única
16.
Cancer Sci ; 112(7): 2895-2904, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33931909

RESUMO

Several therapeutic regimens, including neoadjuvant chemoradiation therapy (NACRT), have been reported to serve as anticancer immune effectors. However, there remain insufficient data regarding the immune response after NACRT in pancreatic ductal adenocarcinoma (PDAC) patients. Data from 40 PDAC patients that underwent surgical resection after NACRT (NACRT group) and 30 PDAC patients that underwent upfront surgery (US group) were analyzed to examine alterations in immune cell counts/distribution using a multiplexed fluorescent immunohistochemistry system. All immune cells were more abundant in the cancer stroma than in the cancer cell nest regardless of preoperative therapy. Although the stromal counts of CD4+ T cells, CD20+ B cells, and Foxp3+ T cells in the NACRT group were drastically decreased in comparison with those of the US group, counts of these cell types in the cancer cell nest were not significantly different between the two groups. In contrast, CD204+ macrophage counts in the cancer stroma were similar between the NACRT and US groups, while those in the cancer cell nests were significantly reduced in the NACRT group. Following multivariate analysis, only a high CD204+ macrophage count in the cancer cell nest remained an independent predictor of shorter relapse-free survival (odds ratio = 2.37; P = .033). NACRT for PDAC decreased overall immune cell counts, but these changes were heterogeneous within the cancer cell nests and cancer stroma. The CD204+ macrophage count in the cancer cell nest is an independent predictor of early disease recurrence in PDAC patients after NACRT.


Assuntos
Carcinoma Ductal Pancreático/terapia , Quimiorradioterapia Adjuvante , Imunidade Celular , Neoplasias Pancreáticas/terapia , Microambiente Tumoral/imunologia , Idoso , Antígenos CD20 , Linfócitos B/imunologia , Contagem de Linfócito CD4 , Carcinoma Ductal Pancreático/imunologia , Carcinoma Ductal Pancreático/cirurgia , Feminino , Fatores de Transcrição Forkhead/imunologia , Humanos , Imuno-Histoquímica/métodos , Contagem de Linfócitos , Macrófagos/imunologia , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Terapia Neoadjuvante/métodos , Recidiva Local de Neoplasia/imunologia , Neoplasias Pancreáticas/imunologia , Neoplasias Pancreáticas/cirurgia , Cuidados Pré-Operatórios
17.
Cancer Invest ; 39(6-7): 550-558, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34027748

RESUMO

This study aimed to examine the prognostic significance of peripheral absolute monocyte count (AMC) in combination with absolute lymphocyte count (ALC) at the time of relapse in a cohort of 57 patients with early relapsed (first complete remission <12 months) acute myeloid leukemia (AML). Both univariate and multivariate Cox proportional hazard regression analyses revealed that normal AMC in combination with normal/high ALC (versus low/high AMC in combination with low ALC) was significantly associated with improved OS. We concluded that the combination of AMC and ALC could be used as a prognostic marker for survival outcomes in early relapsed AML.


Assuntos
Leucemia Mieloide Aguda/mortalidade , Leucócitos Mononucleares/metabolismo , Recidiva Local de Neoplasia/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Leucemia Mieloide Aguda/imunologia , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/imunologia , Prognóstico , Análise de Regressão , Estudos Retrospectivos , Análise de Sobrevida , Adulto Jovem
18.
Nat Immunol ; 22(6): 769-780, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34017122

RESUMO

Progression and persistence of malignancies are influenced by the local tumor microenvironment, and future eradication of currently incurable tumors will, in part, hinge on our understanding of malignant cell biology in the context of their nourishing surroundings. Here, we generated paired single-cell transcriptomic datasets of tumor cells and the bone marrow immune and stromal microenvironment in multiple myeloma. These analyses identified myeloma-specific inflammatory mesenchymal stromal cells, which spatially colocalized with tumor cells and immune cells and transcribed genes involved in tumor survival and immune modulation. Inflammatory stromal cell signatures were driven by stimulation with proinflammatory cytokines, and analyses of immune cell subsets suggested interferon-responsive effector T cell and CD8+ stem cell memory T cell populations as potential sources of stromal cell-activating cytokines. Tracking stromal inflammation in individuals over time revealed that successful antitumor induction therapy is unable to revert bone marrow inflammation, predicting a role for mesenchymal stromal cells in disease persistence.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Células-Tronco Mesenquimais/imunologia , Mieloma Múltiplo/imunologia , Recidiva Local de Neoplasia/imunologia , Microambiente Tumoral/imunologia , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Medula Óssea/efeitos dos fármacos , Medula Óssea/imunologia , Medula Óssea/patologia , Linhagem Celular Tumoral , Progressão da Doença , Feminino , Regulação Neoplásica da Expressão Gênica/imunologia , Humanos , Masculino , Células-Tronco Mesenquimais/patologia , Pessoa de Meia-Idade , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/patologia , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/prevenção & controle , Cultura Primária de Células , Estudos Prospectivos , RNA-Seq , Análise de Célula Única , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/genética
19.
Front Immunol ; 12: 642087, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33841425

RESUMO

Haploidentical hematopoietic stem cell transplantation (Haplo-HSCT) with high-dose cyclophosphamide (PTCy) has resulted in a low incidence of graft-vs.-host disease (GVHD), graft failure, and non-relapse mortality. However, post-transplantation relapse remains a common cause of treatment failure in high-risk patients. Unraveling the mechanisms of relapse is therefore crucial for designing effective relapse treatment strategies. One of these mechanisms is the loss of the mismatched HLA on the recipient's leukemic cells. To study the incidence and clinical relevance of this phenomenon, we analyzed 181 patients treated with Haplo-HSCT with PTCy (2007-2019), of which 37 relapsed patients after transplantation. According to the kit employed for HLA-loss analysis, among 22 relapsed patients, we identified HLA loss at relapse in 6 of the 22 patients (27%) studied. Based on the results obtained, the genomic loss of HLA was more common in females than males (66 vs. 33%) and HLA-loss relapses occurred later than classical relapses (345 vs. 166 days). Moreover, the patients with HLA-loss had a greater presence of active disease at the time of transplantation and had undergone a larger number of treatment lines than the group with classical relapses (66 vs. 43% and 66 vs. 18%, respectively). Four of these relapses were studied retrospectively, while two were studied prospectively, the results of which could be considered for patient management. Additionally, two relapsed patients analyzed retrospectively had myeloid neoplasms. One patient had not undergone any treatment, and three had undergone donor lymphocyte infusions (DLIs) and chemotherapy. All presented severe GVHD and disease progression. In contrast, the two patients studied prospectively had a lymphoid neoplasm and were not treated with DLIs. One of them was treated with chemotherapy but died from disease progression, and the other patient underwent a second Haplo-HSCT from a different donor and is still alive. We can conclude that the detection of HLA-loss at the onset of relapse after Haplo-HSCT with PTCy could help in clinical practice to select appropriate rescue treatment, thereby avoiding the use of DLIs or a second transplantation from the same donor.


Assuntos
Antígenos HLA/imunologia , Neoplasias Hematológicas/imunologia , Neoplasias Hematológicas/terapia , Transplante de Células-Tronco Hematopoéticas/métodos , Transplante Haploidêntico/métodos , Adolescente , Adulto , Idoso , Ciclofosfamida/uso terapêutico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Agonistas Mieloablativos/uso terapêutico , Recidiva Local de Neoplasia/imunologia , Recidiva , Evasão Tumoral/imunologia , Adulto Jovem
20.
Nat Commun ; 12(1): 2281, 2021 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-33863879

RESUMO

Interleukin (IL)-11 is a member of the IL-6 family of cytokines and is involved in multiple cellular responses, including tumor development. However, the origin and functions of IL-11-producing (IL-11+) cells are not fully understood. To characterize IL-11+ cells in vivo, we generate Il11 reporter mice. IL-11+ cells appear in the colon in murine tumor and acute colitis models. Il11ra1 or Il11 deletion attenuates the development of colitis-associated colorectal cancer. IL-11+ cells express fibroblast markers and genes associated with cell proliferation and tissue repair. IL-11 induces the activation of colonic fibroblasts and epithelial cells through phosphorylation of STAT3. Human cancer database analysis reveals that the expression of genes enriched in IL-11+ fibroblasts is elevated in human colorectal cancer and correlated with reduced recurrence-free survival. IL-11+ fibroblasts activate both tumor cells and fibroblasts via secretion of IL-11, thereby constituting a feed-forward loop between tumor cells and fibroblasts in the tumor microenvironment.


Assuntos
Adenoma/imunologia , Colite/patologia , Neoplasias Colorretais/imunologia , Fibroblastos/imunologia , Interleucina-11/metabolismo , Recidiva Local de Neoplasia/epidemiologia , Adenoma/genética , Adenoma/mortalidade , Adenoma/cirurgia , Idoso , Idoso de 80 Anos ou mais , Animais , Linhagem Celular Tumoral , Colite/induzido quimicamente , Colite/imunologia , Colo/citologia , Colo/imunologia , Colo/patologia , Colo/cirurgia , Neoplasias Colorretais/genética , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/cirurgia , Sulfato de Dextrana/administração & dosagem , Sulfato de Dextrana/toxicidade , Modelos Animais de Doenças , Intervalo Livre de Doença , Feminino , Fibroblastos/metabolismo , Regulação Neoplásica da Expressão Gênica/imunologia , Técnicas de Silenciamento de Genes , Genes Reporter , Proteínas de Fluorescência Verde/genética , Humanos , Interleucina-11/genética , Subunidade alfa de Receptor de Interleucina-11/genética , Subunidade alfa de Receptor de Interleucina-11/metabolismo , Mucosa Intestinal/citologia , Mucosa Intestinal/imunologia , Mucosa Intestinal/patologia , Estimativa de Kaplan-Meier , Masculino , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/imunologia , Organoides , Cultura Primária de Células , Estudos Retrospectivos , Transcriptoma/imunologia , Microambiente Tumoral/imunologia
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