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1.
Nat Commun ; 12(1): 5764, 2021 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-34599187

RESUMO

Regulatory T (Treg) cells are one of the major immunosuppressive cell types in cancer and a potential target for immunotherapy, but targeting tumor-infiltrating (TI) Treg cells has been challenging. Here, using single-cell RNA sequencing of immune cells from renal clear cell carcinoma (ccRCC) patients, we identify two distinct transcriptional fates for TI Treg cells, Fate-1 and Fate-2. The Fate-1 signature is associated with a poorer prognosis in ccRCC and several other solid cancers. CD177, a cell surface protein normally expressed on neutrophil, is specifically expressed on Fate-1 TI Treg cells in several solid cancer types, but not on other TI or peripheral Treg cells. Mechanistically, blocking CD177 reduces the suppressive activity of Treg cells in vitro, while Treg-specific deletion of Cd177 leads to decreased tumor growth and reduced TI Treg frequency in mice. Our results thus uncover a functional CD177+ TI Treg population that may serve as a target for TI Treg-specific immunotherapy.


Assuntos
Proteínas Ligadas por GPI/metabolismo , Homeostase , Isoantígenos/metabolismo , Linfócitos do Interstício Tumoral/metabolismo , Receptores de Superfície Celular/metabolismo , Linfócitos T Reguladores/metabolismo , Animais , Sequência de Bases , Carcinogênese/genética , Carcinogênese/patologia , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/imunologia , Carcinoma de Células Renais/patologia , Proteínas Ligadas por GPI/deficiência , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Renais/genética , Neoplasias Renais/imunologia , Neoplasias Renais/patologia , Camundongos Knockout , Prognóstico , Receptores de Superfície Celular/deficiência , Análise de Célula Única , Transcrição Genética
2.
Front Immunol ; 12: 657951, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34531849

RESUMO

Kidney renal papillary cell carcinoma (KIRP), the second most common subtype of renal cell carcinoma, still lacks effective treatment regimens for individualized immunotherapy because of the heterogeneity of its elusive immune microenvironment. Therefore, we aimed to comprehensively evaluate the immune microenvironment of KIRP by using the computational biology strategy to analyze the expression profile data of 289 KIRP patients obtained from The Cancer Genome Atlas database. Based on multidimensional, multi-omics bioinformatics analysis, we found that the tumor of patients with KIRP exhibited "hot" tumor characteristics but the CD8+ T cells in the tumor tissues did not limit tumor progression. Thus, patients with KIRP may realize higher clinical benefits by receiving treatment that can reverse CD8+ T-cell exhaustion. Among them, C1 and C3 immune subtypes could realize the best efficacy of reversing CD8+ T-cell exhaustion. Moreover, CCL5 and FASLG expression may be related to the formation of the immunosuppressive microenvironment in the tumors of patients with KIRP. In conclusion, the immune microenvironment landscape presented in this study provides a novel insight for further experimental and clinical exploration of tailored immunotherapy for patients with KIRP.


Assuntos
Carcinoma de Células Renais/genética , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica , Neoplasias Renais/genética , Microambiente Tumoral/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Carcinoma de Células Renais/imunologia , Carcinoma de Células Renais/terapia , Feminino , Ontologia Genética , Redes Reguladoras de Genes/genética , Humanos , Inibidores de Checkpoint Imunológico/uso terapêutico , Imunoterapia/métodos , Estimativa de Kaplan-Meier , Neoplasias Renais/imunologia , Neoplasias Renais/terapia , Masculino , Pessoa de Meia-Idade , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia
3.
Nat Commun ; 12(1): 5547, 2021 09 20.
Artigo em Inglês | MEDLINE | ID: mdl-34545095

RESUMO

A cutting edge therapy for future immuno-oncology is targeting a new series of inhibitory receptors (IRs): LAG-3, TIM-3, and TIGIT. Both immunogenomic analyses and diagnostic platforms to distinguish candidates and predict good responders to these IR-related agents are vital in clinical pathology. By applying an automated single-cell count for immunolabelled LAG-3, TIM-3, and TIGIT, we reveal that individual IR levels with exclusive domination in each tumour can serve as valid biomarkers for profiling human renal cell carcinoma (RCC). We uncover the immunogenomic landscape associated with individual IR levels in human RCC tumours with metastases in various organs and histological subtypes. We then externally validate our results and devise a workflow with optimal biomarker cut-offs for discriminating the LAG-3, TIM-3, and TIGIT tumour profiles. The discrimination of LAG-3, TIM-3, and TIGIT profiles in tumours may have a broad impact on investigations of immunotherapy responses after targeting a new series of IRs.


Assuntos
Antígenos CD/metabolismo , Carcinoma de Células Renais/metabolismo , Receptor Celular 2 do Vírus da Hepatite A/metabolismo , Neoplasias Renais/metabolismo , Receptores Imunológicos/metabolismo , Idoso , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/imunologia , Carcinoma de Células Renais/patologia , Feminino , Humanos , Neoplasias Renais/genética , Neoplasias Renais/imunologia , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Fenótipo , Reprodutibilidade dos Testes
4.
Cancer Radiother ; 25(6-7): 565-569, 2021 Oct.
Artigo em Francês | MEDLINE | ID: mdl-34391648

RESUMO

Immunotherapy occupies a growing place in urologic oncology, mainly for kidney and bladder cancers. On the basis of encouraging preclinical work, the combination of immunotherapy with radiotherapy aims to increase the tumor response, including in metastatic tumors, which raises many hopes, which this article reviews.


Assuntos
Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias Renais/terapia , Neoplasias da Próstata/terapia , Radioterapia/métodos , Neoplasias da Bexiga Urinária/terapia , Terapia Combinada/métodos , Humanos , Imunomodulação , Neoplasias Renais/imunologia , Masculino , Neoplasias da Próstata/imunologia , Neoplasias da Bexiga Urinária/imunologia
5.
Am J Hum Genet ; 108(9): 1590-1610, 2021 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-34390653

RESUMO

Our study investigated the underlying mechanism for the 14q24 renal cell carcinoma (RCC) susceptibility risk locus identified by a genome-wide association study (GWAS). The sentinel single-nucleotide polymorphism (SNP), rs4903064, at 14q24 confers an allele-specific effect on expression of the double PHD fingers 3 (DPF3) of the BAF SWI/SNF complex as assessed by massively parallel reporter assay, confirmatory luciferase assays, and eQTL analyses. Overexpression of DPF3 in renal cell lines increases growth rates and alters chromatin accessibility and gene expression, leading to inhibition of apoptosis and activation of oncogenic pathways. siRNA interference of multiple DPF3-deregulated genes reduces growth. Our results indicate that germline variation in DPF3, a component of the BAF complex, part of the SWI/SNF complexes, can lead to reduced apoptosis and activation of the STAT3 pathway, both critical in RCC carcinogenesis. In addition, we show that altered DPF3 expression in the 14q24 RCC locus could influence the effectiveness of immunotherapy treatment for RCC by regulating tumor cytokine secretion and immune cell activation.


Assuntos
Carcinoma de Células Renais/genética , Cromossomos Humanos Par 14 , Proteínas de Ligação a DNA/genética , Loci Gênicos , Neoplasias Renais/genética , Fator de Transcrição STAT3/genética , Fatores de Transcrição/genética , Carcinogênese/genética , Carcinogênese/imunologia , Carcinogênese/patologia , Carcinoma de Células Renais/imunologia , Carcinoma de Células Renais/patologia , Carcinoma de Células Renais/terapia , Linhagem Celular Tumoral , Cromatina/química , Cromatina/imunologia , Montagem e Desmontagem da Cromatina/imunologia , Citocinas/genética , Citocinas/imunologia , Proteínas de Ligação a DNA/imunologia , Regulação da Expressão Gênica , Predisposição Genética para Doença , Genoma Humano , Estudo de Associação Genômica Ampla , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Imunoterapia/métodos , Neoplasias Renais/imunologia , Neoplasias Renais/patologia , Neoplasias Renais/terapia , Polimorfismo de Nucleotídeo Único , Fator de Transcrição STAT3/imunologia , Linfócitos T Citotóxicos , Fatores de Transcrição/imunologia
6.
Front Immunol ; 12: 646085, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34211459

RESUMO

There is little evidence around Camrelizumab combined with cytoreductive nephrectomy (CN) and radiotherapy (RT) as a treatment option for metastatic renal cell carcinoma (mRCC). The influence of CN on immune responses and the abscopal effect are not well understood. In this paper, we report a case of anti-programmed cell death-1 (PD-1) treated with combined RT once CN reduced the primary tumor burden (TB). This patient also encountered an increased response to targeted radiotherapy after immune resistance. We also observed a macrophage-to-lymphocyte ratio (MLR) peak, which may be correlated with subsequent pseudoprogression after thoracic radiotherapy. Consequently, even with the disease, this patient has remained stable. This peculiar instance suggests there is a need to investigate the underlying mechanisms of CN in promoting the abscopal effect during immunotherapy when combined with RT. It also suggests that there is a need for further investigation into the role of RT in overcoming immune resistance, and the value of MLR in predicting pseudoprogression. We hypothesize that a heavy tumor burden might suppress the abscopal effect, thereby ensuring that CN promotes it. However, radiotherapy may overcome immune resistance during oligoprogression.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Carcinoma de Células Renais/terapia , Procedimentos Cirúrgicos de Citorredução/métodos , Neoplasias Renais/terapia , Nefrectomia/métodos , Idoso , Carcinoma de Células Renais/imunologia , Carcinoma de Células Renais/patologia , Terapia Combinada , Humanos , Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias Renais/imunologia , Neoplasias Renais/patologia , Teste de Cultura Mista de Linfócitos , Masculino , Metástase Neoplásica , Dosagem Radioterapêutica , Receptores de Antígenos de Linfócitos T alfa-beta/fisiologia , Macrófagos Associados a Tumor/imunologia
7.
Biomed Res Int ; 2021: 3771866, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34258261

RESUMO

Cytochrome P450 family 2 subfamily J member 2 (CYP2J2), a member of the monooxygenase cytochrome P450 (CYP) family and the only member of the human CYP2J subfamily, has many functions, including regulation of oxidative stress, inflammation, apoptosis, and immune responses. However, its role in cancer development has not been clearly elucidated. In this study, expression levels of CYP2J2 in various cancer types were determined using the Oncomine, the Gene Expression Profiling Interactive Analysis (GEIPA), DriverDBv3, UALCAN, and Tumor Immune Estimation Resource (TIMER) databases. The prognostic value of CYP2J2 for KIRC was analyzed using GEPIA, UALCAN, OSkirc, and DriverDBv3 databases. We evaluated the expression levels of CYP2J2 transcript, protein, and promoter methylation at different clinical characteristics in KIRC through the UALCAN database. Simultaneously, CYP2J2 network-related functions were evaluated using the GeneMANIA interactive tool while the biological processes involved in CYP2J2 and its interactive genes were investigated through Metascape and FunRich. Then, we used TIMER to determine the correlation between CYP2J2 expression levels and immune infiltration levels in KIRC. In KIRC, the CYP2J2 gene, RNA, and protein were found to be overexpressed. However, the methylation level of CYP2J2 promoter in KIRC was lower than in normal tissues. Surprisingly, elevated expression levels of CYP2J2 exhibited better prognostic outcomes in KIRC. Evaluation of protein-protein interaction networks and biological processes revealed that CYP2J2 was principally involved in immune responses, apoptosis, and other metabolic processes. Moreover, we found that the expression levels of CYP2J2 were positively correlated with infiltration levels of B cells, CD8 + T cells, neutrophils, and dendritic cells in KIRC. Therefore, we speculated that the overexpression of CYP2J2 prolonged the survival outcome of KIRC patients, which may be related to the change of tumor immune microenvironment. Moreover, all these new understandings of CYP2J2 may provide important value for the early diagnosis and new targeted drug therapy of KIRC.


Assuntos
Biomarcadores Tumorais/metabolismo , Carcinoma de Células Renais/imunologia , Sistema Enzimático do Citocromo P-450/metabolismo , Neoplasias Renais/imunologia , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/patologia , Sistema Enzimático do Citocromo P-450/genética , Metilação de DNA/genética , Bases de Dados Genéticas , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Renais/genética , Neoplasias Renais/patologia , Prognóstico , Regiões Promotoras Genéticas/genética , Mapas de Interação de Proteínas/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
8.
J Immunother Cancer ; 9(7)2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34272309

RESUMO

The clinical and immunologic implications of the SARS-CoV-2 pandemic for patients with cancer receiving systemic anticancer therapy have introduced a multitude of clinical challenges and academic controversies. This review summarizes the current evidence, discussion points, and recommendations regarding the use of immune checkpoint inhibitors (ICIs) in patients with cancer during the SARS-CoV-2 pandemic, with a focus on patients with melanoma and renal cell carcinoma (RCC). More specifically, we summarize the theoretical concepts and available objective data regarding the relationships between ICIs and the antiviral immune response, along with recommended clinical approaches to the management of melanoma and RCC patient cohorts receiving ICIs throughout the course of the COVID-19 pandemic. Additional insights regarding the use of ICIs in the setting of current and upcoming COVID-19 vaccines and broader implications toward future pandemics are also discussed.


Assuntos
COVID-19/imunologia , Carcinoma de Células Renais/imunologia , Inibidores de Checkpoint Imunológico/imunologia , Neoplasias Renais/imunologia , Melanoma/imunologia , SARS-CoV-2/imunologia , COVID-19/tratamento farmacológico , COVID-19/epidemiologia , Vacinas contra COVID-19/imunologia , Vacinas contra COVID-19/uso terapêutico , Carcinoma de Células Renais/terapia , Humanos , Inibidores de Checkpoint Imunológico/uso terapêutico , Imunoterapia/métodos , Neoplasias Renais/terapia , Melanoma/terapia , Pandemias/prevenção & controle , SARS-CoV-2/efeitos dos fármacos
9.
Cancer Sci ; 112(9): 3469-3483, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34157192

RESUMO

Renal carcinoma shows a high risk of invasion and metastasis without effective treatment. Herein, we developed a chitosan (CS) nanoparticle-mediated DNA vaccine containing an activated factor L-Myc and a tumor-specific antigen CAIX for renal carcinoma treatment. The subcutaneous tumor models were intramuscularly immunized with CS-pL-Myc/pCAIX or control vaccine, respectively. Compared with single immunization group, the tumor growth was significantly suppressed in CS-pL-Myc/pCAIX co-immunization group. The increased proportion and mature of CD11c+ DCs, CD8+ CD11c+ DCs and CD103+ CD11c+ DCs were observed in the splenocytes from CS-pL-Myc/pCAIX co-immunized mice. Furthermore, the enhanced antigen-specific CD8+ T lymphocyte proliferation, cytotoxic T lymphocyte (CTL) responses, and multi-functional CD8+ T cell induction were detected in CS-pL-Myc/pCAIX co-immunization group compared with CS-pCAIX immunization group. Of note, the depletion of CD8 T cells resulted in the reduction of CD8+ T cells or CD8+ CD11c+ DCs and the loss of anti-tumor efficacy induced by CS-pL-Myc/pCAIX vaccine, suggesting the therapeutic efficacy of the vaccine was required for CD8+ DCs and CD103+ DCs mediated CD8+ T cells responses. Likewise, CS-pL-Myc/pCAIX co-immunization also significantly inhibited the lung metastasis of renal carcinoma models accompanied with the increased induction of multi-functional CD8+ T cell responses. Therefore, these results indicated that CS-pL-Myc/pCAIX vaccine could effectively induce CD8+ DCs and CD103+ DCs mediated tumor-specific multi-functional CD8+ T cell responses and exert the anti-tumor efficacy. This vaccine strategy offers a potential and promising approach for solid or metastatic tumor treatment.


Assuntos
Antígenos CD/metabolismo , Antígenos de Neoplasias/administração & dosagem , Antígenos CD8/metabolismo , Linfócitos T CD8-Positivos/imunologia , Anidrase Carbônica IX/administração & dosagem , Carcinoma de Células Renais/terapia , Quitosana/química , Células Dendríticas/imunologia , Sistemas de Liberação de Medicamentos/métodos , Imunidade , Imunização/métodos , Cadeias alfa de Integrinas/metabolismo , Neoplasias Renais/terapia , Nanopartículas/química , Proteínas Proto-Oncogênicas c-myc/administração & dosagem , Vacinas de DNA/administração & dosagem , Animais , Antígenos de Neoplasias/genética , Anidrase Carbônica IX/genética , Carcinoma de Células Renais/imunologia , Carcinoma de Células Renais/patologia , Modelos Animais de Doenças , Feminino , Células HEK293 , Humanos , Neoplasias Renais/imunologia , Neoplasias Renais/patologia , Camundongos , Camundongos Endogâmicos BALB C , Proteínas Proto-Oncogênicas c-myc/genética , Resultado do Tratamento , Vacinas de DNA/imunologia
10.
BMC Cancer ; 21(1): 746, 2021 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-34187413

RESUMO

BACKGROUND: Considerable evidence has indicated an association between the immune microenvironment and clinical outcome in ccRCC. The purpose of this study is to extensively figure out the influence of immune-related genes of tumors on the prognosis of patients with ccRCC. METHODS: Files containing 2498 immune-related genes were obtained from the Immunology Database and Analysis Portal (ImmPort), and the transcriptome data and clinical information relevant to patients with ccRCC were identified and downloaded from the TCGA data-base. Univariate and multivariate Cox regression analyses were used to screen out prognostic immune genes. The immune risk score model was established in light of the regression coefficient between survival and hub immune-related genes. We eventually set up a nomogram for the prediction of the overall survival for ccRCC. Kaplan-Meier (K-M) and ROC curve was used in evaluating the value of the predictive risk model. A P value of < 0.05 indicated statistically significant differences throughout data analysis. RESULTS: Via differential analysis, we found that 556 immune-related genes were expressed differentially between tumor and normal tissues (p < 0. 05). The analysis of univariate Cox regression exhibited that there was a statistical correlation between 43 immune genes and survival risk in patients with ccRCC (p < 0.05). Through Lasso-Cox regression analysis, we established an immune genetic risk scoring model based on 18 immune-related genes. The high-risk group showed a bad prognosis in K-M analysis. (p < 0.001). ROC curve showed that it was reliable of the immune risk score model to predict survival risk (5 year over survival, AUC = 0.802). The model indicated satisfactory AUC and survival correlation in the validation data set (5 year OS, Area Under Curve = 0.705, p < 0.05). From Multivariate regression analysis, the immune-risk score model plays an isolated role in the prediction of the prognosis of ccRCC. Under multivariate-Cox regression analysis, we set up a nomogram for comprehensive prediction of ccRCC patients' survival rate. At last, it was identified that 18 immune-related genes and risk scores were not only tremendously related to clinical prognosis but also contained in a variety of carcinogenic pathways. CONCLUSION: In general, tumor immune-related genes play essential roles in ccRCC development and progression. Our research established an unequal 18-immune gene risk index to predict the prognosis of ccRCC visually. This index was found to be an independent predictive factor for ccRCC.


Assuntos
Carcinoma de Células Renais/imunologia , Perfilação da Expressão Gênica/métodos , Neoplasias Renais/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Renais/patologia , Feminino , Humanos , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico
11.
Cancer Treat Rev ; 99: 102228, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34111642

RESUMO

Papillary Renal Cell Carcinoma (pRCC) is the most common non-clear cell RCC (nccRCC) and a distinct entity, although heterogenous, associated with poor outcomes. The treatment landscape of metastatic pRCC (mpRCC) relied so far on targeted therapies, mimicking previous developments in metastatic clear-cell renal cell carcinoma. However, antiangiogenics as well as mTOR inhibitors retain only limited activity in mpRCC. As development of immune checkpoint inhibitors (ICI) is now underway in patients with mpRCC, we aimed at discussing early activity data and potential for future therapeutic strategies in monotherapy or combination. Expression of immune checkpoints such as PD-L1 and infiltrative immune cells in pRCC could provide insights into their potential immunogenicity, although this is currently poorly described. Based on retrospective and prospective data, efficacy of ICI as single agent remains limited. Combinations with tyrosine-kinase inhibitors, notably with anti-MET inhibitors, harbor promising response rates and may enter the standard of care in untreated patients. Collaborative work is needed to refine the molecular and immune landscape of pRCC, and pursue efforts to set up predictive biomarker-driven clinical trials in these rare tumors.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Papilar/tratamento farmacológico , Carcinoma de Células Renais/tratamento farmacológico , Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias Renais/tratamento farmacológico , Carcinoma Papilar/imunologia , Carcinoma de Células Renais/imunologia , Ensaios Clínicos Fase II como Assunto , Ensaios Clínicos Fase III como Assunto , Humanos , Inibidores de Checkpoint Imunológico/administração & dosagem , Neoplasias Renais/imunologia , Inibidores de Proteínas Quinases/administração & dosagem , Ensaios Clínicos Controlados Aleatórios como Assunto
12.
Cancer Treat Rev ; 99: 102242, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34153830

RESUMO

BACKGROUND: The programmed cell death ligand-1 (PD-L1)/programmed cell death-1 (PD-1) pathway is important in metastatic renal cell carcinoma (mRCC). However, some dissimilarities between anti-PD-1 and anti-PD-L1 inhibitors have emerged. We aimed to assess differences between anti-PD-1 and anti-PD-L1 combination immunotherapies as first-line treatments in mRCC patients. METHODS: Multiple databases (PubMed, Web of Science, and Scopus) were searched for articles published until March 2021. Studies were eligible if they compared overall survival (OS), progression-free survival (PFS), objective response rates (ORR), complete response rates (CRR), and adverse events. RESULTS: Five studies met the eligibility criteria. PD-1 combination therapy was associated with significantly better OS and PFS and higher ORR and CRR than sunitinib (hazard ratio [HR]: 0.60, 95% confidence interval [CI]: 0.40-0.89; HR: 0.52, 95% CI: 0.37-0.75; odds ratio [OR]: 3.20, 95% CI: 2.18-4.68; and OR: 3.05, 95% CI: 2.13-4.37, respectively; P < 0.001). For all oncological outcomes, anti-PD-1 agents were superior to anti-PD-L1 agents based on HR and OR (OS: HR = 0.88, PFS: HR = 0.76, ORR: OR = 1.85, and CRR: OR = 2.24). Conversely, anti-PD-L1 agents were superior to anti-PD-1 agents in their safety profiles. In network meta-analyses, pembrolizumab plus lenvatinib seemed the worst tolerated anti-PD-1 combination therapy. CONCLUSIONS: Our analysis indicates the superior oncologic benefits of first-line anti-PD-1 combination therapies over anti-PD-L1 combination therapies in mRCC patients. This biological difference is of vital importance for clinical treatment decision making and the design of future rational combination therapy trials in mRCC.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Carcinoma de Células Renais/tratamento farmacológico , Inibidores de Checkpoint Imunológico/efeitos adversos , Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias Renais/tratamento farmacológico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Antígeno B7-H1/imunologia , Carcinoma de Células Renais/imunologia , Ensaios Clínicos Fase III como Assunto , Humanos , Inibidores de Checkpoint Imunológico/administração & dosagem , Neoplasias Renais/imunologia , Receptor de Morte Celular Programada 1/imunologia , Ensaios Clínicos Controlados Aleatórios como Assunto
13.
Cancer Treat Rev ; 99: 102239, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34157582

RESUMO

Immune-checkpoint inhibitor-based therapy has revolutionized the natural history of metastatic renal cell carcinoma (mRCC) providing better survival outcomes, higher rates of complete responses (CR) and durable remissions. Along with these advances, new challenges have emerged. RECIST and new immune-response criteria may be equivocal identifying complete responses. How to define a durable response and what is the optimal treatment duration remains unclear. Furthermore, the real value of a complete and deep response, whether or not it can be considered curation and whether or not immunotherapy discontinuation should be considered after complete response, are questions that remain open. The present article reviews the current evidence regarding the impact and challenges of managing complete and durable responses in mRCC treated with immune-checkpoint inhibitors.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/tratamento farmacológico , Carcinoma de Células Renais/imunologia , Ensaios Clínicos Fase III como Assunto , Humanos , Inibidores de Checkpoint Imunológico/administração & dosagem , Imunoterapia/métodos , Neoplasias Renais/imunologia , Ensaios Clínicos Controlados Aleatórios como Assunto
14.
Int J Biol Sci ; 17(8): 1925-1939, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34131396

RESUMO

Background: Angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2) allow entry of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) into host cells and play essential roles in cancer therapy. However, the functions of ACE2 and TMPRSS2 in kidney cancer remain unclear, especially as kidneys are targets for SARS-CoV-2 infection. Methods: UCSC Xena project, the Cancer Genome Atlas (TCGA), and Gene Expression Omnibus (GEO) databases (GSE30589 and GSE59185) were searched for gene expression in human tissues, gene expression data, and clinical information. Several bioinformatics methods were utilized to analyze the correlation between ACE2 and TMPRSS2 with respect to the prognosis of kidney renal clear cell carcinoma (KIRC) and kidney renal papillary cell carcinoma (KIRP). Results: ACE2 expression was significantly upregulated in tumor tissue, while its downregulation was associated with low survival in KIRC and KIRP patients. TMPRSS2 was downregulated in KIRC and KIRP, and its expression was not correlated with patient survival. According to clinical risk factor-based prediction models, ACE2 exhibits predictive accuracy for kidney cancer prognosis and is correlated with metabolism and immune infiltration. In an animal model, ACE2 expression was remarkably downregulated in SARS-CoV-2-infected cells compared to in the control. Conclusion: ACE2 expression is highly correlated with various metabolic pathways and is involved in immune infiltration.it plays a crucial role than TMPRSS2 in diagnosing and prognosis of kidney cancer patients. The overlap in ACE2 expression between kidney cancer and SARS-CoV-2 infection suggests that patients with KIRC or KIRP are at high risk of developing serious symptoms.


Assuntos
Enzima de Conversão de Angiotensina 2/biossíntese , COVID-19/complicações , Carcinoma de Células Renais/complicações , Neoplasias Renais/complicações , Receptores Virais/biossíntese , SARS-CoV-2 , Adulto , Idoso , Enzima de Conversão de Angiotensina 2/genética , Enzima de Conversão de Angiotensina 2/fisiologia , Animais , Carcinoma de Células Renais/imunologia , Carcinoma de Células Renais/metabolismo , Carcinoma de Células Renais/mortalidade , Chlorocebus aethiops , Regulação para Baixo , Resistencia a Medicamentos Antineoplásicos , Feminino , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes , Humanos , Estimativa de Kaplan-Meier , Neoplasias Renais/imunologia , Neoplasias Renais/metabolismo , Neoplasias Renais/mortalidade , Linfócitos do Interstício Tumoral/imunologia , Masculino , Pessoa de Meia-Idade , Modelos Animais , Proteínas de Neoplasias/biossíntese , Proteínas de Neoplasias/genética , Especificidade de Órgãos , Prognóstico , Modelos de Riscos Proporcionais , Receptores Virais/genética , Sistema Renina-Angiotensina/fisiologia , Serina Endopeptidases/biossíntese , Serina Endopeptidases/genética , Serina Endopeptidases/fisiologia , Análise Serial de Tecidos , Células Vero
15.
Lancet Oncol ; 22(7): 946-958, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34143969

RESUMO

BACKGROUND: Despite advances in the first-line treatment of metastatic renal cell carcinoma (RCC), there is an unmet need for options to address disease progression during or after treatment with immune checkpoint inhibitors (ICIs). Pembrolizumab and lenvatinib are active as monotherapies in RCC; thus, we aimed to evaluate the combination of lenvatinib plus pembrolizumab in these patients. METHODS: We report results of the metastatic RCC cohort from an open-label phase 1b/2 study of lenvatinib plus pembrolizumab in patients aged at least 18 years with selected solid tumours and an Eastern Cooperative Oncology Group performance status of 0-1. Oral lenvatinib at 20 mg was given once daily along with intravenous pembrolizumab at 200 mg once every 3 weeks. Patients remained on study drug treatment until disease progression, development of unacceptable toxicity, or withdrawal of consent. Efficacy was analysed in patients with clear cell metastatic RCC receiving study drug by previous therapy grouping: treatment naive, previously treated ICI naive (previously treated with at least one line of therapy but not with an anti-PD-1 or anti-PD-L1 ICI), and ICI pretreated (ie, anti-PD-1 or anti-PD-L1) patients. Safety was analysed in all enrolled and treated patients. The primary endpoint was the objective response rate at week 24 per immune-related Response Evaluation Criteria In Solid Tumors (irRECIST) by investigator assessment. This trial is registered with ClinicalTrials.gov (NCT02501096) and with the EU Clinical Trials Register (EudraCT2017-000300-26), and is closed to new participants. FINDINGS: Between July 21, 2015, and Oct 16, 2019, 145 patients were enrolled in the study. Two patients had non-clear cell RCC and were excluded from the efficacy analysis (one in the treatment-naive group and one in the ICI-pretreated group); thus, the population evaluated for efficacy comprised 143 patients (n=22 in the treatment-naive group, n=17 in the previously treated ICI-naive group, and n=104 in the ICI-pretreated group). All 145 enrolled patients were included in the safety analysis. The median follow-up was 19·8 months (IQR 14·3-28·4). The number of patients with an objective response at week 24 by irRECIST was 16 (72·7%, 95% CI 49·8-89·3) of 22 treatment-naive patients, seven (41·2%, 18·4-67·1) of 17 previously treated ICI-naive patients, and 58 (55·8%, 45·7-65·5) of 104 ICI-pretreated patients. Of 145 patients, 82 (57%) had grade 3 treatment-related adverse events and ten (7%) had grade 4 treatment-related adverse events. The most common grade 3 treatment-related adverse event was hypertension (30 [21%] of 145 patients). Treatment-related serious adverse events occurred in 36 (25%) patients, and there were three treatment-related deaths (upper gastrointestinal haemorrhage, sudden death, and pneumonia). INTERPRETATION: Lenvatinib plus pembrolizumab showed encouraging antitumour activity and a manageable safety profile and might be an option for post-ICI treatment of metastatic RCC. FUNDING: Eisai and Merck Sharp & Dohme.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias Renais/tratamento farmacológico , Compostos de Fenilureia/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Quinolinas/uso terapêutico , Idoso , Anticorpos Monoclonais Humanizados/efeitos adversos , Antineoplásicos Imunológicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma de Células Renais/imunologia , Carcinoma de Células Renais/secundário , Europa (Continente) , Feminino , Humanos , Inibidores de Checkpoint Imunológico/efeitos adversos , Neoplasias Renais/imunologia , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , Compostos de Fenilureia/efeitos adversos , Inibidores de Proteínas Quinases/efeitos adversos , Quinolinas/efeitos adversos , Fatores de Tempo , Resultado do Tratamento , Estados Unidos
16.
Anticancer Res ; 41(6): 2841-2848, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34083274

RESUMO

BACKGROUND/AIM: Expression of human leukocyte antigen (HLA) class I and II and CD74, which functions as a chaperone of MHC class II, play essential roles in T-cell recognition. The aim of this study was to elucidate the association between the HLAs and CD74, and their correlation with the infiltrated immune cells in renal cell carcinoma (RCC). MATERIALS AND METHODS: We retrospectively investigated the expression of HLA-A/B/C, HLA-DR, and CD74 in 38 patients with advanced RCC (T3/T4), and evaluated their correlations with CD4 and CD8-positive T-cell infiltration using immunohistochemistry. RESULTS: The expression of HLA-A/B/C, HLA-DR, and CD74 on cancer cells was observed in 37, 20, and 31 patients, respectively. The density of CD8- and CD4-positive T cells showed a positive correlation with HLA-DR expression. The density of CD4-positive lymphocytes was significantly associated with CD74 expression. CONCLUSION: The expression of HLA-DR, rather than CD74, on cancer cells was potentially associated with the anti-cancer immune microenvironment.


Assuntos
Antígenos de Diferenciação de Linfócitos B/imunologia , Carcinoma de Células Renais/imunologia , Antígenos HLA-DR/imunologia , Antígenos de Histocompatibilidade Classe II/imunologia , Neoplasias Renais/imunologia , Microambiente Tumoral , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
17.
BMC Cancer ; 21(1): 553, 2021 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-33993869

RESUMO

BACKGROUND: The tumor microenvironment acts a pivotal part in the occurrence and development of tumor. However, there are few studies on the microenvironment of papillary renal cell carcinoma (PRCC). Our study aims to explore prognostic genes related to tumor microenvironment in PRCC. METHODS: PRCC expression profiles and clinical data were extracted from The Cancer Gene Atlas (TCGA) and Gene Expression Omnibus (GEO) database. Immune/stromal scores were performed utilizing the ESTIMATE algorithm. Three hundred fifty-seven samples were split into two groups on the basis of median immune/stromal score, and comparison of gene expression was conducted. Intersect genes were obtained by Venn diagrams. Hub genes were selected through protein-protein interaction (PPI) network construction, and relevant functional analysis was conducted by DAVID. We used Kaplan-Meier analysis to identify the correlations between genes and overall survival (OS) and progression-free survival (PFS). Univariate and multivariate cox regression analysis were employed to construct survival model. Cibersort was used to predict the immune cell composition of high and low risk group. Combined nomograms were built to predict PRCC prognosis. Immune properties of PRCC were validated by The Cancer Immunome Atlas (TCIA). RESULTS: We found immune/stromal score was correlated with T pathological stages and PRCC subtypes. Nine hundred eighty-nine differentially expressed genes (DEGs) and 1169 DEGs were identified respectively on the basis of immune and stromal score. Venn diagrams indicated that 763 co-upregulated genes and 4 co-downregulated genes were identified. Kaplan-Meier analysis revealed that 120 genes were involved in tumor prognosis. Then PPI network analysis identified 22 hub genes, and four of which were significantly related to OS in patients with PRCC confirmed by cox regression analysis. Finally, we constructed a prognostic nomogram which combined with influence factors. CONCLUSIONS: Four tumor microenvironment-related genes (CD79A, CXCL13, IL6 and CCL19) were identified as biomarkers for PRCC prognosis.


Assuntos
Biomarcadores Tumorais/genética , Carcinoma de Células Renais/mortalidade , Neoplasias Renais/mortalidade , Nomogramas , Microambiente Tumoral/genética , Fatores Etários , Idoso , Antígenos CD79/genética , Carcinoma de Células Renais/diagnóstico , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/imunologia , Quimiocina CCL19/genética , Quimiocina CXCL13/genética , Conjuntos de Dados como Assunto , Estudos de Viabilidade , Feminino , Regulação Neoplásica da Expressão Gênica/imunologia , Humanos , Interleucina-6/genética , Estimativa de Kaplan-Meier , Rim/imunologia , Rim/patologia , Neoplasias Renais/diagnóstico , Neoplasias Renais/genética , Neoplasias Renais/imunologia , Masculino , Pessoa de Meia-Idade , Modelos Genéticos , Gradação de Tumores , Mapas de Interação de Proteínas/genética , Mapas de Interação de Proteínas/imunologia , Curva ROC , Medição de Risco/métodos , Medição de Risco/estatística & dados numéricos , Fatores Sexuais , Microambiente Tumoral/imunologia , Regulação para Cima/imunologia
18.
BMC Cancer ; 21(1): 595, 2021 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-34030645

RESUMO

BACKGROUND: Renal cancer is a common malignant tumor with an increasing incidence rate. METHODS: In this study, based on the gene expression profiles, we analyzed the compositions of tumor-infiltrating immune cells (TIICs) in renal cancer and paracancerous samples using CIBERSORT. The proportions of 22 TIICs subsets in 122 paired renal carcinoma and paracancerous samples, and 224 Wilms tumor (WT) samples varied between intragroup and intergroup. RESULTS: After analyzed the difference of TIICs composition between renal cancer and paired paracancerous samples, we found that M0 macrophages and CD8 T cells were significantly elevated, while naive B cells were significantly decreased in renal cancer samples compared with paracancerous samples. Survival analysis showed that high overall TIICs proportion, the low proportion of resting mast cells and the high proportion of activated memory CD4 T cells were associated with poor prognosis of renal cancer patients. In addition, 3 clusters were identified by hierarchical clustering analysis, and they presented a distinct prognosis. Cluster 1 had superior survival outcomes, while cluster 2 had an inferior survival outcome. CONCLUSIONS: Our study indicated that overall TIICs proportion, certain TIICs subset proportion, including resting mast cells and activated memory CD4 T cells, and distinct cluster patterns were associated with the prognosis of renal cancer, which was significant for the clinical surveillance and treatment of renal cancer.


Assuntos
Carcinoma de Células Renais/imunologia , Neoplasias Renais/imunologia , Microambiente Tumoral/genética , Tumor de Wilms/imunologia , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/mortalidade , Carcinoma de Células Renais/patologia , Conjuntos de Dados como Assunto , Perfilação da Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Rim/imunologia , Rim/patologia , Neoplasias Renais/genética , Neoplasias Renais/mortalidade , Neoplasias Renais/patologia , Linfócitos do Interstício Tumoral/imunologia , Mastócitos/imunologia , Prognóstico , Análise de Sobrevida , Microambiente Tumoral/imunologia , Macrófagos Associados a Tumor/imunologia , Tumor de Wilms/genética , Tumor de Wilms/mortalidade , Tumor de Wilms/patologia
19.
Aging (Albany NY) ; 13(10): 14304-14321, 2021 05 19.
Artigo em Inglês | MEDLINE | ID: mdl-34016791

RESUMO

Renal cell carcinoma is characterized by high immunogenicity and infiltration of immune cells. CD45RO+CD8+ T cells are well known as a critical role in host defense of the immune environment. However, their role in clear cell renal carcinoma (ccRCC) remains unknown. To elucidate the clinical importance of CD45RO+CD8+ T cells in ccRCC as well as its underlying mechanism, we analyzed several types of peripheral immune cells from 274 patients with ccRCC who have received radical or partial nephrectomy and 350 healthy people. Flow cytomety assays showed there was no significant difference in the proportions of CD8+ T cells and its subtypes other than CD45RO+/CD45RA+CD8+ cells. Both gene and protein expression levels of CD45RO in ccRCC tissues were decreased. CD45RO+CD8+ T cells showed increased proliferative abilities but decreased apoptotic abilities through MAPK signaling activation in ccRCC. High expression level of CD45RO+CD8+ T cells inhibited ccRCC progression, including proliferation, invasion, as well as autophagy of ccRCC through many signaling pathways. Bioinformatics and immunohistochemical chip analysis measured gene and protein levels of CD45RO and other related proteins. The combination of UCHL1, HMGB3, and CD36 has diagnostic value in ccRCC and is able to predict prognosis. Collectively, CD45RO+CD8+ T cells play a critical role in ccRCC progression and may be regarded as clinical indicators.


Assuntos
Biomarcadores Tumorais/metabolismo , Linfócitos T CD8-Positivos/imunologia , Carcinoma de Células Renais/imunologia , Neoplasias Renais/imunologia , Antígenos Comuns de Leucócito/metabolismo , Animais , Apoptose , Antígenos CD36/metabolismo , Carcinoma de Células Renais/diagnóstico , Carcinoma de Células Renais/patologia , Linhagem Celular Tumoral , Proliferação de Células , Progressão da Doença , Proteína HMGB3/metabolismo , Humanos , Neoplasias Renais/diagnóstico , Neoplasias Renais/patologia , Subpopulações de Linfócitos/imunologia , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , Gradação de Tumores , Prognóstico , Fatores de Risco , Transdução de Sinais
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