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1.
Medicine (Baltimore) ; 100(35): e27058, 2021 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-34477137

RESUMO

ABSTRACT: The treatment for squamous cell lung cancer (SqCLC) is limited, and the prognosis of SqCLC is poor. In this article, we aimed to analyze and identify immune-related cells and competition endogenous RNA (ceRNA) that influence the prognosis of SqCLC. SqCLC and lung adenocarcinoma data were downloaded from TCGA-GDC. A total of 22 types of immune cell fractions were estimated using CIBERSORT. R software was used to identify any significantly different transcriptome data, including mRNA, LncRNA, and miRNA. The univariate cox regression method was applied to screen for prognosis-related lncRNA, miRNA, mRNA and tumor-infiltrating immune cells. There were 504 patients included in this study. There was a higher proportion of memory activated CD4+ T cells and CD8+ T cells in younger women. Follicular helper T (Tfh) cells were predictive of a good prognosis and reflected immune activation in SqCLC. The SFTA1P/NKX2-1-AS1, hsa-mir-503, GREM2 ceRNA axes and NKX2-1-AS1, hsa-mir-96, PROK2 ceRNA axes were found to be important for the immune function, pathogenesis, and prognosis of SqCLC. Collectively, the immune-related ceRNA and tumor-infiltrating immune cells in SqCLC are likely important determinants of SqCLC pathogenesis, prognosis, and immune status.


Assuntos
Neoplasias Pulmonares/imunologia , Neoplasias de Células Escamosas/imunologia , Adolescente , Idoso , Criança , Células Epiteliais/patologia , Feminino , Ontologia Genética , Humanos , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Neoplasias de Células Escamosas/patologia , Estudos Retrospectivos , Tomografia Computadorizada por Raios X/métodos
2.
Nat Commun ; 12(1): 4852, 2021 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-34381028

RESUMO

Oncogenic activation of KRAS and its surrogates is essential for tumour cell proliferation and survival, as well as for the development of protumourigenic microenvironments. Here, we show that the deubiquitinase USP12 is commonly downregulated in the KrasG12D-driven mouse lung tumour and human non-small cell lung cancer owing to the activation of AKT-mTOR signalling. Downregulation of USP12 promotes lung tumour growth and fosters an immunosuppressive microenvironment with increased macrophage recruitment, hypervascularization, and reduced T cell activation. Mechanistically, USP12 downregulation creates a tumour-promoting secretome resulting from insufficient PPM1B deubiquitination that causes NF-κB hyperactivation in tumour cells. Furthermore, USP12 inhibition desensitizes mouse lung tumour cells to anti-PD-1 immunotherapy. Thus, our findings propose a critical component downstream of the oncogenic signalling pathways in the modulation of tumour-immune cell interactions and tumour response to immune checkpoint blockade therapy.


Assuntos
Resistencia a Medicamentos Antineoplásicos , Neoplasias Pulmonares/terapia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Microambiente Tumoral/imunologia , Ubiquitina Tiolesterase/metabolismo , Animais , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/terapia , Quimiocinas/metabolismo , Regulação para Baixo , Humanos , Tolerância Imunológica , Imunoterapia , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Camundongos , Proteína Fosfatase 2C/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo , Ubiquitina Tiolesterase/antagonistas & inibidores
3.
Front Immunol ; 12: 697840, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34394090

RESUMO

Monocytes are antigen-presenting cells (APCs) that play diverse roles in promoting or regulating inflammatory responses, but their role in T cell stimulation is not well defined. In inflammatory conditions, monocytes frequently show increased expression of CD169/Siglec-1, a type-I interferon (IFN-I)-regulated protein. However, little is known about the phenotype and function of these CD169+ monocytes. Here, we have investigated the phenotype of human CD169+ monocytes in different diseases, their capacity to activate CD8+ T cells, and the potential for a targeted-vaccination approach. Using spectral flow cytometry, we detected CD169 expression by CD14+ CD16- classical and CD14+ CD16+ intermediate monocytes and unbiased analysis showed that they were distinct from dendritic cells, including the recently described CD14-expressing DC3. CD169+ monocytes expressed higher levels of co-stimulatory and HLA molecules, suggesting an increased activation state. IFNα treatment highly upregulated CD169 expression on CD14+ monocytes and boosted their capacity to cross-present antigen to CD8+ T cells. Furthermore, we observed CD169+ monocytes in virally-infected patients, including in the blood and bronchoalveolar lavage fluid of COVID-19 patients, as well as in the blood of patients with different types of cancers. Finally, we evaluated two CD169-targeting nanovaccine platforms, antibody-based and liposome-based, and we showed that CD169+ monocytes efficiently presented tumor-associated peptides gp100 and WT1 to antigen-specific CD8+ T cells. In conclusion, our data indicate that CD169+ monocytes are activated monocytes with enhanced CD8+ T cell stimulatory capacity and that they emerge as an interesting target in nanovaccine strategies, because of their presence in health and different diseases.


Assuntos
Apresentação do Antígeno/imunologia , Linfócitos T CD8-Positivos/imunologia , Ativação Linfocitária/imunologia , Monócitos/imunologia , Lectina 1 Semelhante a Ig de Ligação ao Ácido Siálico/metabolismo , COVID-19/imunologia , Carcinoma Ductal Pancreático/imunologia , Células Cultivadas , Citometria de Fluxo , Humanos , Influenza Humana/imunologia , Interferon-alfa/farmacologia , Receptores de Lipopolissacarídeos/metabolismo , Neoplasias Pulmonares/imunologia , Neoplasias Pancreáticas/imunologia , SARS-CoV-2/imunologia
5.
Ann Clin Lab Sci ; 51(4): 487-493, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34452886

RESUMO

OBJECTIVE: Hepatitis B X-interacting protein (HBXIP) interacts with hepatitis B virus X protein to participate in the replication of the hepatitis B virus and carcinogenesis. Cellular growth and metastasis of non-small-cell lung cancer (NSCLC) are repressed by HBXIP inhibition. However, the role and mechanism of HBXIP on NSCLC cell growth remain unknown. MATERIALS: Expression of HBXIP was assessed by qRT-PCR and Western blot. siRNA targeting HBXIP was applied to detect cell viability and proliferation by MTT and colony formation assays. In vivo tumor growth was assessed, and anti-tumor immunity was determined by flow cytometry. The downstream partners involved in HBXIP-mediated tumorigenesis were detected by Western blot. RESULTS: Expression of HBXIP and neuropilin1-1 (NRP-1) was higher in NSCLC tissues and cells than in paracancerous tissues and human lung epithelial cells. siRNA-mediated knockdown of HBXIP decreased the cell viability of NSCLC and suppressed proliferation. Protein expression of Lin28B and NRP-1 was reduced by the knockdown of HBXIP, and over-expression of Lin28B attenuated the HBXIP silence-induced decrease of NRP-1. In vivo tumor growth was suppressed by HBXIP silencing, and the knockdown of HBXIP enhanced anti-tumor immunity through the increase of CD4+ and CD8+ T lymphocytes. CONCLUSION: Down-regulation of HBXIP reduced Lin28B-mediated NRP-1 to suppress NSCLC cell growth and enhance anti-tumor immunity.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Biomarcadores Tumorais/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Regulação Neoplásica da Expressão Gênica , Neoplasias Pulmonares/patologia , Neuropilina-1/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Apoptose , Biomarcadores Tumorais/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Proliferação de Células , Feminino , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Neuropilina-1/genética , Prognóstico , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
6.
Oxid Med Cell Longev ; 2021: 6614574, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34457117

RESUMO

Inflammatory reactions mediated by the NACHT, LRR, and PYD domain-containing protein 3 (NLRP3) inflammasome contributes to non-small-cell lung cancer (NSCLC) progression, particularly in patients with bacterial infections. Salidroside (SAL) has recently been shown to suppress lipopolysaccharide- (LPS-) induced NSCLC proliferation and migration, but its mechanism of action remains unclear. It has been shown that SAL improves metabolic inflammation in diabetic rodents through AMP-activated protein kinase- (AMPK-) dependent inhibition of the NLRP3 inflammasome. However, whether the NLRP3 inflammasome is regulated by SAL in NSCLC cells and how its underlying mechanism(s) can be determined require clarification. In this study, human lung alveolar basal carcinoma epithelial (A549) cells were treated with LPS, and the effects of SAL on cell proliferation, migration, AMPK activity, reactive oxygen species (ROS) production, and NLRP3 inflammasome activation were investigated. We found that LPS induction increases the proliferation and migration of A549 cells which was suppressed by SAL. Moreover, SAL protected A549 cells against LPS-induced AMPK inhibition, ROS production, and NLRP3 inflammasome activation. Blocking AMPK using Compound C almost completely suppressed the beneficial effects of SAL. In summary, these results indicate that SAL suppresses the proliferation and migration of human lung cancer cells through AMPK-dependent NLRP3 inflammasome regulation.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Glucosídeos/farmacologia , Inflamassomos/efeitos dos fármacos , Neoplasias Pulmonares/tratamento farmacológico , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Fenóis/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Apoptose , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Movimento Celular , Proliferação de Células , Humanos , Inflamassomos/metabolismo , Lipopolissacarídeos/farmacologia , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Transdução de Sinais , Células Tumorais Cultivadas
7.
Nat Commun ; 12(1): 4365, 2021 07 16.
Artigo em Inglês | MEDLINE | ID: mdl-34272369

RESUMO

Activating RAS missense mutations are among the most prevalent genomic alterations observed in human cancers and drive oncogenesis in the three most lethal tumor types. Emerging evidence suggests mutant KRAS (mKRAS) may be targeted immunologically, but mKRAS epitopes remain poorly defined. Here we employ a multi-omics approach to characterize HLA class I-restricted mKRAS epitopes. We provide proteomic evidence of mKRAS epitope processing and presentation by high prevalence HLA class I alleles. Select epitopes are immunogenic enabling mKRAS-specific TCRαß isolation. TCR transfer to primary CD8+ T cells confers cytotoxicity against mKRAS tumor cell lines independent of histologic origin, and the kinetics of lytic activity correlates with mKRAS peptide-HLA class I complex abundance. Adoptive transfer of mKRAS-TCR engineered CD8+ T cells leads to tumor eradication in a xenograft model of metastatic lung cancer. This study validates mKRAS peptides as bona fide epitopes facilitating the development of immune therapies targeting this oncoprotein.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Carcinogênese/imunologia , Epitopos de Linfócito T/imunologia , Neoplasias Pulmonares/imunologia , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteínas Proto-Oncogênicas p21(ras)/imunologia , Receptores de Antígenos de Linfócitos T alfa-beta/imunologia , Transferência Adotiva , Alelos , Animais , Carcinogênese/genética , Linhagem Celular Tumoral , Antígenos de Histocompatibilidade Classe I/imunologia , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Camundongos , Mutação , Peptídeos/genética , Peptídeos/imunologia , Proteômica , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Receptores de Antígenos de Linfócitos T alfa-beta/genética , Ensaios Antitumorais Modelo de Xenoenxerto
8.
Nature ; 596(7870): 126-132, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34290408

RESUMO

PD-1 blockade unleashes CD8 T cells1, including those specific for mutation-associated neoantigens (MANA), but factors in the tumour microenvironment can inhibit these T cell responses. Single-cell transcriptomics have revealed global T cell dysfunction programs in tumour-infiltrating lymphocytes (TIL). However, the majority of TIL do not recognize tumour antigens2, and little is known about transcriptional programs of MANA-specific TIL. Here, we identify MANA-specific T cell clones using the MANA functional expansion of specific T cells assay3 in neoadjuvant anti-PD-1-treated non-small cell lung cancers (NSCLC). We use their T cell receptors as a 'barcode' to track and analyse their transcriptional programs in the tumour microenvironment using coupled single-cell RNA sequencing and T cell receptor sequencing. We find both MANA- and virus-specific clones in TIL, regardless of response, and MANA-, influenza- and Epstein-Barr virus-specific TIL each have unique transcriptional programs. Despite exposure to cognate antigen, MANA-specific TIL express an incompletely activated cytolytic program. MANA-specific CD8 T cells have hallmark transcriptional programs of tissue-resident memory (TRM) cells, but low levels of interleukin-7 receptor (IL-7R) and are functionally less responsive to interleukin-7 (IL-7) compared with influenza-specific TRM cells. Compared with those from responding tumours, MANA-specific clones from non-responding tumours express T cell receptors with markedly lower ligand-dependent signalling, are largely confined to HOBIThigh TRM subsets, and coordinately upregulate checkpoints, killer inhibitory receptors and inhibitors of T cell activation. These findings provide important insights for overcoming resistance to PD-1 blockade.


Assuntos
Antígenos de Neoplasias/imunologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Regulação da Expressão Gênica , Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/imunologia , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Antígenos de Neoplasias/genética , Linfócitos T CD8-Positivos/imunologia , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/imunologia , Células Cultivadas , Humanos , Memória Imunológica , Neoplasias Pulmonares/genética , Receptor de Morte Celular Programada 1/antagonistas & inibidores , RNA-Seq , Receptores de Interleucina-7/imunologia , Análise de Célula Única , Transcriptoma/genética , Microambiente Tumoral
9.
Adv Clin Chem ; 103: 1-45, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34229848

RESUMO

Lung cancer (LC) accounts for the majority of cancer-related deaths worldwide. Although screening the high-risk population by low-dose CT (LDCT) has reduced mortality, the cost and high false positivity rate has prevented its general diagnostic use. As such, better and more specific minimally invasive biomarkers are needed in general and for early LC detection, specifically. Autoantibodies produced by humoral immune response to tumor-associated antigens (TAA) are emerging as a promising noninvasive biomarker for LC. Given the low sensitivity of any one single autoantibody, a panel approach could provide a more robust and promising strategy to detect early stage LC. In this review, we summarize the background of TAA autoantibodies (TAAb) and the techniques currently used for identifying TAA, as well as recent findings of LC specific antigens and TAAb. This review provides guidance toward the development of accurate and reliable TAAb as immunodiagnostic biomarkers in the early detection of LC.


Assuntos
Anticorpos Antineoplásicos/sangue , Antígenos de Neoplasias/imunologia , Autoanticorpos/sangue , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/imunologia , Humanos , Proteínas de Neoplasias/sangue , Proteínas de Neoplasias/metabolismo
10.
Anticancer Res ; 41(8): 3989-3995, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34281863

RESUMO

BACKGROUND/AIM: Non-small cell lung cancer (NSCLC) is one of the most lethal tumors. Given the failure of conventional therapeutic strategies, immunotherapy has emerged as a promising treatment modality that may improve the survival of patients with operable and advanced disease. PATIENTS AND METHODS: We examined the relative presence of CD20+ B-cells, CD8+ cytotoxic, and CD4+ helper/regulatory T-cells in the tumor-infiltrating lymphocyte (TIL)-population in a series of surgically-treated NSCLCs, and assessed their role as prognostic indicators after surgery. RESULTS: A high percent of CD4+ and CD8+ TILs in the tumor stroma was linked with poor (p=0.003) and good prognosis (p=0.01), respectively. High CD4/CD8 ratio defined a significantly worst prognosis [median survival 22 months vs. undefined, p=0.0002, hazard ratio (HR) 0.3 vs. 3.0]. Statistically significant results were also noted when the analysis was focused on the invading tumor front. In a multivariate model, the CD4/CD8-ratio assessed in the tumor stroma and the stage of disease were independent prognostic variables (p=0.0001, HR=4.1 and p=0.001, HR=1.5, respectively). CONCLUSION: The balance between CD4+ and CD8+ lymphocytes infiltrating the tumor stroma is a crucial factor defining anti-tumor immune surveillance, has strong prognostic value, and may be tested as a predictive biomarker for immunotherapy in operable NSCLC.


Assuntos
Antígenos CD20/imunologia , Linfócitos B/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Carcinoma Pulmonar de Células não Pequenas/imunologia , Neoplasias Pulmonares/imunologia , Linfócitos do Interstício Tumoral/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/patologia , Feminino , Humanos , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico
11.
Anticancer Res ; 41(7): 3673-3682, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34230166

RESUMO

AIM: This study aimed to investigate useful prognostic factors of immunotherapy in patients with lung cancer. PATIENTS AND METHODS: We retrospectively observed 73 patients who underwent immunotherapy (nivolumab, pembrolizumab, and atezolizumab) for lung cancer. The systemic inflammatory score (SIS) was calculated as the sum of the following factors scored one point each: Hemoglobin <12.5 g/dl and serum albumin <3.6 g/dl, resulting in scores of 0-2. We examined the correlation between the SIS and initial tumor response and progression-free and overall survival with other existing markers, namely tumor programmed death-ligand 1 (PD-L1) expression level; neutrophil-to-lymphocyte ratio (NLR); modified Glasgow prognostic score; and prognostic nutritional index, etc. Results: SIS ≤1 was significantly associated with better initial tumor response. In multivariate analysis, PD-L1 expression ≥50% (p=0.010), SIS ≤1 (p=0.028) and NLR <5.6 (p=0.047) were significantly associated with longer progression-free survival, and SIS ≤1 (p=0.030) and NLR <5.6 (p=0.037) were associated with longer overall survival. CONCLUSION: SIS is a useful marker of the efficacy of immunotherapy that can be obtained via routine blood tests.


Assuntos
Inflamação/patologia , Neoplasias Pulmonares/patologia , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/uso terapêutico , Antígeno B7-H1/metabolismo , Biomarcadores Tumorais/metabolismo , Feminino , Humanos , Imunoterapia/métodos , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/terapia , Linfócitos/metabolismo , Linfócitos/patologia , Masculino , Pessoa de Meia-Idade , Neutrófilos/metabolismo , Neutrófilos/patologia , Nivolumabe/uso terapêutico , Prognóstico , Intervalo Livre de Progressão , Estudos Retrospectivos
12.
Molecules ; 26(13)2021 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-34203519

RESUMO

Histone acetylation is an epigenetic mechanism that regulates the expression of various genes, such as natural killer group 2, member D (NKG2D) ligands. These NKG2D ligands are the key molecules that activate immune cells expressing the NKG2D receptor. It has been observed that cancer cells overexpress histone deacetylases (HDACs) and show reduced acetylation of nuclear histones. Furthermore, HDAC inhibitors are known to upregulate the expression of NKG2D ligands. Humans have 18 known HDAC enzymes that are divided into four classes. At present, it is not clear which types of HDAC are involved in the expression of NKG2D ligands. We hypothesized that specific types of HDAC genes might be responsible for altering the expression of NKG2D ligands. In this study, we monitored the expression of NKG2D ligands and major histocompatibility complex (MHC) class I molecules in lung cancer cells which were treated with six selective HDAC inhibitors and specific small interfering RNAs (siRNAs). We observed that treatment with FK228, which is a selective HDAC1/2 inhibitor, also known as Romidepsin, induced NKG2D ligand expression at the transcriptional and proteomic levels in two different lung cancer cell lines. It also caused an increase in the susceptibility of NCI-H23 cells to NK cells. Silencing HDAC1 or HDAC2 using specific siRNAs increased NKG2D ligand expression. In conclusion, it appears that HDAC1 and HDAC2 might be the key molecules regulating the expression of NKG2D ligands. These results imply that specifically inhibiting HDAC1 and HDAC2 could induce the expression of NKG2D ligands and improve the NK cell-mediated anti-cancer immunity.


Assuntos
Regulação Neoplásica da Expressão Gênica/imunologia , Histona Desacetilase 1/imunologia , Histona Desacetilase 2/imunologia , Imunidade Celular/imunologia , Neoplasias Pulmonares/imunologia , Subfamília K de Receptores Semelhantes a Lectina de Células NK/imunologia , Proteínas de Neoplasias/imunologia , Células A549 , Histona Desacetilase 1/genética , Histona Desacetilase 2/genética , Humanos , Células Matadoras Naturais , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Subfamília K de Receptores Semelhantes a Lectina de Células NK/genética , Proteínas de Neoplasias/genética
13.
Int J Mol Sci ; 22(12)2021 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-34208111

RESUMO

Anti-PD1/PD-L1 immunotherapy has emerged as a standard of care for stage III-IV non-small cell lung cancer (NSCLC) over the past decade. Patient selection is usually based on PD-L1 expression by tumor cells and/or tumor mutational burden. However, mutations in oncogenic drivers such as EGFR, ALK, BRAF, or MET modify the immune tumor microenvironment and may promote anti-PD1/PD-L1 resistance. In this review, we discuss the molecular mechanisms associated with these mutations, which shape the immune tumor microenvironment and may impede anti-PD1/PD-L1 efficacy. We provide an overview of the current clinical data on anti-PD1/PD-L1 efficacy in NSCLC with oncogenic driver mutation.


Assuntos
Antígeno B7-H1/antagonistas & inibidores , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma Pulmonar de Células não Pequenas/terapia , Imunoterapia , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/terapia , Mutação/genética , Oncogenes/genética , Animais , Antígeno B7-H1/metabolismo , Carcinoma Pulmonar de Células não Pequenas/genética , Humanos , Neoplasias Pulmonares/genética
14.
Cancer Sci ; 112(9): 3437-3454, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34152672

RESUMO

Metastasis is the main cause of death in individuals with cancer. Immune checkpoint blockade (ICB) can potentially reverse CD8+ cytotoxic T lymphocytes (CTLs) dysfunction, leading to significant remission in multiple cancers. However, the mechanism underlying the development of CTL exhaustion during metastatic progression remains unclear. Here, we established an experimental pulmonary metastasis model with melanoma cells and discovered a critical role for melanoma-released exosomes in metastasis. Using genetic knockdown of nSMase2 and Rab27a, 2 key enzymes for exosome secretion, we showed that high levels of effector-like tumor-specific CD8+ T cells with transitory exhaustion, instead of terminal exhaustion, were observed in mice without exosomes; these cells showed limited inhibitory receptors and strong proliferation and cytotoxicity. Mechanistically, the immunosuppression of exosomes depends on exogenous PD-L1, which can be largely rescued by pretreatment with antibody blockade. Notably, we also found that exosomal PD-L1 acts as a promising predictive biomarker for ICB therapies during metastasis. Together, our findings suggest that exosomal PD-L1 may be a potential immunotherapy target, suggesting a new curative therapy for tumor metastasis.


Assuntos
Antígeno B7-H1/metabolismo , Exossomos/metabolismo , Tolerância Imunológica , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/secundário , Melanoma/metabolismo , Melanoma/patologia , Linfócitos T Citotóxicos/imunologia , Transferência Adotiva/métodos , Idoso , Animais , Antígeno B7-H1/antagonistas & inibidores , Biomarcadores Tumorais/metabolismo , Linhagem Celular Tumoral , Modelos Animais de Doenças , Feminino , Técnicas de Silenciamento de Genes , Humanos , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/imunologia , Masculino , Melanoma/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Esfingomielina Fosfodiesterase/deficiência , Esfingomielina Fosfodiesterase/genética , Resultado do Tratamento , Proteínas rab27 de Ligação ao GTP/deficiência , Proteínas rab27 de Ligação ao GTP/genética
15.
Theranostics ; 11(14): 7029-7044, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34093869

RESUMO

Background: Increased IL-6 level, M2 macrophages and PD-1+CD8+ T cells in tumor microenvironments (TME) have been identified to correlate with resistance to checkpoint blockade immunotherapy, yet the mechanism remains poorly understood. Rab small GTPase-mediated trafficking of cytokines is critical in immuno-modulation. We have previously reported dysregulation of Rab37 in lung cancer cells, whereas the roles of Rab37 in tumor-infiltrating immune cells and cancer immunotherapy are unclear. Methods: The tumor growth of the syngeneic mouse allograft in wild type or Rab37 knockout mice was analyzed. Imaging analyses and vesicle isolation were conducted to determine Rab37-mediated IL-6 secretion. STAT3 binding sites at PD-1 promoter in T cells were identified by chromatin immunoprecipitation assay. Multiplex fluorescence immunohistochemistry was performed to detect the protein level of Rab37, IL-6 and PD-1 and localization of the tumor-infiltrating immune cells in allografts from mice or tumor specimens from lung cancer patients. Results: We revealed that Rab37 regulates the secretion of IL-6 in a GTPase-dependent manner in macrophages to trigger M2 polarization. Macrophage-derived IL-6 promotes STAT3-dependent PD-1 mRNA expression in CD8+ T cells. Clinically, tumors with high stromal Rab37 and IL-6 expression coincide with tumor infiltrating M2-macrophages and PD1+CD8+ T cells that predicts poor prognosis in lung cancer patients. In addition, lung cancer patients with an increase in plasma IL-6 level are found to be associated with immunotherapeutic resistance. Importantly, combined blockade of IL-6 and CTLA-4 improves survival of tumor-bearing mice by reducing infiltration of PD1+CD8+ T cells and M2 macrophages in TME. Conclusions: Rab37/IL-6 trafficking pathway links with IL-6/STAT3/PD-1 transcription regulation to foster an immunosuppressive TME and combined IL-6/CTLA-4 blockade therapy exerts potent anti-tumor efficacy.


Assuntos
Interleucina-6/metabolismo , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/metabolismo , Receptor de Morte Celular Programada 1/metabolismo , Fator de Transcrição STAT3/metabolismo , Microambiente Tumoral/imunologia , Proteínas rab de Ligação ao GTP/metabolismo , Aloenxertos , Animais , Linfócitos T CD8-Positivos/metabolismo , Antígeno CTLA-4/antagonistas & inibidores , Antígeno CTLA-4/metabolismo , Linhagem Celular Tumoral , Imunoprecipitação da Cromatina , Regulação Neoplásica da Expressão Gênica , Humanos , Imuno-Histoquímica , Interleucina-6/antagonistas & inibidores , Interleucina-6/sangue , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microscopia Eletrônica , Prognóstico , Receptor de Morte Celular Programada 1/genética , Fator de Transcrição STAT3/genética , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Microambiente Tumoral/genética , Proteínas rab de Ligação ao GTP/genética , Proteínas rab de Ligação ao GTP/ultraestrutura
16.
Theranostics ; 11(14): 7072-7091, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34093872

RESUMO

Simultaneous targeting of both the tumor microenvironment and cancer cells by a single nanomedicine has not been reported to date. Here, we report the dual properties of zero-valent-iron nanoparticle (ZVI-NP) to induce cancer-specific cytotoxicity and anti-cancer immunity. Methods: Cancer-specific cytotoxicity induced by ZVI-NP was determined by MTT assay. Mitochondria functional assay, immunofluorescence staining, Western blot, RT-qPCR, and ChIP-qPCR assays were used to dissect the mechanism underlying ZVI-NP-induced ferroptotic cancer cell death. The therapeutic potential of ZVI-NP was evaluated in immunocompetent mice and humanized mice. Immune cell profiles of allografts and ex vivo cultured immune cells were examined by flow cytometry analysis, RT-qPCR assay, and immunofluorescence. Results: ZVI-NP caused mitochondria dysfunction, intracellular oxidative stress, and lipid peroxidation, leading to ferroptotic death of lung cancer cells. Degradation of NRF2 by GSK3/ß-TrCP through AMPK/mTOR activation was enhanced in such cancer-specific ferroptosis. In addition, ZVI-NP attenuated self-renewal ability of cancer and downregulated angiogenesis-related genes. Importantly, ZVI-NP augmented anti-tumor immunity by shifting pro-tumor M2 macrophages to anti-tumor M1, decreasing the population of regulatory T cells, downregulating PD-1 and CTLA4 in CD8+ T cells to potentiate their cytolytic activity against cancer cells, while attenuating PD-L1 expression in cancer cells in vitro and in tumor-bearing immunocompetent mice. In particular, ZVI-NPs preferentially accumulated in tumor and lung tissues, leading to prominent suppression of tumor growth and metastasis. Conclusions: This dual-functional nanomedicine established an effective strategy to synergistically induce ferroptotic cancer cell death and reprogram the immunosuppressive microenvironment, which highlights the potential of ZVI-NP as an advanced integrated anti-cancer strategy.


Assuntos
Ferroptose/efeitos dos fármacos , Ferro/farmacologia , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/metabolismo , Macrófagos/efeitos dos fármacos , Nanopartículas Metálicas/química , Fator 2 Relacionado a NF-E2/metabolismo , Microambiente Tumoral/efeitos dos fármacos , Aloenxertos , Animais , Antineoplásicos/farmacologia , Linfócitos T CD8-Positivos/imunologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Movimento Celular/imunologia , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/imunologia , Imunoprecipitação da Cromatina , Quinase 3 da Glicogênio Sintase/metabolismo , Humanos , Ferro/química , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Macrófagos/metabolismo , Nanopartículas Metálicas/administração & dosagem , Nanopartículas Metálicas/ultraestrutura , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Camundongos SCID , Microscopia Eletrônica de Transmissão , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/patologia , Mitocôndrias/ultraestrutura , Fator 2 Relacionado a NF-E2/genética , Estresse Oxidativo/efeitos dos fármacos , Proteínas Quinases , Serina-Treonina Quinases TOR/metabolismo , Microambiente Tumoral/imunologia
17.
Aging (Albany NY) ; 13(12): 16144-16164, 2021 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-34115610

RESUMO

BACKGROUND: Lung adenocarcinoma (LUAD) is a heterogeneous disease characterized by high mortality and poor prognosis. Ferroptosis, a newly discovered iron-dependent type of cell death, has been found to play a crucial role in the development of cancers. However, little is known about the prognostic value of ferroptosis-related genes (FRGs) in LUAD. METHODS: In the present study, RNA-seq transcriptome data of LUAD patients were obtained from The Cancer Genome Atlas (TCGA) database. Cox regression analysis was used to construct a multigene signature. Kaplan-Meier survival and receiver operating characteristic (ROC) curves were utilized to assess the prognostic prediction efficiency of the constructed survival model. LUAD patients from the GSE30219 dataset were used for validation. RESULTS: We found 46 differentially expressed FRGs between LUAD and adjacent normal tissues. Via univariate and multivariate Cox regression analyses, 5 differentially expressed FRGs were identified as being highly correlated with LUAD. Patients were divided into low- and high-risk groups according to the risk score. We found that the overall survival (OS) of patients in the high-risk group was significantly worse than that of their low-risk counterparts. (P < 0.0001 in the TCGA dataset and P = 0.044 in the GSE30219 cohort). In addition, gene set variation analysis (GSVA) of the tumor microenvironment of the two groups may explain the different survival of LUAD patients. CONCLUSIONS: Our study identified a novel FRG signature that could be used to evaluate and predict the prognosis of LUAD patients, which might provide a new therapeutic target for the treatment of LUAD patients.


Assuntos
Adenocarcinoma de Pulmão/genética , Ferroptose/genética , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Neoplasias Pulmonares/genética , Adenocarcinoma de Pulmão/imunologia , Análise por Conglomerados , Estudos de Coortes , Humanos , Neoplasias Pulmonares/imunologia , Linfócitos do Interstício Tumoral/imunologia , Análise Multivariada , Prognóstico , Reprodutibilidade dos Testes , Análise de Sobrevida
18.
Cancer Invest ; 39(6-7): 514-520, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34075845

RESUMO

OBJECTIVE: The aim of study is to investigate whether hematological inflammatory biomarkers could be useful to detect patients with lung cancer. METHODS: The contribution of hematological biomarkers to the diagnosis of lung cancer and prediction of TNM was examined. RESULTS: NLR, PLR, MPV values were found to be higher in patients with lung cancer (all p < .001). NLR and PLR were found to be high, MPV was found to be lower in disease of advanced stage (p < .001). CONCLUSIONS: This study found that NLR, PLR and MPV values were significantly higher in patients with lung cancer.


Assuntos
Biomarcadores Tumorais/imunologia , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/imunologia , Neutrófilos/metabolismo , Idoso , Estudos de Casos e Controles , Detecção Precoce de Câncer , Feminino , Humanos , Neoplasias Pulmonares/patologia , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Contagem de Plaquetas , Estudos Retrospectivos
19.
Int J Biol Macromol ; 185: 111-121, 2021 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-34119543

RESUMO

Fucoidan is a sulfated polysaccharide, derived from various marine brown seaweeds, that has immunomodulatory effects. In this study, we analyzed the effects of five different fucoidans, which were extracted from Ascophyllum nodosum, Undaria pinnatifida, Macrocystis pyrifera, Fucus vesiculosus, and Ecklonia cava, on natural killer (NK) cell activation in mice. Among these, E. cava fucoidan (ECF) promoted an increase in the number of NK cells in the spleen and had the strongest effect on the activation of NK cells. Additionally, we observed that DC stimulation was required for NK cell activation and that ECF had the most potent effect on splenic dendritic cells (DC). Finally, ECF treatment effectively prevented infiltration of CT-26 carcinoma cells in the lungs of BALB/c mice in an NK cell dependent manner. Collectively, these results suggest that ECF could be a suitable candidate for enhancing NK cell-mediated anti-cancer immunity.


Assuntos
Antineoplásicos/administração & dosagem , Neoplasias do Colo/tratamento farmacológico , Células Matadoras Naturais/metabolismo , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/secundário , Feófitas/química , Polissacarídeos/administração & dosagem , Animais , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Neoplasias do Colo/imunologia , Feminino , Neoplasias Pulmonares/imunologia , Ativação Linfocitária/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB C , Polissacarídeos/farmacologia , Baço/efeitos dos fármacos , Baço/imunologia , Ensaios Antitumorais Modelo de Xenoenxerto
20.
Oncology ; 99(8): 528-538, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34107469

RESUMO

BACKGROUND: Sex-determining region Y-box 2 (SOX2) is a transcriptional factor that drives embryonic stem cells to neuroendocrine cells in lung development and is highly expressed in small-cell lung cancer (SCLC). However, the prognostic role of SOX2 and its relationship with tumor-infiltrating lymphocytes (TILs) has not been determined in SCLC. Herein, we assessed the expression of SOX2 and CD8+ TILs to obtain insights into the prognostic role of SOX2 and CD8+ TILs in limited-stage (LS)-SCLC. METHODS: A total of 75 patients with LS-SCLC was enrolled. The SOX2 expression and CD8+ TILs were evaluated by immunohistochemistry. RESULTS: High SOX2 and CD8+ TIL levels were identified in 52 (69.3%) and 40 (53.3%) patients, respectively. High SOX2 expression was correlated with increased density of CD8+ TILs (p = 0.041). Unlike SOX2, high CD8+ TIL numbers were associated with significantly longer progression-free survival (PFS; 13.9 vs. 8.0 months, p = 0.014). Patients with both high SOX2 expression and CD8+ TIL numbers (n = 29, 38.7%) had significantly longer PFS and overall survival (OS) compared to those from the other groups (median PFS 19.3 vs. 8.4 months; p = 0.002 and median OS 35.7 vs. 17.4 months; p = 0.004, respectively). Multivariate Cox regression analysis showed that the combination of high SOX2 expression and CD8+ TIL levels was an independent good prognostic factor for OS (HR = 0.471, 95% CI, 0.250-0.887, p = 0.02) and PFS (HR = 0.447, 95% CI, 0.250-0.801, p = 0.007) in SCLC. CONCLUSIONS: Evaluation of the combination of SOX2 and CD8+ TIL levels may be of a prognostic value in LS-SCLC.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/metabolismo , Linfócitos do Interstício Tumoral/imunologia , Fatores de Transcrição SOXB1/biossíntese , Adulto , Idoso , Idoso de 80 Anos ou mais , Linfócitos T CD8-Positivos/patologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Feminino , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/patologia , Linfócitos do Interstício Tumoral/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Taxa de Sobrevida
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