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RATIONALE: Despite significant advances in precision treatments and immunotherapy, lung cancer is the most common cause of cancer death worldwide. To reduce incidence and improve survival rates, a deeper understanding of lung premalignancy and the multistep process of tumorigenesis is essential, allowing for timely and effective intervention before cancer development. OBJECTIVES: To summarize existing information, identify knowledge gaps, formulate research questions, prioritize potential research topics, and propose strategies for future investigations into the premalignant progression in the lung. METHODS: An international multidisciplinary team of basic, translational, and clinical scientists reviewed available data to develop and refine research questions pertaining to the transformation of premalignant lung lesions to advanced lung cancer. RESULTS: This research statement identifies significant gaps in knowledge and proposes potential research questions aimed at expanding our understanding of the mechanisms underlying the progression of premalignant lung lesions to lung cancer in an effort to explore potential innovative modalities to intercept lung cancer at its nascent stages. CONCLUSIONS: The identified gaps in knowledge about the biological mechanisms of premalignant progression in the lung, along with ongoing challenges in screening, detection, and early intervention, highlight the critical need to prioritize research in this domain. Such focused investigations are essential to devise effective preventive strategies that may ultimately decrease lung cancer incidence and improve patient outcomes.
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Early-stage lung adenocarcinoma (LUAD) patients remain at substantial risk for recurrence and disease-related death, highlighting the unmet need of biomarkers for the assessment and identification of those in an early stage who would likely benefit from adjuvant chemotherapy. To identify circulating miRNAs useful for predicting recurrence in early-stage LUAD, we performed miRNA microarray analysis with pools of pretreatment plasma samples from patients with stage I LUAD who developed recurrence or remained recurrence-free during the follow-up period. Subsequent validation in 85 patients with stage I LUAD resulted in the development of a circulating miRNA panel comprising miR-23a-3p, miR-320c, and miR-125b-5p and yielding an area under the curve (AUC) of 0.776 in predicting recurrence. Furthermore, the three-miRNA panel yielded an AUC of 0.804, with a sensitivity of 45.8% at 95% specificity in the independent test set of 57 stage I and II LUAD patients. The miRNA panel score was a significant and independent factor for predicting disease-free survival (p < 0.001, hazard ratio [HR] = 1.64, 95% confidence interval [CI] = 1.51-4.22) and overall survival (p = 0.001, HR = 1.51, 95% CI = 1.17-1.94). This circulating miRNA panel is a useful noninvasive tool to stratify early-stage LUAD patients and determine an appropriate treatment plan with maximal efficacy.
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Adenocarcinoma de Pulmão , MicroRNA Circulante , Neoplasias Pulmonares , MicroRNAs , Humanos , MicroRNA Circulante/genética , Biomarcadores Tumorais/genética , Adenocarcinoma de Pulmão/genética , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/genéticaRESUMO
Rationale: Early pathogenesis of lung adenocarcinoma (LUAD) remains largely unknown. We found that, relative to wild-type littermates, the innate immunomodulator Lcn2 (lipocalin-2) was increased in normal airways from mice with knockout of the airway lineage gene Gprc5a (Gprc5a-/-) and that are prone to developing inflammation and LUAD. Yet, the role of LCN2 in lung inflammation and LUAD is poorly understood.Objectives: Delineate the role of Lcn2 induction in LUAD pathogenesis.Methods: Normal airway brushings, uninvolved lung tissues, and tumors from Gprc5a-/- mice before and after tobacco carcinogen exposure were analyzed by RNA sequencing. LCN2 mRNA was analyzed in public and in-house data sets of LUAD, lung squamous cancer (LUSC), chronic obstructive pulmonary disease (COPD), and LUAD/LUSC with COPD. LCN2 protein was immunohistochemically analyzed in a tissue microarray of 510 tumors. Temporal lung tumor development, gene expression programs, and host immune responses were compared between Gprc5a-/- and Gprc5a-/-/Lcn2-/- littermates.Measurements and Main Results:Lcn2 was progressively elevated during LUAD development and positively correlated with proinflammatory cytokines and inflammation gene sets. LCN2 was distinctively elevated in human LUADs, but not in LUSCs, relative to normal lungs and was associated with COPD among smokers and patients with LUAD. Relative to Gprc5a-/- mice, Gprc5a-/-/Lcn2-/- littermates exhibited significantly increased lung tumor development concomitant with reduced T-cell abundance (CD4+) and richness, attenuated antitumor immune gene programs, and increased immune cell expression of protumor inflammatory cytokines.Conclusions: Augmented LCN2 expression is a molecular feature of COPD-associated LUAD and counteracts LUAD development in vivo by maintaining antitumor immunity.
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Adenocarcinoma de Pulmão/imunologia , Antineoplásicos/imunologia , Lipocalina-2/genética , Lipocalina-2/imunologia , Neoplasias Pulmonares/imunologia , Doença Pulmonar Obstrutiva Crônica/sangue , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Animais , Biomarcadores/sangue , Feminino , Regulação da Expressão Gênica , Humanos , Lipocalina-2/sangue , Masculino , Camundongos , RNA MensageiroRESUMO
The extraordinarily thin alveolar type 1 (AT1) cell constitutes nearly the entire gas exchange surface and allows passive diffusion of oxygen into the blood stream. Despite such an essential role, the transcriptional network controlling AT1 cells remains unclear. Using cell-specific knockout mouse models, genomic profiling, and 3D imaging, we found that NK homeobox 2-1 (Nkx2-1) is expressed in AT1 cells and is required for the development and maintenance of AT1 cells. Without Nkx2-1, developing AT1 cells lose 3 defining features-molecular markers, expansive morphology, and cellular quiescence-leading to alveolar simplification and lethality. NKX2-1 is also cell-autonomously required for the same 3 defining features in mature AT1 cells. Intriguingly, Nkx2-1 mutant AT1 cells activate gastrointestinal (GI) genes and form dense microvilli-like structures apically. Single-cell RNA-seq supports a linear transformation of Nkx2-1 mutant AT1 cells toward a GI fate. Whole lung ChIP-seq shows NKX2-1 binding to 68% of genes that are down-regulated upon Nkx2-1 deletion, including 93% of known AT1 genes, but near-background binding to up-regulated genes. Our results place NKX2-1 at the top of the AT1 cell transcriptional hierarchy and demonstrate remarkable plasticity of an otherwise terminally differentiated cell type.
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Células Epiteliais Alveolares/citologia , Regulação da Expressão Gênica no Desenvolvimento , Redes Reguladoras de Genes , Pulmão/crescimento & desenvolvimento , Mutação , Organogênese , Fator Nuclear 1 de Tireoide/metabolismo , Células Epiteliais Alveolares/metabolismo , Animais , Diferenciação Celular , Pulmão/metabolismo , Camundongos , Análise de Célula Única , Fator Nuclear 1 de Tireoide/antagonistas & inibidores , Fator Nuclear 1 de Tireoide/genéticaRESUMO
There is substantial interest in mining neoantigens for cancer applications. Non-canonical proteins resulting from frameshift mutations have been identified as neoantigens in cancer. We investigated the landscape of non-canonical proteins in non-small cell lung cancer (NSCLC) and their induced immune response in the form of autoantibodies. A database of cryptoproteins was computationally constructed and comprised all alternate open reading frames (altORFs) and ORFs identified in pseudogenes, noncoding RNAs, and untranslated regions of mRNAs that did not align with known canonical proteins. Proteomic profiles of seventeen lung adenocarcinoma (LUAD) cell lines were searched to evaluate the occurrence of cryptoproteins. To assess the immunogenicity, immunoglobulin (Ig)-bound cryptoproteins in plasmas were profiled by mass spectrometry. The specimen set consisted of plasmas from 30 newly diagnosed NSCLC cases, pre-diagnostic plasmas from 51 NSCLC cases, and 102 control plasmas. An analysis of LUAD cell lines identified 420 cryptoproteins. Plasma Ig-bound analyses revealed 90 cryptoproteins uniquely found in cases and 14 cryptoproteins that had a fold-change >2 compared to controls. In pre-diagnostic samples, 17 Ig-bound cryptoproteins yielded an odds ratio ≥2. Eight Ig-bound cryptoproteins were elevated in both pre-diagnostic and newly diagnosed cases compared to controls. Cryptoproteins represent a class of neoantigens that induce an autoantibody response in NSCLC.
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Adenocarcinoma de Pulmão , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Adenocarcinoma de Pulmão/patologia , Carcinoma Pulmonar de Células não Pequenas/genética , Humanos , Imunidade , Proteínas , Proteômica/métodosRESUMO
The entire lung epithelium arises from SRY box 9 (SOX9)-expressing progenitors that form the respiratory tree and differentiate into airway and alveolar cells. Despite progress in understanding their initial specification within the embryonic foregut, how these progenitors are subsequently maintained is less clear. Using inducible, progenitor-specific genetic mosaic mouse models, we showed that ß-catenin (CTNNB1) maintains lung progenitors by promoting a hierarchical lung progenitor gene signature, suppressing gastrointestinal (GI) genes, and regulating NK2 homeobox 1 (NKX2.1) and SRY box 2 (SOX2) in a developmental stage-dependent manner. At the early, but not later, stage post-lung specification, CTNNB1 cell-autonomously maintained normal NKX2.1 expression levels and suppressed ectopic SOX2 expression. Genetic epistasis analyses revealed that CTNNB1 is required for fibroblast growth factor (Fgf)/Kirsten rat sarcoma viral oncogene homolog (Kras)-mediated promotion of the progenitors. In silico screening of Eurexpress and translating ribosome affinity purification (TRAP)-RNAseq identified a progenitor gene signature, a subset of which depends on CTNNB1. Wnt signaling also maintained NKX2.1 expression and suppressed GI genes in cultured human lung progenitors derived from embryonic stem cells.
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Linhagem da Célula/genética , Células-Tronco Embrionárias/metabolismo , Células Epiteliais/citologia , Pulmão/embriologia , Mucosa Respiratória/citologia , Mucosa Respiratória/embriologia , beta Catenina/fisiologia , Animais , Células Cultivadas , Embrião de Mamíferos , Desenvolvimento Embrionário/genética , Células-Tronco Embrionárias/citologia , Células-Tronco Embrionárias/fisiologia , Células Epiteliais/metabolismo , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Pulmão/citologia , Pulmão/metabolismo , Masculino , Camundongos , Camundongos Knockout , Gravidez , Mucosa Respiratória/metabolismo , Transcriptoma , beta Catenina/genéticaRESUMO
K-ras mutant lung adenocarcinoma (LUAD) is the most common type of lung cancer, displays abysmal prognosis and is tightly linked to tumor-promoting inflammation, which is increasingly recognized as a target for therapeutic intervention. We have recently shown a gender-specific role for epithelial Stat3 signaling in the pathogenesis of K-ras mutant LUAD. The absence of epithelial Stat3 in male K-ras mutant mice (LR/Stat3Δ/Δ mice) promoted tumorigenesis and induced a nuclear factor-kappaB (NF-κB)-driven pro-tumor immune response while reducing tumorigenesis and enhancing anti-tumor immunity in female counterparts. In the present study, we manipulated estrogen and NF-κB signaling to study the mechanisms underlying this intriguing gender-disparity. In LR/Stat3Δ/Δ females, estrogen deprivation by bilateral oophorectomy resulted in higher tumor burden, an induction of NF-κB-driven immunosuppressive response, and reduced anti-tumor cytotoxicity, whereas estrogen replacement reversed these changes. On the other hand, exogenous estrogen in males successfully inhibited tumorigenesis, attenuated NF-κB-driven immunosuppression and boosted anti-tumor immunity. Mechanistically, genetic targeting of epithelial NF-κB activity resulted in reduced tumorigenesis and enhanced the anti-tumor immune response in LR/Stat3Δ/Δ males, but not females. Our data suggest that estrogen exerts a context-specific anti-tumor effect through inhibiting NF-κB-driven tumor-promoting inflammation and provide insights into developing novel personalized therapeutic strategies for K-ras mutant LUAD.
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Adenocarcinoma de Pulmão/imunologia , Transformação Celular Neoplásica/imunologia , Estrogênios/metabolismo , Imunomodulação , Neoplasias Pulmonares/imunologia , NF-kappa B/metabolismo , Fator de Transcrição STAT3/metabolismo , Adenocarcinoma de Pulmão/metabolismo , Adenocarcinoma de Pulmão/patologia , Animais , Transformação Celular Neoplásica/metabolismo , Transformação Celular Neoplásica/patologia , Feminino , Humanos , Imunidade/imunologia , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Masculino , Camundongos , Mutação , NF-kappa B/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Fator de Transcrição STAT3/genética , Células Tumorais CultivadasRESUMO
Alveolar type 1 (AT1) cells cover >95% of the gas exchange surface and are extremely thin to facilitate passive gas diffusion. The development of these highly specialized cells and its coordination with the formation of the honeycomb-like alveolar structure are poorly understood. Using new marker-based stereology and single-cell imaging methods, we show that AT1 cells in the mouse lung form expansive thin cellular extensions via a non-proliferative two-step process while retaining cellular plasticity. In the flattening step, AT1 cells undergo molecular specification and remodel cell junctions while remaining connected to their epithelial neighbors. In the folding step, AT1 cells increase in size by more than 10-fold and undergo cellular morphogenesis that matches capillary and secondary septa formation, resulting in a single AT1 cell spanning multiple alveoli. Furthermore, AT1 cells are an unexpected source of VEGFA and their normal development is required for alveolar angiogenesis. Notably, a majority of AT1 cells proliferate upon ectopic SOX2 expression and undergo stage-dependent cell fate reprogramming. These results provide evidence that AT1 cells have both structural and signaling roles in alveolar maturation and can exit their terminally differentiated non-proliferative state. Our findings suggest that AT1 cells might be a new target in the pathogenesis and treatment of lung diseases associated with premature birth.
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Células Epiteliais Alveolares/citologia , Plasticidade Celular/fisiologia , Reprogramação Celular/fisiologia , Pneumopatias/patologia , Alvéolos Pulmonares/embriologia , Animais , Diferenciação Celular , Células Cultivadas , Células Epiteliais/citologia , Imageamento Tridimensional , Hibridização in Situ Fluorescente , Camundongos , Camundongos Transgênicos , Neovascularização Fisiológica/fisiologia , Alvéolos Pulmonares/citologia , Fatores de Transcrição SOXB1/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
The immunoproteasome plays a key role in generation of HLA peptides for T cell-mediated immunity. Integrative genomic and proteomic analysis of non-small cell lung carcinoma (NSCLC) cell lines revealed significantly reduced expression of immunoproteasome components and their regulators associated with epithelial to mesenchymal transition. Low expression of immunoproteasome subunits in early stage NSCLC patients was associated with recurrence and metastasis. Depleted repertoire of HLA class I-bound peptides in mesenchymal cells deficient in immunoproteasome components was restored with either IFNγ or 5-aza-2'-deoxycytidine (5-aza-dC) treatment. Our findings point to a mechanism of immune evasion of cells with a mesenchymal phenotype and suggest a strategy to overcome immune evasion through induction of the immunoproteasome to increase the cellular repertoire of HLA class I-bound peptides.
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Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/mortalidade , Complexo de Endopeptidases do Proteassoma/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos CD/imunologia , Antígenos CD/metabolismo , Caderinas/imunologia , Caderinas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Intervalo Livre de Doença , Transição Epitelial-Mesenquimal/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Antígenos HLA/metabolismo , Humanos , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Complexo de Endopeptidases do Proteassoma/imunologia , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/imunologia , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/imunologiaRESUMO
Several promising chemopreventive agents have for lung cancer emerged in preclinical models and in retrospective trials. These agents have been shown to modulate pathways altered in carcinogenesis and reduce markers of carcinogenesis in animal and cell culture models. Cancer-prone transgenic mice with oncogenic Kras expressed in the airway epithelium (CcspCre/+ ; KrasLSL-G12D/+ ) were raised on diets compounded with myo-inositol. These animals form lung premalignant lesions in a stereotypical fashion over the ten weeks following weaning. Mice raised on myo-inositol containing diets showed potent reduction in the number, size, and stage of lesions as compared to those raised on control diets. myo-inositol has previously been reported to inhibit phosphoinositide 3-kinase (PI3K) signaling. However, in mice raised on myo-inositol, total PI3K signaling was largely unaffected. Proteomic and cytokine analyses revealed large reduction in IL-6 related pathways, including STAT3 phosphorylation. This effect was not due to direct inhibition of IL-6 production and autocrine signaling within the tumor cell, but rather through alteration in macrophage recruitment and in phenotype switching, with an increase in antitumoral M1 macrophages.
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Inositol/farmacologia , Interleucina-6/metabolismo , Neoplasias Pulmonares/patologia , Macrófagos/efeitos dos fármacos , Fator de Transcrição STAT3/metabolismo , Animais , Anticarcinógenos/farmacologia , Modelos Animais de Doenças , Humanos , Camundongos , Camundongos Transgênicos , FosforilaçãoRESUMO
This study aimed to assess a four-marker protein panel (4MP)'s performance, including the precursor form of surfactant protein B, cancer antigen 125, carcinoembryonic antigen, and cytokeratin-19, for predicting lung cancer in a cohort enriched with never- and ever-smokers. Blinded pre-diagnostic plasma samples collected within 2 years prior to a lung cancer diagnosis from 25 cases and 100 sex-, age-, and smoking-matched controls were obtained from the Physicians' Health Study (PHS). The 4MP yielded AUC performance estimates of 0.76 (95% CI: 0.61-0.92) and 0.69 (95% CI: 0.56-0.82) for predicting lung cancer within one year and within two years of diagnosis, respectively. When stratifying into ever-smokers and never-smokers, the 4MP had respective AUCs of 0.77 (95% CI: 0.63-0.92) and 0.72 (95% CI: 0.17-1.00) for a 1-year risk of lung cancer. The AUCs of the 4MP for predicting metastatic lung cancer within one year and two years of the blood draw were 0.95 (95% CI: 0.87-1.00) and 0.78 (95% CI: 0.62-0.94), respectively. Our findings indicate that a blood-based biomarker panel may be useful in identifying ever- and never-smokers at high risk of a diagnosis of lung cancer within one-to-two years.
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[18F]Fluorodeoxyglucose positron emission tomography (FDG-PET) and computed tomography (CT) are indispensable components in modern medicine. Although PET can provide additional diagnostic value, it is costly and not universally accessible, particularly in low-income countries. To bridge this gap, we have developed a conditional generative adversarial network pipeline that can produce FDG-PET from diagnostic CT scans based on multi-center multi-modal lung cancer datasets (n = 1,478). Synthetic PET images are validated across imaging, biological, and clinical aspects. Radiologists confirm comparable imaging quality and tumor contrast between synthetic and actual PET scans. Radiogenomics analysis further proves that the dysregulated cancer hallmark pathways of synthetic PET are consistent with actual PET. We also demonstrate the clinical values of synthetic PET in improving lung cancer diagnosis, staging, risk prediction, and prognosis. Taken together, this proof-of-concept study testifies to the feasibility of applying deep learning to obtain high-fidelity PET translated from CT.
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Neoplasias Pulmonares , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Humanos , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Fluordesoxiglucose F18 , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/genética , Tomografia Computadorizada por Raios X , PrognósticoRESUMO
RATIONALE: Changes in airway epithelial cell differentiation, driven in part by IL-13, are important in asthma. Micro-RNAs (miRNAs) regulate cell differentiation in many systems and could contribute to epithelial abnormalities in asthma. OBJECTIVES: To determine whether airway epithelial miRNA expression is altered in asthma and identify IL-13-regulated miRNAs. METHODS: We used miRNA microarrays to analyze bronchial epithelial brushings from 16 steroid-naive subjects with asthma before and after inhaled corticosteroids, 19 steroid-using subjects with asthma, and 12 healthy control subjects, and the effects of IL-13 and corticosteroids on cultured bronchial epithelial cells. We used quantitative polymerase chain reaction to confirm selected microarray results. MEASUREMENTS AND MAIN RESULTS: Most (12 of 16) steroid-naive subjects with asthma had a markedly abnormal pattern of bronchial epithelial miRNA expression by microarray analysis. Compared with control subjects, 217 miRNAs were differentially expressed in steroid-naive subjects with asthma and 200 in steroid-using subjects with asthma (false discovery rate < 0.05). Treatment with inhaled corticosteroids had modest effects on miRNA expression in steroid-naive asthma, inducing a statistically significant (false discovery rate < 0.05) change for only nine miRNAs. qPCR analysis confirmed differential expression of 22 miRNAs that were highly differentially expressed by microarrays. IL-13 stimulation recapitulated changes in many differentially expressed miRNAs, including four members of the miR-34/449 family, and these changes in miR-34/449 family members were resistant to corticosteroids. CONCLUSIONS: Dramatic alterations of airway epithelial cell miRNA levels are a common feature of asthma. These alterations are only modestly corrected by inhaled corticosteroids. IL-13 effects may account for some of these alterations, including repression of miR-34/449 family members that have established roles in airway epithelial cell differentiation. Clinical trial registered with www.clinicaltrials.gov (NCT 00595153).
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Asma/metabolismo , Brônquios/metabolismo , Células Epiteliais/metabolismo , MicroRNAs/metabolismo , Administração por Inalação , Adulto , Asma/tratamento farmacológico , Asma/genética , Brônquios/efeitos dos fármacos , Budesonida/administração & dosagem , Células Cultivadas , Relação Dose-Resposta a Droga , Células Epiteliais/efeitos dos fármacos , Feminino , Glucocorticoides/administração & dosagem , Humanos , Interleucina-13/farmacologia , Masculino , MicroRNAs/genética , MicroRNAs/fisiologia , Análise em Microsséries , Reação em Cadeia da PolimeraseRESUMO
Current lung cancer screening protocols use low-dose computed tomography scans in selected high-risk individuals. Unfortunately, utilization is low, and the rate of false-positive screens is high. Peripheral biomarkers carry meaningful promise in diagnosing and monitoring cancer with added potential advantages reducing invasive procedures and improving turnaround time. Herein, the use of such blood-based assays is considered as an adjunct to further utilization and accuracy of lung cancer screening.
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Neoplasias Pulmonares , Humanos , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/patologia , Detecção Precoce de Câncer/métodos , Tomografia Computadorizada por Raios X/métodos , Pulmão/diagnóstico por imagem , Pulmão/patologia , Biópsia Líquida , Programas de RastreamentoRESUMO
The nuclear factor erythroid 2-related factor 2 (NRF2) pathway is frequently activated in various cancer types. Aberrant activation of NRF2 in cancer is attributed to gain-of-function mutations in the NRF2-encoding gene NFE2L2 or a loss of function of its suppressor, Kelch-like ECH-associated protein 1 (KEAP1). NRF2 activation exerts pro-tumoral effects in part by altering cancer cell metabolism. Previously, we reported a novel mechanism of NRF2 tumoral immune suppression through the selective upregulation of the tryptophan-metabolizing enzyme kynureninase (KYNU) in lung adenocarcinoma. In the current study, we explored the relevance of NRF2-mediated KYNU upregulation across multiple cancer types. Specifically, using a gene expression dataset for 9801 tumors representing 32 cancer types from The Cancer Genome Atlas (TCGA), we demonstrated that elevated KYNU parallels increased gene-based signatures of NRF2-activation and that elevated tumoral KYNU mRNA expression is strongly associated with an immunosuppressive tumor microenvironment, marked by high expression of gene-based signatures of Tregs as well as the immune checkpoint blockade-related genes CD274 (PDL-1), PDCD1 (PD-1), and CTLA4, regardless of the cancer type. Cox proportional hazard models further revealed that increased tumoral KYNU gene expression was prognostic for poor overall survival in several cancer types, including thymoma, acute myeloid leukemia, low-grade glioma, kidney renal papillary cell carcinoma, stomach adenocarcinoma, and pancreatic ductal adenocarcinoma (PDAC). Using PDAC as a model system, we confirmed that siRNA-mediated knockdown of NRF2 reduced KYNU mRNA expression, whereas activation of NFE2L2 (the coding gene for NRF2) through either small-molecule agonists or siRNA-mediated knockdown of KEAP1 upregulated KYNU in PDAC cells. Metabolomic analyses of the conditioned medium from PDAC cell lines revealed elevated levels of KYNU-derived anthranilate, confirming that KYNU was enzymatically functional. Collectively, our study highlights the activation of the NRF2-KYNU axis as a multi-cancer phenomenon and supports the relevance of tumoral KYNU as a marker of tumor immunosuppression and as a prognostic marker for poor overall survival.
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PURPOSE: To investigate the utility of integrating a panel of circulating protein biomarkers in combination with a risk model on the basis of subject characteristics to identify individuals at high risk of harboring a lethal lung cancer. METHODS: Data from an established logistic regression model that combines four-marker protein panel (4MP) together with the Prostate, Lung, Colorectal, and Ovarian (PLCO) risk model (PLCOm2012) assayed in prediagnostic sera from 552 lung cancer cases and 2,193 noncases from the PLCO cohort were used in this study. Of the 552 lung cancer cases, 387 (70%) died of lung cancer. Cumulative incidence of lung cancer death and subdistributional and cause-specific hazard ratios (HRs) were calculated on the basis of 4MP + PLCOm2012 risk scores at a predefined 1.0% and 1.7% 6-year risk thresholds, which correspond to the current and former US Preventive Services Task Force screening criteria, respectively. RESULTS: When considering cases diagnosed within 1 year of blood draw and all noncases, the area under receiver operation characteristics curve estimate of the 4MP + PLCOm2012 model for risk prediction of lung cancer death was 0.88 (95% CI, 0.86 to 0.90). The cumulative incidence of lung cancer death was statistically significantly higher in individuals with 4MP + PLCOm2012 scores above the 1.0% 6-year risk threshold (modified χ2, 166.27; P < .0001). Corresponding subdistributional and lung cancer death-specific HRs for test-positive cases were 9.88 (95% CI, 6.44 to 15.18) and 10.65 (95% CI, 6.93 to 16.37), respectively. CONCLUSION: The blood-based biomarker panel in combination with PLCOm2012 identifies individuals at high risk of a lethal lung cancer.
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Neoplasias Colorretais , Neoplasias Pulmonares , Masculino , Humanos , Medição de Risco , Próstata , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/epidemiologia , Pulmão , Biomarcadores , Neoplasias Colorretais/diagnóstico , Detecção Precoce de CâncerRESUMO
Respiratory inflammation in bronchiolitis obliterans syndrome (BOS) after hematopoietic cell transplantation (HCT) is poorly understood. Clinical criteria for early-stage BOS (stage 0p) often capture HCT recipients without BOS. Measuring respiratory tract inflammation may help identify BOS, particularly early BOS. We conducted a prospective observational study in HCT recipients with new-onset BOS (n = 14), BOS stage 0p (n = 10), and recipients without lung impairment with (n = 3) or without (n = 8) chronic graft-versus-host disease and measured nasal inflammation using nasosorption at enrollment and then every 3 mo for 1 y. We divided BOS stage 0p into impairment that did not return to baseline values (preBOS, n = 6), or transient impairment (n = 4). We tested eluted nasal mucosal lining fluid from nasosorption matrices for inflammatory chemokines and cytokines using multiplex magnetic bead immunoassays. We analyzed between-group differences using the Kruskal-Wallis method, adjusting for multiple comparisons. We found increased nasal inflammation in preBOS and therefore directly compared patients with preBOS to those with transient impairment, as this would be of greatest diagnostic relevance. After adjusting for multiple corrections, we found significant increases in growth factors (FGF2, TGF-α, GM-CSF, VEGF), macrophage activation (CCL4, TNF-α, IL-6), neutrophil activation (CXCL2, IL-8), T cell activation (CD40 ligand, IL-2, IL-12p70, IL-15), type 2 inflammation (eotaxin, IL-4, IL-13), type 17 inflammation (IL-17A), dendritic maturation (FLT3 ligand, IL-7), and counterregulatory molecules (PD-L1, IL-1 receptor antagonist, IL-10) in preBOS patients compared to transient impairment. These differences waned over time. In conclusion, a transient multifaceted nasal inflammatory response is associated with preBOS. Our findings require validation in larger longitudinal cohorts.
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Síndrome de Bronquiolite Obliterante , Bronquiolite Obliterante , Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Transplante de Pulmão , Humanos , Citocinas , Bronquiolite Obliterante/diagnóstico , Bronquiolite Obliterante/etiologia , Bronquiolite Obliterante/metabolismo , Pulmão/metabolismo , Doença Enxerto-Hospedeiro/diagnóstico , Inflamação , Transplante de Células-Tronco Hematopoéticas/efeitos adversosRESUMO
There is unmet need to develop circulating biomarkers that would enable earlier interception of lung cancer when more effective treatment options are available. Here, a set of 30 miRNAs, selected from a review of the published literature were assessed for their predictive performance in identifying lung cancer cases in the pre-diagnostic setting. The 30 miRNAs were assayed using sera collected from 102 individuals diagnosed with lung cancer within one year following blood draw and 212 controls matched for age, sex, and smoking status. The additive performance of top-performing miRNA candidates in combination with a previously validated four-protein marker panel (4MP) consisting of the precursor form of surfactant protein B (Pro-SFTPB), cancer antigen 125 (CA125), carcinoembryonic antigen (CEA) and cytokeratin-19 fragment (CYFRA21-1) was additionally assessed. Of the 30 miRNAs evaluated, five (miR-320a-3p, miR-210-3p, miR-92a-3p, miR-21-5p, and miR-140-3p) were statistically significantly (Wilcoxon rank sum test p < 0.05) elevated in case sera compared to controls, with individual AUCs ranging from 0.57−0.62. Compared to the 4MP alone, the combination of 3-miRNAs + 4MP improved sensitivity at 95% specificity by 19.1% ((95% CI of difference 0.0−28.6); two-sided p: 0.006). Our findings demonstrate utility for miRNAs for early detection of lung cancer in combination with a four-protein marker panel.
RESUMO
K-ras-mutant lung adenocarcinoma (KM-LUAD) is associated with abysmal prognosis and is tightly linked to tumor-promoting inflammation. A human mAb, canakinumab, targeting the proinflammatory cytokine IL-1ß, significantly decreased the risk of lung cancer in the Canakinumab Anti-inflammatory Thrombosis Outcomes Study. Interestingly, we found high levels of IL-1ß in the lungs of mice with K-rasG12D-mutant tumors (CC-LR mice). Here, we blocked IL-1ß using an anti-IL-1ß mAb in cohorts of 6- or 14-week-old CC-LR mice to explore its preventive and therapeutic effect, respectively. IL-1ß blockade significantly reduced lung tumor burden, which was associated with reprogramming of the lung microenvironment toward an antitumor phenotype characterized by increased infiltration of cytotoxic CD8+ T cells (with high IFN-γ and granzyme B expression but low programmed cell death 1 [PD-1] expression) while suppressing neutrophils and polymorphonuclear (PMN) myeloid-derived suppressor cells. When querying the Cancer Genome Atlas data set, we found positive correlations between IL1B expression and infiltration of immunosuppressive PMNs and expression of their chemoattractant, CXCL1, and PDCD1 expressions in patients with KM-LUAD. Our data provide evidence that IL-1ß blockade may be a preventive strategy for high-risk individuals and an alternative therapeutic approach in combination with currently available treatments for KM-LUAD.
Assuntos
Adenocarcinoma de Pulmão , Anticorpos Monoclonais Humanizados , Interleucina-1beta , Neoplasias Pulmonares , Adenocarcinoma de Pulmão/tratamento farmacológico , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/imunologia , Animais , Anticorpos Monoclonais Humanizados/farmacologia , Citocinas/biossíntese , Citocinas/imunologia , Genes ras , Humanos , Interleucina-1beta/antagonistas & inibidores , Interleucina-1beta/imunologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/imunologia , Camundongos , Terapia de Alvo Molecular , Mutação , Neutrófilos/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/genética , Microambiente TumoralRESUMO
Activation of the NRF2 pathway through gain-of-function mutations or loss-of-function of its suppressor KEAP1 is a frequent finding in lung cancer. NRF2 activation has been reported to alter the tumor microenvironment. Here, we demonstrated that NRF2 alters tryptophan metabolism through the kynurenine pathway that is associated with a tumor-promoting, immune suppressed microenvironment. Specifically, proteomic profiles of 47 lung adenocarcinoma (LUAD) cell lines (11 KEAP1 mutant and 36 KEAP1 wild-type) revealed the tryptophan-kynurenine enzyme kynureninase (KYNU) as a top overexpressed protein associated with activated NRF2. The siRNA-mediated knockdown of NFE2L2, the gene encoding for NRF2, or activation of the NRF2 pathway through siRNA-mediated knockdown of KEAP1 or via chemical induction with the NRF2-activator CDDO-Me confirmed that NRF2 is a regulator of KYNU expression in LUAD. Metabolomic analyses confirmed KYNU to be enzymatically functional. Analysis of multiple independent gene expression datasets of LUAD, as well as a LUAD tumor microarray demonstrated that elevated KYNU was associated with immunosuppression, including potent induction of T-regulatory cells, increased levels of PD1 and PD-L1, and resulted in poorer survival. Our findings indicate a novel mechanism of NRF2 tumoral immunosuppression through upregulation of KYNU.