RESUMO
Metabolic abnormalities represent one of the pathological features of chronic obstructive pulmonary disease (COPD). Glutamic pyruvate transaminase 2 (GPT2) is involved in glutamate metabolism and lipid synthesis pathways, whilst the exact roles of GPT2 in the occurrence and development of COPD remains uncertain. This study aims at investigating how GPT2 and the associated genes modulate smoking-induced airway epithelial metabolism and damage by reprogramming lipid synthesis. The circulating or human airway epithelial metabolomic and lipidomic profiles of COPD patients or cell-lines explored with smoking were assessed to elucidate the pivotal roles of GPT2 in reprogramming processes. We found that GPT2 regulate the reprogramming of lipid metabolisms caused by smoking, especially phosphatidylcholine (PC) and triacylglycerol (TAG), along with changes in the expression of lipid metabolism-associated genes. GPT2 modulated cell sensitivities and survival in response to smoking by enhancing mitochondrial functions and maintaining lipid and energy homeostasis. Our findings provide evidence for the involvement of GPT2 in the reprogramming of airway epithelial lipids following smoking, as well as the molecular mechanisms underlying GPT2-mediated regulation, which may offer an alternative of therapeutic strategies for chronic lung diseases.
Assuntos
Lipidômica , Doença Pulmonar Obstrutiva Crônica , Humanos , Doença Pulmonar Obstrutiva Crônica/metabolismo , Doença Pulmonar Obstrutiva Crônica/genética , Lipidômica/métodos , Fumar/efeitos adversos , Fumar/metabolismo , Metabolismo dos Lipídeos/genética , Masculino , Feminino , Metabolômica/métodos , Pessoa de Meia-IdadeRESUMO
Lung cancer is a common malignancy that is frequently associated with systemic metabolic disorders. Early detection is pivotal to survival improvement. Although blood biomarkers have been used in its early diagnosis, missed diagnosis and misdiagnosis still exist due to the heterogeneity of lung cancer. Integration of multiple biomarkers or trans-omics results can improve the accuracy and reliability for lung cancer diagnosis. As metabolic reprogramming is a hallmark of lung cancer, metabolites, specifically lipids might be useful for lung cancer detection, yet systematic characterizations of metabolites in lung cancer are still incipient. The present study profiled the polar metabolome and lipidome in the plasma of lung cancer patients to construct an inclusive metabolomic atlas of lung cancer. A comprehensive analysis of lung cancer was also conducted combining metabolomics with clinical phenotypes. Furthermore, the differences in plasma lipid metabolites were compared and analyzed among different lung cancer subtypes. Alcohols, amides, and peptide metabolites were significantly increased in lung cancer, while carboxylic acids, hydrocarbons, and fatty acids were remarkably decreased. Lipid profiling revealed a significant increase in plasma levels of CER, PE, SM, and TAG in individuals with lung cancer as compared to those in healthy controls. Correlation analysis confirmed the association between a panel of metabolites and TAGs. Clinical trans-omics studies elucidated the complex correlations between lipidomic data and clinical phenotypes. The present study emphasized the clinical importance of lipidomics in lung cancer, which involves the correlation between metabolites and the expressions of other omics, ultimately influencing clinical phenotypes. This novel trans-omics network approach would facilitate the development of precision therapy for lung cancer.
Assuntos
Neoplasias Pulmonares , Metabolômica , Medicina de Precisão , Humanos , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/metabolismo , Metabolômica/métodos , Medicina de Precisão/métodos , Biomarcadores Tumorais/sangue , Masculino , Pessoa de Meia-Idade , Feminino , Lipidômica/métodos , Fenótipo , Metaboloma , Idoso , Lipídeos/sangueRESUMO
T cell immunity is critical for human defensive immune response. Exploring the key molecules during the process provides new targets for T cell-based immunotherapies. CMC1 is a mitochondrial electron transport chain (ETC) complex IV chaperon protein. By establishing in-vitro cell culture system and Cmc1 gene knock out mice, we evaluated the role of CMC1 in T cell activation and differentiation. The B16-OVA tumor model was used to test the possibility of targeting CMC1 for improving T cell anti-tumor immunity. We identified CMC1 as a positive regulator in CD8+T cells activation and terminal differentiation. Meanwhile, we found that CMC1 increasingly expressed in exhausted T (Tex) cells. Genetic lost of Cmc1 inhibits the development of CD8+T cell exhaustion in mice. Instead, deletion of Cmc1 in T cells prompts cells to differentiate into metabolically and functionally quiescent cells with increased memory-like features and tolerance to cell death upon repetitive or prolonged T cell receptor (TCR) stimulation. Further, the in-vitro mechanistic study revealed that environmental lactate enhances CMC1 expression by inducing USP7, mediated stabilization and de-ubiquitination of CMC1 protein, in which a mechanism we propose here that the lactate-enriched tumor microenvironment (TME) drives CD8+TILs dysfunction through CMC1 regulatory effects on T cells. Taken together, our study unraveled the novel role of CMC1 as a T cell regulator and its possibility to be utilized for anti-tumor immunotherapy.
Assuntos
Linfócitos T CD8-Positivos , Camundongos Knockout , Proteínas Mitocondriais , Animais , Camundongos , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Diferenciação Celular/imunologia , Ativação Linfocitária/imunologia , Melanoma Experimental/imunologia , Melanoma Experimental/patologia , Melanoma Experimental/genética , Camundongos Endogâmicos C57BL , Proteínas Mitocondriais/genética , Proteínas Mitocondriais/metabolismo , Ubiquitina Tiolesterase/metabolismo , Ubiquitina Tiolesterase/genéticaRESUMO
Cancer-associated fibroblasts (CAFs) are the main components in the tumor microenvironment. Tumors activate fibroblasts from quiescent state into activated state by secreting cytokines, and activated CAFs may in turn promote tumor progression and metastasis. Therefore, studies targeting CAFs could enrich the therapeutic options for tumor treatment. In this study, we demonstrate that the content of lipid droplets and the expression of autophagosomes were higher in CAFs than in peri-tumor fibroblasts (PTFs), which was inhibited by 5-(tetradecyloxy)-2-furoic acid(TOFA). The expression of CD36 in CAFs was higher than that in PTFs at both mRNA and protein levels. Inhibition of CD36 activity using either the CD36 inhibitor SSO or siRNA had a significant negative impact on the proliferation and migration abilities of CAFs, which was associated with reduced levels of relevant activated genes (α-SMA, FAP, Vimentin) and cytokines (IL-6, TGF-ß and VEGF-α). SSO also inhibited HCC growth and tumorigenesis in nude mice orthotopically implanted with CAFs and HCC cells. Our data further show that CD36+CAFs affected the expression of PD-1 in CTLs leading to CTL exhaustion, and that patients with high CD36 expression in CAFs were correlated with shorter overall survival (OS). Together, our data demonstrate that CAFs were active in lipid metabolism with increased lipid content and lipophagy activity. CD36 may play a key role in the regulation of the biological behaviors of CAFs, which may influence the proliferation and migration of tumor cells by reprograming the lipid metabolism in tumor cells. Thus, CD36 could be an effective therapeutic target for the treatment of HCC.
Assuntos
Fibroblastos Associados a Câncer , Carcinoma Hepatocelular , Neoplasias Hepáticas , Animais , Camundongos , Humanos , Carcinoma Hepatocelular/patologia , Fibroblastos Associados a Câncer/patologia , Neoplasias Hepáticas/patologia , Camundongos Nus , Reprogramação Metabólica , Linhagem Celular Tumoral , Fibroblastos/metabolismo , Citocinas/metabolismo , Microambiente Tumoral , Proliferação de CélulasRESUMO
Neutrophils play a crucial role in the immune system within tumor microenvironment. At present, numerous studies have explored the changes of neutrophils' automatic killing effect and cellular communication with other immune cells under pathological conditions through single-cell sequencing. However, there remains a lack of definite conclusion about the identification criteria of neutrophil subgroups. Here, we collected tumor and para-carcinoma tissues, pre- and postoperative blood from patients with non-small cell lung cancer (NSCLC), and performed single-cell RNA (scRNA) sequencing to evaluate the distribution of neutrophil subgroups. We have developed a computational method of over expression rate (OER) to evaluate the specificity of neutrophil subgroups, in order to target gene panels with potential clinical application value. In addition, OER was used to evaluate specificity of neutrophil subsets in healthy people and patients with various diseases to further validate the feasibility of this evaluation system. As a result, we found the specificity of Neu_ c1_ IL1B and Neu_ c2_ cxcr4 (low) in postoperative blood has increased, while that of IL-7R + neutrophils has decreased, indicating that these groups of cells possibly differentiated or migrated to other subgroups in the state of lung cancer. In addition, seven gene panels (Neu_c3_CST7, RSAD2_Neu, S100A2/Pabpc1_Neu, ISG15/Ifit3_Neu, CD74_Neu, PTGS2/Actg1_Neu, SPP1_Neu) were high specific in all the four NSCLC-associated samples, meaning that changes in the percentage of these cell populations would have a high degree of confidence in assessing changes of disease status. In conclusion, combined consideration of the distribution characteristics of neutrophil subgroups could help evaluate the diagnosis and prognosis of NSCLC.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Microambiente Tumoral , Neutrófilos , PulmãoRESUMO
We present an integrated analysis of the clinical measurements, immune cells, and plasma lipidomics of 2000 individuals representing different age stages. In the study, we explore the interplay of systemic lipids metabolism and circulating immune cells through in-depth analysis of immune cell phenotype and function in peripheral dynamic lipids environment. The population makeup of circulation lymphocytes and lipid metabolites changes dynamically with age. We identified a major shift between young group and middle age group, at which point elevated, immune response is accompanied by the elevation of specific classes of peripheral phospholipids. We tested the effects in mouse model and found that 10-month-dietary added phospholipids induced T-cell senescence. However, the chronic malignant disease, the crosstalk between systemic metabolism and immunity, is completely changed. In cancer patients, the unusual plasma cholesteryl esters emerged, and free fatty acids decreased. The study reveals how immune cell classes and peripheral metabolism coordinate during age acceleration and suggests immune senescence is not isolated, and thus, system effect is the critical point for cell- and function-specific immune-metabolic targeting. ⢠The study identifies a major shift of immune phenotype between young group and middle age group, and the immune response is accompanied by the elevation of specific classes of peripheral phospholipids; ⢠The study suggests potential implications for translational studies such as using metabolic drug to regulate immune activity.
Assuntos
Fosfolipídeos , Exaustão das Células T , Pessoa de Meia-Idade , Camundongos , Animais , Humanos , Fosfolipídeos/análise , Fosfolipídeos/metabolismo , Ácidos Graxos/metabolismo , Ésteres do ColesterolRESUMO
More immune-related adverse events (irAEs) have emerged along with increased immune checkpoint inhibitor (ICI) treatment. ICI-induced myocarditis is a rare type of irAE with early onset, rapid progression, and high mortality. Its specific pathophysiological mechanism is not fully understood. In total, 46 patients with tumors and 16 patients with ICI-induced myocarditis were included. We performed single-cell RNA sequencing on CD3 + T cells, flow cytometry, proteomics, and lipidomics to improve our understanding of the disease. First, we demonstrate the clinical features of patients with PD-1 inhibitor-induced myocarditis. We then identified 18 subsets of T cells using single-cell RNA sequencing and performed comparative analysis and further verification. The composition of T cells in the peripheral blood of patients has changed remarkably. Compared with non-irAE patients, effector T cells were increased in irAE patients, while naive T cells, γδ T cells, and mucosal-associated invariant T cell cluster cells were decreased. Besides, reduced γδ T cells characterized with effector functions, increased natural killer T cells with high levels of FCER1G in patients may suggest an association with disease development. Meanwhile, the peripheral inflammatory response was exacerbated in patients, accompanied by upregulation of exocytosis as well as increased levels of multiple lipids. We provide a comprehensive overview of the composition, gene profiles, and pathway signatures of CD3+ T cells driven by PD-1 inhibitor-induced myocarditis, as well as illustrate clinical features and multi-omic characteristics, providing a unique perspective on disease progression and therapy in clinical practice.
Assuntos
Inibidores de Checkpoint Imunológico , Miocardite , Humanos , Progressão da Doença , Exocitose , Inibidores de Checkpoint Imunológico/efeitos adversos , Multiômica , Miocardite/induzido quimicamenteRESUMO
Hepatocellular carcinoma (HCC) is an immunotherapy-resistant malignancy characterized by high cellular heterogeneity. The diversity of cell types and the interplay between tumor and non-tumor cells remain to be clarified. Single cell RNA sequencing of human and mouse HCC tumors revealed heterogeneity of cancer-associated fibroblast (CAF). Cross-species analysis determined the prominent CD36+ CAFs exhibited high-level lipid metabolism and expression of macrophage migration inhibitory factor (MIF). Lineage-tracing assays showed CD36+CAFs were derived from hepatic stellate cells. Furthermore, CD36 mediated oxidized LDL uptake-dependent MIF expression via lipid peroxidation/p38/CEBPs axis in CD36+ CAFs, which recruited CD33+myeloid-derived suppressor cells (MDSCs) in MIF- and CD74-dependent manner. Co-implantation of CD36+ CAFs with HCC cells promotes HCC progression in vivo. Finally, CD36 inhibitor synergizes with anti-PD-1 immunotherapy by restoring antitumor T-cell responses in HCC. Our work underscores the importance of elucidating the function of specific CAF subset in understanding the interplay between the tumor microenvironment and immune system.
RESUMO
Introduction: Although multiple targeted treatments have appeared, hepatocellular carcinoma (HCC) is still one of the most common causes of cancer-related deaths. The immunosuppressive tumor microenvironment (TME) is a critical factor in the oncogenesis and progression of HCC. The emerging scRNA-seq makes it possible to explore the TME at a high resolution. This study was designed to reveal the immune-metabolic crosstalk between immune cells in HCC and provide novel strategies to regulate immunosuppressive TME. Method: In this study, we performed scRNA-seq on paired tumor and peri-tumor tissues of HCC. The composition and differentiation trajectory of the immune populations in TME were portrayed. Cellphone DB was utilized to calculate interactions between the identified clusters. Besides, flow cytometry, RT-PCR and seahorse experiments were implemented to explore potential metabolic and epigenetic mechanisms of the inter-cellular interaction. Result: A total of 19 immune cell clusters were identified and 7 were found closely related to HCC prognosis. Besides, differentiation trajectories of T cells were also presented. Moreover, a new population, CD3+C1q+ tumor-associated macrophages (TAM) were identified and found significantly interacted with CD8+ CCL4+T cells. Compared to the peri-tumor tissue, their interaction was attenuated in tumor. Additionally, the dynamic presence of this newly found cluster was also verified in the peripheral blood of patients with sepsis. Furthermore, we found that CD3+C1q+TAM affected T cell immunity through C1q signaling-induced metabolic and epigenetic reprogramming, thereby potentially affecting tumor prognosis. Conclusion: Our study revealed the interaction between CD3+C1q+TAM and CD8+ CCL4+T cells and may provide implications for tackling the immunosuppressive TME in HCC.
Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Linfócitos T CD8-Positivos , Doença Crônica , Complemento C1q/metabolismo , Recidiva Local de Neoplasia/patologia , Microambiente Tumoral , Macrófagos Associados a Tumor/metabolismo , Complexo CD3/imunologiaRESUMO
Cell-state transition can reveal additional information from single-cell ribonucleic acid (RNA)-sequencing data in time-resolved biological phenomena. However, most of the current methods are based on the time derivative of the gene expression state, which restricts them to the short-term evolution of cell states. Here, we present single-cell State Transition Across-samples of RNA-seq data (scSTAR), which overcomes this limitation by constructing a paired-cell projection between biological conditions with an arbitrary time span by maximizing the covariance between two feature spaces using partial least square and minimum squared error methods. In mouse ageing data, the response to stress in CD4+ memory T cell subtypes was found to be associated with ageing. A novel Treg subtype characterized by mTORC activation was identified to be associated with antitumour immune suppression, which was confirmed by immunofluorescence microscopy and survival analysis in 11 cancers from The Cancer Genome Atlas Program. On melanoma data, scSTAR improved immunotherapy-response prediction accuracy from 0.8 to 0.96.
Assuntos
Perfilação da Expressão Gênica , RNA , Animais , Camundongos , RNA/genética , Perfilação da Expressão Gênica/métodos , Análise de Sequência de RNA/métodos , GenomaRESUMO
N-acetyltransferase 10 (NAT10), a nuclear acetyltransferase and a member of the GNAT family, plays critical roles in RNA stability and translation processes as well as cell proliferation. Little is known about regulatory effects of NAT10 in lung epithelial cell proliferation. We firstly investigated NTA10 mRNA expression in alveolar epithelial types I and II, basal, ciliated, club, and goblet/mucous epithelia from heathy and patients with chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, lung adenocarcinoma, para-tumor tissue, and systemic sclerosis, respectively. We selected A549 cells for representative of alveolar epithelia or H1299 and H460 cells as airway epithelia with different genetic backgrounds and studied dynamic responses of NAT10-down-regulated epithelia to high temperature, lipopolysaccharide, cigarette smoking extract (CSE), drugs, radiation, and phosphoinositide 3-kinase (PI3K) inhibitors at various doses. We also compared transcriptomic profiles between alveolar and airway epithelia, between cells with or without NAT10 down-regulation, between early and late stages, and between challenges. The present study demonstrated that NAT10 expression increased in human lung epithelia and varied among epithelial types, challenges, and diseases. Knockdown of NAT10 altered epithelial mitochondrial functions, dynamic responses to LPS, CSE, or PI3K inhibitors, and transcriptomic phenomes. NAT10 regulates biological phenomes, and behaviors are more complex and are dependent upon multiple signal pathways. Thus, NAT10-associated signal pathways can be a new alternative for understanding the disease and developing new biomarkers and targets.
Assuntos
Células Epiteliais , Fosfatidilinositol 3-Quinases , Humanos , Fosfatidilinositol 3-Quinases/metabolismo , Células Epiteliais/metabolismo , Pulmão/metabolismo , Acetiltransferases/metabolismo , Acetiltransferases/farmacologia , Células A549 , Acetiltransferases N-Terminal/metabolismoRESUMO
BACKGROUND: With the advent of immune checkpoint inhibitors (ICIs) therapies, a major breakthrough has been made in cancer treatment. However, instead of good results, some patients experienced a deterioration of their disease. This unexpected result is termed as hyper-progressive disease (HPD). The biology of HPD is currently not fully understood. METHODS: Isolation of CD3+ cells from peripheral blood mononuclear cells (PBMC) in healthy control, tumor patients receiving immunotherapy with or without immunotherapy-induced HPD, then conducted single-cell RNA sequencing (scRNA-seq). RESULTS: By analyzing scRNA-seq data, we identified 15 cell clusters. We observed developed-exhausted CD4+ T cells and regulatory T cells (Tregs) increasingly enriched in HPD group. Meanwhile, some effector T cells were decreased in HPD. The imbalance potentially contributes to the occurrence of HPD and poor clinical prognosis. In addition, we analyzed ligand-receptor interactions between subsets. The ligand-receptor interaction "CD74-MIF" was absent in HPD. However, in vitro experiment, we found that CD74 regulated effector function of effector CD8+ T cells. Overall, the article provides a primary study of immune profile in HPD.
Assuntos
Leucócitos Mononucleares , Fatores Inibidores da Migração de Macrófagos , Humanos , Linfócitos T CD8-Positivos/metabolismo , Ligantes , Transdução de Sinais , Imunoterapia/efeitos adversos , Fatores Inibidores da Migração de Macrófagos/metabolismo , Oxirredutases Intramoleculares/metabolismoRESUMO
Lipids and lipid metabolism play crucial roles in regulating T cell function and are tightly related to the establishment of immune memory. It is reported that tumor-infiltrating CD8+T lymphocytes (CD8+TILs) burn fats to restore their impaired effector function due to the lack of glucose. Conversely, fatty acids (FAs) and cholesterol in the tumor microenvironment (TME) drive the CD8+ TILs dysfunction. The origin of dysfunctional CD8+ TILs shares important features with memory T cell's precursor, but whether lipids and/or lipid metabolism reprogramming directly influence the memory plasticity of dysfunctional CD8+ TILs remains elusive. It is necessary to understand the interplay between cellular lipid metabolism and dysfunction of CD8+ TILs in the case of targeting T cell's metabolism to synergize cancer immunotherapy. Therefore, in this review, we summarize the latest research on CD8+ TILs lipid metabolism, evaluate the impacts of lipids in the TME to CD8+ TILs, and highlight the significance of promoting memory phenotype cell formation by targeting CD8+ T cells lipid metabolism to provide longer duration of cancer immunotherapy efficacy.
Assuntos
Linfócitos T CD8-Positivos , Neoplasias , Humanos , Linfócitos do Interstício Tumoral , Glucose/metabolismo , Ácidos Graxos/metabolismo , Lipídeos , Microambiente TumoralRESUMO
Background: Recent studies show that myeloid-derived suppressor cells (MDSCs) and M2-like macrophages are involved in the treatment of tumors; however, their therapeutic response role is rarely known in non-small cell lung cancer (NSCLC) during radiotherapy. We aim to explore the dynamic alteration of the circulating MDSCs and M2-like macrophages, to examine their relationship, and to evaluate their therapeutic response value for NSCLC patients in radiotherapy. Methods: Peripheral blood mononuclear cells from healthy controls and NSCLC patients with different radiotherapy phases were isolated to examine the circulating MDSCs and M2-like macrophages by flow cytometry. 40 plasma inflammatory cytokines were measured by multiplex ELISA. Results: In comparison with healthy controls, the percentages of MDSCs and CD68+CD163+M2-like macrophages of NSCLC patients were significantly elevated and were distinctly higher in radiotherapy than in preradiotherapy. MDSCs were correlated positively with CD68+CD163+M2-like macrophages in NSCLC patients in radiotherapy and postradiotherapy. Especially, we found that in comparison with those in the poor group, the percentages of two cells in the good response group were markedly increased during radiotherapy and they had a significantly positive correlation. During radiotherapy, the proportions of MDSCs were clearly increased in adenocarcinoma patients and the percentages of CD68+CD163+M2-like macrophages were markedly elevated in squamous carcinoma patients. We found that after radiotherapy, the expressions of eotaxin, MIP-1ß, MCP-1, and BLC were significantly increased in NSCLC patients. Further results showed that the low levels of eotaxin and TNF RII expression before radiotherapy could predict a good therapeutic response. IL-1ra and MIP-1ß had a positive relation with MDSCs or CD68+CD163+M2-like macrophages in NSCLC patients during radiotherapy, and eotaxin was correlated with CD68+CD163+M2-like macrophages but not MDSCs in NSCLC patients after radiotherapy. Conclusions: MDSCs and CD68+CD163+M2-like macrophages serve as therapeutic response biomarkers and are associated with the expressions of plasma inflammatory cytokines for NSCLC patients during radiotherapy.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Células Supressoras Mieloides , Antígenos CD , Antígenos de Diferenciação Mielomonocítica/metabolismo , Biomarcadores/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Quimiocina CCL4/metabolismo , Citocinas/metabolismo , Humanos , Contagem de Leucócitos , Leucócitos Mononucleares/metabolismo , Neoplasias Pulmonares/patologia , Macrófagos/metabolismo , Células Supressoras Mieloides/metabolismo , Receptores de Superfície CelularRESUMO
Background: Melanoma is a highly malignant and aggressive tumor. The search for new and effective biomarkers facilitates early diagnosis and treatment, ultimately improving the prognosis of melanoma patients. Although the transmembrane protein TMEM176B has been linked to a number of cancers, its role in cancer immunity remains unknown. Methods: Expression levels of TMEM176B in normal tissues and several cancers, including Skin Cutaneous Melanoma (SKCM), were collected from TCGA and GTEx. We used Receiver operating characteristic and Kaplan-Meier survival curves and performed regression analysis to elucidate the link between TMEM176B and clinicopathological features of SKCM in order to determine the prognostic significance of TMEM176B in SKCM. We then used the GEPIA and STRING websites to search for proteins and associated top genes that may interact with TMEM176B and enriched them for analysis. The link between TMEM176B and immune cells infiltration was then investigated using TIMER, CIBERSORT algorithm and GSVA package of R (v3.6.3). Finally, animal tests were conducted to confirm the expression of Tmem176b and its influence on T-cell immune infiltration. Results: TMEM176B expression was considerably elevated in SKCM compared to normal tissues. Particularly, TMEM176B expression was also linked to pathological stage, tumor ulceration and radiation therapy. Patients with elevated TMEM176B expression had a better prognosis, according to the survival analysis. The majority of tumor infiltrating lymphocytes (TILs) especially T cells in SKCM was positively linked with TMEM176B expression. Our animal experiments also verified that the T-cell infiltration was significantly inhibited in local melanoma tissue of Tmem176b knockout mice. At the same time deleting Tmem176b accelerated tumor progress and impaired T cells effector function. Conclusion: Upregulated expression of TMEM176B in SKCM is associated with a better prognosis and it has the potential to serve as a diagnostic and prognostic marker for the disease. It may serve as a target for SKCM immunotherapy by regulating CD8+ T cells although it requires more evidence.
RESUMO
Spatial transcriptomics is considered as an important part of spatiotemporal molecular images to bridge molecular information with clinical images. Of those potentials and opportunities, the excellent quality of human sample preparation and handling will ensure the precise and reliable information generated from clinical spatial transcriptome. The present study aims at defining potential factors that might influence the quality of spatial transcriptomics in lung cancer, para-cancer, or normal tissues, pathological images of sections and the RNA integrity before spatial transcriptome sequencing. We categorised potential influencing factors from clinical aspects, including patient selection, pathological definition, surgical types, sample harvest, temporary preservation conditions and solutions, frozen approaches, transport and storage conditions and duration. We emphasis on the relationship between the combination of histological scores with RNA integrity number (RIN) and the unique molecular identifier (UMI), which is determines the quality of of spatial transcriptomics; however, we did not find significantly relevance between them. Our results showed that isolated times and dry conditions of sample are critical for the UMI and the quality of spatial transcriptomic samples. Thus, clinical procedures of sample preparation should be furthermore optimised and standardised as new standards of operation performance for clinical spatial transcriptome. Our data suggested that the temporary preservation time and condition of samples at operation room should be within 30 min and in 'dry' status. The direct cryo-preservation within OCT media for human lung sample is recommended. Thus, we believe that clinical spatial transcriptome will be a decisive approach and bridge in the development of spatiotemporal molecular images and provide new insights for understanding molecular mechanisms of diseases at multi-orientations.
Assuntos
Perfilação da Expressão Gênica/instrumentação , Perfilação da Expressão Gênica/métodos , Manejo de Espécimes/métodos , Humanos , Manejo de Espécimes/tendênciasRESUMO
Increasing evidence supports a central role of the immune system in lung diseases. Understanding how immunological alterations between lung diseases provide opportunities for immunotherapy. Exhausted T cells play a key role of immune suppression in lung cancer and chronic obstructive pulmonary disease was proved in our previous study. The present study aims to furthermore define molecular landscapes and heterogeneity of systemic immune cell target proteomic and transcriptomic profiles and interactions between circulating immune cells and lung residential cells in various lung diseases. We firstly measured target proteomic profiles of circulating immune cells from healthy volunteers and patients with stable pneumonia, stable asthma, acute asthma, acute exacerbation of chronic obstructive pulmonary disease, chronic obstructive pulmonary disease and lung cancer, using single-cell analysis by cytometry by time-of-flight with 42 antibodies. The nine immune cells landscape was mapped among those respiratory system diseases, including CD4+ T cells, CD8+ T cells, dendritic cells, B cells, eosinophil, γδT cells, monocytes, neutrophil and natural killer cells. The double-negative T cells and exhausted CD4+ central memory T cells subset were identified in patients with acute pneumonia. This T subset expressed higher levels of T-cell immunoglobulin and mucin domain-containing protein 3 (Tim3) and T-cell immunoreceptor with Ig and ITIM domains (TIGIT) in patients with acute pneumonia and stable pneumonia. Biological processes and pathways of immune cells including immune response activation, regulation of cell cycle and pathways in cancer in peripheral blood immune cells were defined by bulk RNA sequencing (RNA-seq). The heterogeneity among immune cells including CD4+ , CD8+ T cells and NK T cells by single immune cell RNA-seq with significant difference was found by single-cell sequencing. The effect of interstitial telocytes on the immune cell types and immune function was finally studied and the expressions of CD8a and chemokine C-C motif receptor 7 (CCR7) were increased significantly in co-cultured groups. Our data indicate that proteomic and transcriptomic profiles and heterogeneity of circulating immune cells provides new insights for understanding new molecular mechanisms of immune cell function, interaction and modulation as a source to identify and develop biomarkers and targets for lung diseases.
Assuntos
Censos , Células Matadoras Naturais/imunologia , Pneumopatias/metabolismo , Adulto , Feminino , Humanos , Células Matadoras Naturais/metabolismo , Pneumopatias/fisiopatologia , Masculino , Pessoa de Meia-IdadeRESUMO
T cells play an important role in antitumor immunity. Numbers and function of T cells are controlled by regulating the uptake and utilization of nutrients, and their antitumor activity can be promoted by targeting metabolic pathways. In this review, we highlight the relationship between metabolism and cellular function of T cells. Specifically, we emphasize the metabolic state of tumor-infiltrating T cells and review key pathways that affect the antitumor function of T cells. In the field of tumor immunotherapy, targeting T cell metabolism to enhance the immune response is a new therapeutic strategy for enhancing immunotherapy combined with traditional treatments.
Assuntos
Imunoterapia Adotiva/métodos , Neoplasias/imunologia , Neoplasias/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo , Animais , Antineoplásicos/imunologia , Antineoplásicos/metabolismo , Humanos , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Neoplasias/terapiaRESUMO
The use of immune checkpoint inhibitors (ICIs) is rising exponentially in numerous cancers, but immune-related adverse events can occur. We report a rare case of high-grade drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome developed stepwise in a patient with gastric cancer after nivolumab treatment. Subclinical myocarditis was sensitively detected by cardiovascular magnetic resonance 3 weeks after initiating nivolumab. Eruption, eosinophilia, and interstitial pneumonitis occurred 1 week later. Corticosteroids were started and his condition improved. Four months later, when he was still on steroids tapering off, acute kidney injury and sequential herpes zoster virus activation developed. Severe acute tubulointerstitial nephritis (ATN) with an intense infiltration of lymphocytes was observed on renal biopsy. In blood, a substantial shift to Th2 response, an increase of Th17 cells, and strikingly enriched granzyme B+ and perforin+ CD8+ T cells were detected at ATN onset. Serum interleukin (IL)-5, IL-17, interferon gamma, and IL-6 levels were consistently elevated. Further molecular profiling identified a DRESS risk allele human leukocyte antigen (HLA)-A*31:01 in this patient. His ATN responded favorably to a high dose of corticosteroids. In parallel, complete antitumor response was observed during the clinical course of DRESS. This is the first ever case report of nivolumab-associated DRESS syndrome with exploration of the mechanisms from the histopathological, cellular and molecular aspects. Nivolumab-induced DRESS may result from type IV hypersensitivity-related 'off-target effect' and PD-1 block-mediated 'on-target effect'. HLA risk alleles may constitute the genetic susceptible basis. HLA typing assay has the potential to screen susceptible individuals to avoid ICI-induced DRESS.