ABSTRACT
Tumor aerobic glycolysis is one of the main features of tumor metabolic reprogramming. This abnormal glycolytic metabolism provides bioenergy and biomaterials for tumor growth and proliferation. It is worth noting that aerobic glycolysis will not only provide biological materials and energy for tumor cells, but also help tumor cells to escape immune surveillance through regulation of immune microenvironment, thereby resisting tumor immunotherapy and promoting tumor progression. Based on the pathogenesis of renal cell carcinoma, this paper describes the characteristics of aerobic glycolysis, the effect of glycolytic metabolism on the immune microenvironment of renal cell carcinoma, the effect of glycolysis inhibitors on the immune microenvironment of renal cell carcinoma, and the prospect of glycolysis inhibitors combined with immune checkpoint inhibitors in the treatment of renal cell carcinoma.
Subject(s)
Humans , Carcinoma, Renal Cell/therapy , Immunotherapy , Glycolysis , Metabolic Reprogramming , Kidney Neoplasms/therapy , Tumor MicroenvironmentABSTRACT
Hepatocellular carcinoma (HCC) is well characterized as a heterogeneous disease. Its late-stage diagnosis and chemotherapy resistance make it one of the refractory tumors in China. Natural killer (NK) cells play a significant role in immune surveillance. However, NK cells become dysfunctional in the progression of HCC, leading to tumor immune escape. This article reviews the recent progress on different strategies of NK cell-based immunotherapy in treating HCC, including direct adoptive NK cell transfer, gene engineering in NK cell, NK cell receptor targeting, immunosuppressive microenvironment modification, and tumor toxicity enhancement by cytokines or traditional Chinese medicine. These NK cell-based strategies have shown promising therapeutic potential.
Subject(s)
Humans , Carcinoma, Hepatocellular/therapy , Liver Neoplasms/therapy , Immunotherapy , Killer Cells, Natural , Receptors, Natural Killer Cell , Tumor MicroenvironmentABSTRACT
Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are currently the first-line standard of care for patients with non-small cell lung cancer (NSCLC) that harbor EGFR mutations. Nevertheless, resistance to EGFR-TKIs is inevitable. In recent years, although immune checkpoint inhibitors (ICIs) have significantly shifted the treatment paradigm in advanced NSCLC without driver mutation, clinical benefits of these agents are limited in patients with EGFR-mutated NSCLC. Compared with wild-type tumors, tumors with EGFR mutations show more heterogeneity in the expression level of programmed cell death ligand 1 (PD-L1), tumor mutational burden (TMB), and other tumor microenvironment (TME) characteristics. Whether ICIs are suitable for NSCLC patients with EGFR mutations is still worth exploring. In this review, we summarized the clinical data with regard to the efficacy of ICIs in patients with EGFR-mutated NSCLC and deciphered the unique TME in EGFR-mutated NSCLC. .
Subject(s)
Humans , Carcinoma, Non-Small-Cell Lung/genetics , Lung Neoplasms/genetics , ErbB Receptors/metabolism , Immunotherapy , Mutation , B7-H1 Antigen/genetics , Protein Kinase Inhibitors/pharmacology , Tumor MicroenvironmentABSTRACT
So far, the monoclonal hypothesis of tumor occurrence and development cannot be justified. The genetic diversity selection hypothesis for the occurrence and development of lung cancer links Mendelian genetics with Darwin's theory of evolution, suggesting that the genetic diversity of tumor cell populations with polyclonal origins-monoclonal selection-subclonal expansion is the result of selection pressure. Normal cells acquire mutations in oncogenic driver genes and have a selective advantage over other cells, becoming tumor initiating cells; In the interaction with the tumor microenvironment (TME), the vast majority of initiating cells are recognized and killed by the human immune system. If immune escape occurs, the incidence of malignant tumors will greatly increase, and subclonal expansion, intratumour heterogeneity, etc. will occur. This article proposed the hypothesis of genetic diversity selection and analyzed its clinical significance. .
Subject(s)
Humans , Lung Neoplasms/genetics , Clinical Relevance , Evolution, Molecular , Mutation , Tumor MicroenvironmentABSTRACT
BACKGROUND@#With the rise of multicolor flow cytometry, flow cytometry has become an important means to detect the immune microenvironment of lung cancer, but most of them are used to detect the proportion of cell subsets or the function of major cell subsets, and they cannot be detected at the same time. Therefore, a reliable 21-color flow cytometry protocol was established to detect the immune cell subsets in human non-small cell lung cancer (NSCLC) tumor tissues.@*METHODS@#Cell membrane surface antibodies cluster of differentiation (CD)45, CD3, CD19, CD4, CD8, programmed cell death 1 (PD-1), CD39, CD103, CD25, CD127, chemokine receptor 8 (CCR8), CD56, CD11c, human leukocyte antigen (HLA)-DR, CD38, CD27, CD69, CD62L, CD45RA, CCR7 and nucleic acid dye L/D were used to develop the protocol. Firstly, antibody titration experiments, voltage optimization, subtraction of one color staining and single color staining experiments were carried out for each antibody, and after the experimental conditions and detection schemes were determined, the feasibility of the scheme was verified by using peripheral blood mononuclear cells (PBMCs) specimens of six healthy adult volunteers. Tumor tissue samples from 6 NSCLC patients were tested and analyzed.@*RESULTS@#The established 21-color flow cytometry protocol was used to detect the tumor tissue samples of 6 NSCLC patients, and the proportion of each cell subset in lung cancer tissue, as well as the immunophenotype and differentiation of the main cell population, were analyzed.@*CONCLUSIONS@#The successfully established 21-color flow cytometry protocol is suitable for the detection of PBMCs and NSCLC tissue samples, which provides an effective new idea for monitoring the immune microenvironment status in lung cancer.
Subject(s)
Adult , Humans , Carcinoma, Non-Small-Cell Lung/pathology , Lung Neoplasms/pathology , Flow Cytometry , Leukocytes, Mononuclear/pathology , Lung/pathology , Tumor MicroenvironmentABSTRACT
Granulocytic myeloid-derived suppressor cells (G-MDSCs) are one of the main subgroups of MDSCs, which are widely enriched in most cancers. It can inhibit the killing function of T-lymphocyte through the expression of arginase-1 (Arg-1) and reactive oxygen species (ROS), reshape the tumor immune microenvironment, and promote the occurrence and development of tumors. In recent years, more and more studies have found that G-MDSCs are significantly correlated with the prognosis and immunotherapy efficacy of patients with non-small cell lung cancer, and the use of drugs specifically targeting the recruitment, differentiation and function of G-MDSCs can effectively inhibit tumor progression. This article reviews the immunosuppressive effect of G-MDSCs in non-small cell lung cancer and the progress of related pathway targeting drugs. .
Subject(s)
Humans , Myeloid-Derived Suppressor Cells , Carcinoma, Non-Small-Cell Lung , Lung Neoplasms/drug therapy , T-Lymphocytes , Immunotherapy , Tumor MicroenvironmentABSTRACT
Tumor progression is closely related to tumor tissue metabolism and reshaping of the microenvironment. Oral squamous cell carcinoma (OSCC), a representative hypoxic tumor, has a heterogeneous internal metabolic environment. To clarify the relationship between different metabolic regions and the tumor immune microenvironment (TME) in OSCC, Single cell (SC) and spatial transcriptomics (ST) sequencing of OSCC tissues were performed. The proportion of TME in the ST data was obtained through SPOTlight deconvolution using SC and GSE103322 data. The metabolic activity of each spot was calculated using scMetabolism, and k-means clustering was used to classify all spots into hyper-, normal-, or hypometabolic regions. CD4T cell infiltration and TGF-β expression is higher in the hypermetabolic regions than in the others. Through CellPhoneDB and NicheNet cell-cell communication analysis, it was found that in the hypermetabolic region, fibroblasts can utilize the lactate produced by glycolysis of epithelial cells to transform into inflammatory cancer-associated fibroblasts (iCAFs), and the increased expression of HIF1A in iCAFs promotes the transcriptional expression of CXCL12. The secretion of CXCL12 recruits regulatory T cells (Tregs), leading to Treg infiltration and increased TGF-β secretion in the microenvironment and promotes the formation of a tumor immunosuppressive microenvironment. This study delineates the coordinate work axis of epithelial cells-iCAFs-Tregs in OSCC using SC, ST and TCGA bulk data, and highlights potential targets for therapy.
Subject(s)
Humans , Carcinoma, Squamous Cell/metabolism , Squamous Cell Carcinoma of Head and Neck , Mouth Neoplasms/metabolism , Immunosuppression Therapy , Transforming Growth Factor beta , Head and Neck Neoplasms , Gene Expression Profiling , Tumor MicroenvironmentABSTRACT
Small cell lung cancer (SCLC) is a highly malignant tumor with a very poor prognosis; therefore, more effective treatments are urgently needed for patients afflicted with the disease. In recent years, emerging molecular classifications based on key transcription factors of SCLC have provided more information on the tumor pathophysiology, metastasis, immune microenvironment, and acquired therapeutic resistance and reflected the intertumoral heterogeneity of the various SCLC phenotypes. Additionally, advances in genomics and single-cell sequencing analysis have further revealed the high intratumoral heterogeneity and plasticity of the disease. Herein, we review and summarize these recent lines of evidence and discuss the possible pathogenesis of SCLC.
Subject(s)
Humans , Small Cell Lung Carcinoma/genetics , Lung Neoplasms/genetics , Prognosis , Genomics , Phenotype , Tumor MicroenvironmentABSTRACT
BACKGROUND@#Findings on the association of genetic factors and colorectal cancer (CRC) survival are limited and inconsistent, and revealing the mechanism underlying their prognostic roles is of great importance. This study aimed to explore the relationship between functional genetic variations and the prognosis of CRC and further reveal the possible mechanism.@*METHODS@#We first systematically performed expression quantitative trait locus (eQTL) analysis using The Cancer Genome Atlas (TCGA) dataset. Then, the Kaplan-Meier analysis was used to filter out the survival-related eQTL target genes of CRC patients in two public datasets (TCGA and GSE39582 dataset from the Gene Expression Omnibus database). The seven most potentially functional eQTL single nucleotide polymorphisms (SNPs) associated with six survival-related eQTL target genes were genotyped in 907 Chinese CRC patients with clinical prognosis data. The regulatory mechanism of the survival-related SNP was further confirmed by functional experiments.@*RESULTS@#The rs71630754 regulating the expression of endoplasmic reticulum aminopeptidase 1 ( ERAP1 ) was significantly associated with the prognosis of CRC (additive model, hazard ratio [HR]: 1.43, 95% confidence interval [CI]: 1.08-1.88, P = 0.012). The results of dual-luciferase reporter assay and electrophoretic mobility shift assay showed that the A allele of the rs71630754 could increase the binding of transcription factor 3 (TCF3) and subsequently reduce the expression of ERAP1 . The results of bioinformatic analysis showed that lower expression of ERAP1 could affect the tumor immune microenvironment and was significantly associated with severe survival outcomes.@*CONCLUSION@#The rs71630754 could influence the prognosis of CRC patients by regulating the expression of the immune-related gene ERAP1 .@*TRIAL REGISTRATION@#No. NCT00454519 ( https://clinicaltrials.gov/ ).
Subject(s)
Humans , Prognosis , Genotype , Polymorphism, Single Nucleotide/genetics , Quantitative Trait Loci , Colorectal Neoplasms , Tumor Microenvironment , Aminopeptidases/metabolism , Minor Histocompatibility Antigens/geneticsABSTRACT
BACKGROUND@#Radiation (IR)-induced DNA damage triggers cell cycle arrest and has a suppressive effect on the tumor microenvironment (TME). Wee1, a cell cycle regulator, can eliminate G2/M arrest by phosphorylating cyclin-dependent kinase 1 (CDK1). Meanwhile, programed death-1/programed death ligand-1 (PD-1/PDL-1) blockade is closely related to TME. This study aims to investigate the effects and mechanisms of Wee1 inhibitor AZD1775 and anti-PD-1 antibody (anti-PD-1 Ab) on radiosensitization of hepatoma.@*METHODS@#The anti-tumor activity of AZD1775 and IR was determined by 3-(4,5-dimethylthiazol-2-y1)-2,5-diphenyltetrazolium bromide (MTT) assay on human and mouse hepatoma cells HepG2, Hepa1-6, and H22. The anti-hepatoma mechanism of AZD1775 and IR revealed by flow cytometry and Western blot in vitro . A hepatoma subcutaneous xenograft mice model was constructed on Balb/c mice, which were divided into control group, IR group, AZD1775 group, IR + AZD1775 group, IR + anti-PD-1 Ab group, and the IR + AZD1775 + anti-PD-1 Ab group. Cytotoxic CD8 + T cells in TME were analyzed by flow cytometry.@*RESULTS@#Combining IR with AZD1775 synergistically reduced the viability of hepatoma cells in vitro . AZD1775 exhibited antitumor effects by decreasing CDK1 phosphorylation to reverse the IR-induced G2/M arrest and increasing IR-induced DNA damage. AZD1775 treatment also reduced the proportion of PD-1 + /CD8 + T cells in the spleen of hepatoma subcutaneous xenograft mice. Further studies revealed that AZD1775 and anti-PD-1 Ab could enhance the radiosensitivity of hepatoma by enhancing the levels of interferon γ (IFNγ) + or Ki67 + CD8 T cells and decreasing the levels of CD8 + Tregs cells in the tumor and spleen of the hepatoma mice model, indicating that the improvement of TME was manifested by increasing the cytotoxic factor IFNγ expression, enhancing CD8 + T cells proliferation, and weakening CD8 + T cells depletion.@*CONCLUSIONS@#This work suggests that AZD1775 and anti-PD-1 Ab synergistically sensitize hepatoma to radiotherapy by enhancing IR-induced DNA damage and improving cytotoxic CD8 + T cells in TME.
Subject(s)
Humans , Animals , Mice , Carcinoma, Hepatocellular/radiotherapy , Cell Cycle Proteins/metabolism , Protein-Tyrosine Kinases/genetics , Apoptosis , Programmed Cell Death 1 Receptor , Cell Line, Tumor , G2 Phase Cell Cycle Checkpoints , Liver Neoplasms/radiotherapy , Tumor Microenvironment , Pyrazoles , PyrimidinonesABSTRACT
BACKGROUND@#Artificial intelligence (AI) technology represented by deep learning has made remarkable achievements in digital pathology, enhancing the accuracy and reliability of diagnosis and prognosis evaluation. The spatial distribution of CD3 + and CD8 + T cells within the tumor microenvironment has been demonstrated to have a significant impact on the prognosis of colorectal cancer (CRC). This study aimed to investigate CD3 CT (CD3 + T cells density in the core of the tumor [CT]) prognostic ability in patients with CRC by using AI technology.@*METHODS@#The study involved the enrollment of 492 patients from two distinct medical centers, with 358 patients assigned to the training cohort and an additional 134 patients allocated to the validation cohort. To facilitate tissue segmentation and T-cells quantification in whole-slide images (WSIs), a fully automated workflow based on deep learning was devised. Upon the completion of tissue segmentation and subsequent cell segmentation, a comprehensive analysis was conducted.@*RESULTS@#The evaluation of various positive T cell densities revealed comparable discriminatory ability between CD3 CT and CD3-CD8 (the combination of CD3 + and CD8 + T cells density within the CT and invasive margin) in predicting mortality (C-index in training cohort: 0.65 vs. 0.64; validation cohort: 0.69 vs. 0.69). The CD3 CT was confirmed as an independent prognostic factor, with high CD3 CT density associated with increased overall survival (OS) in the training cohort (hazard ratio [HR] = 0.22, 95% confidence interval [CI]: 0.12-0.38, P <0.001) and validation cohort (HR = 0.21, 95% CI: 0.05-0.92, P = 0.037).@*CONCLUSIONS@#We quantify the spatial distribution of CD3 + and CD8 + T cells within tissue regions in WSIs using AI technology. The CD3 CT confirmed as a stage-independent predictor for OS in CRC patients. Moreover, CD3 CT shows promise in simplifying the CD3-CD8 system and facilitating its practical application in clinical settings.
Subject(s)
Humans , Lymphocytes, Tumor-Infiltrating , Colorectal Neoplasms , Artificial Intelligence , Reproducibility of Results , Prognosis , CD8-Positive T-Lymphocytes , Tumor MicroenvironmentABSTRACT
Exosomes are 30-120nm bio particles transferred from donor to recipient cells leading to modification in their regulatory mechanisms depending upon the coded message in the form of loaded biomolecule. Cancer cells derived exosomes the true representatives of the parent cells have been found to modify the tumor surrounding/distinct regions and participate in metastasis, angiogenesis and immune suppression. Tis study was aimed to study the effects of tumor mice derived exosomes on the normal mice spleen isolated T cells by using co-culture experiments and flow cytometer analysis. We mainly focused on some of the T cells population and cytokines including IFN-γ, FOXP3+ regulatory T (Treg) cells and KI67 (proliferation marker). Overall results indicated random changes in different set of experiments, where the cancer derived exosomes reduced the IFN-γ expression in both CD4 and CD8 T cells, similarly the Treg cells were also found decreased in the presence of cancer exosomes. No significant changes were observed on the Ki67 marker expression. Such studies are helpful in understanding the role of cancer exosomes in immune cells suppression in tumor microenvironment. Cancer exosomes will need to be validated in vivo and in vitro on a molecular scale in detail for clinical applications.
Os exossomos são biopartículas de 30-120 nm transferidas de células doadoras para células receptoras, levando à modificação em seus mecanismos reguladores, dependendo da mensagem codificada na forma de biomolécula carregada. Verificou-se que exossomos derivados de células cancerosas os verdadeiros representantes das células-mãe modificam as regiões circundantes / distintas do tumor e participam da metástase, angiogênese e imunossupressão. Este estudo teve como objetivo estudar os efeitos de exossomos derivados de camundongos com tumor nas células T isoladas de baço de camundongos normais, usando experimentos de cocultura e análise de citômetro de fluxo. Concentrou-se, principalmente, em algumas populações de células T e citocinas, incluindo IFN-γ, células T reguladoras FOXP3 + (Treg) e KI67 (marcador de proliferação). Os resultados gerais indicaram mudanças aleatórias em diferentes conjuntos de experimentos, em que os exossomos derivados de câncer reduziram a expressão de IFN-γ em células T CD4 e CD8, da mesma forma que as células Treg também foram encontradas diminuídas na presença de exossomos de câncer. Nenhuma mudança significativa foi observada na expressão do marcador Ki67. Esses dados são úteis para a compreensão do papel dos exossomos do câncer na supressão de células do sistema imunológico no microambiente tumoral. Exossomos de câncer precisarão ser validados in vivo e in vitro em escala molecular com detalhes para aplicações clínicas.
Subject(s)
Animals , Mice , Exosomes , Tumor Microenvironment , Immune System , Neoplasm Metastasis , NeoplasmsABSTRACT
Non-small cell lung cancer (NSCLC) with oncogenic driver mutations was previously deemed " forbidden territory" for immunotherapy. With the growing understanding of the impact of target drugs on the immune microenvironment and the continuous generation of clinical evidence, immunotherapy is expected to bring new hope for the NSCLC with oncogenic driver mutations. This consensus is updated based on the Chinese expert consensus on immunotherapy for advanced non-small lung cancer with oncogenic driver mutations (2022 edition), and developed by the consensus expert panel through symposiums, combining the latest medical evidence and clinical practice. After thorough discussion, the expert panel reached new consensuses on 3 clinical questions: in patients with ALK fusion who are progressing on tyrosine kinase inhibitor(TKI) therapy, immune checkpoint inhibitors (ICIs)-based treatment is not recommended; ICIs-based treatment is recommended for patients with HER-2 mutations; ICIs-based treatment is recommended for NSCLC patients with MET exon 14 skipping after resistance to the targeted therapy. At the same time, with the continuous accumulation of clinical evidence, the recommendation levels of the three consensus opinions were adjusted in this update: the recommendation of ICIs combined with anti-angiogenesis therapy for patients with extensive progression after EGFR-TKIs resistance was adjusted to the level of strong; the ICIs recommendations for patients with advanced KRAS mutant and BRAF mutant NSCLC were adjusted to the level of consistent and strong, respectively. This updated consensus, combined with the latest evidence and clinical experience widely recognized by the expert panel in the immunotherapy of driver gene mutation advanced NSCLC, aims to provide standardized guidance for the clinical practice in China.
Subject(s)
Humans , Carcinoma, Non-Small-Cell Lung/genetics , Consensus , Immunotherapy , Lung Neoplasms/genetics , Mutation , Tumor Microenvironment , ChinaABSTRACT
Immunotherapies based on immune checkpoint blockade (ICB) have significantly improved patient outcomes and offered new approaches to cancer therapy over the past decade. To date, immune checkpoint inhibitors (ICIs) of CTLA-4 and PD-1/PD-L1 represent the main class of immunotherapy. Blockade of CTLA-4 and PD-1/PD-L1 has shown remarkable efficacy in several specific types of cancers, however, a large subset of refractory patients presents poor responsiveness to ICB therapy; and the underlying mechanism remains elusive. Recently, numerous studies have revealed that metabolic reprogramming of tumor cells restrains immune responses by remodeling the tumor microenvironment (TME) with various products of metabolism, and combination therapies involving metabolic inhibitors and ICIs provide new approaches to cancer therapy. Nevertheless, a systematic summary is lacking regarding the manner by which different targetable metabolic pathways regulate immune checkpoints to overcome ICI resistance. Here, we demonstrate the generalized mechanism of targeting cancer metabolism at three crucial immune checkpoints (CTLA-4, PD-1, and PD-L1) to influence ICB therapy and propose potential combined immunotherapeutic strategies co-targeting tumor metabolic pathways and immune checkpoints.
Subject(s)
Humans , Antibodies, Monoclonal/pharmacology , B7-H1 Antigen/antagonists & inhibitors , CTLA-4 Antigen/antagonists & inhibitors , Immune Checkpoint Inhibitors/pharmacology , Neoplasms/drug therapy , Programmed Cell Death 1 Receptor , Tumor MicroenvironmentABSTRACT
Objective To identify the possibility of IgG Fc binding protein (FCGBP) acting as a prognostic marker of low-grade glioma (LGG) and its correlation with immune infiltration. Methods The expression of FCGBP was analyzed in pan-cancer using The Cancer Genome Atlas (TCGA), Genotypic tissue expression (GTEX), and China Glioma Genome Atlas (CGGA) database. Then, GSE15824 and GSE68848 datasets were selected for further verification. And gene expression Profile Interaction analysis (GEPIA) database and R language were used to analyze the relationship between FCGBP and survival prognosis. Metascape and GSEA were used for functional annotation and enrichment analysis. Finally, the expression of FCGBP gene in LGG immune microenvironment and its correlation with immune cells were analyzed by TIMER database. Results FCGBP was highly expressed in LGG tissues, indicating poor prognosis of LGG patients. Receiver operating characteristic (ROC) curve analysis and COX analysis showed that FCGBP was an independent risk factor for the prognosis of LGG. Moreover, Gene Ontology (GO) demonstrated that FCGBP was involved in cell metabolism, localization, positive, and negative regulation of biological processes, as well as biological adhesion, response to viral and microbial stimulation, and inflammation. GSEA pathway enrichment analysis showed that FCGBP was significantly correlated with Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway, Toll-like receptor (TLR) pathway, chemokine pathway, and P53 pathway. In addition, FCGBP expression was positively correlated with the expression of most immune cells in the immune microenvironment of LGG. Conclusion The high expression of FCGBP in LGG is a risk factor for survival and prognosis, and it is positively correlated with the expression of immune cells.
Subject(s)
Humans , Prognosis , Glioma/genetics , China , Gene Ontology , Immunoglobulin G , Tumor Microenvironment , Cell Adhesion MoleculesABSTRACT
Objective To investigate the effects of paclitaxel and doxorubicin on the immune microenvironment of breast cancer in mice. Methods The CTR-DB database, a database for analysis of gene expression profiles and drug resistance characteristics related to tumor drug response, was used to analyze the effect of chemotherapeutic drugs on the immune microenvironment of breast cancer. Mouse models with breast cancer were established by in situ injection with 4T1 cells, a triple-negative breast cancer (TNBC) cells. Then they were treated with doxorubicin and paclitaxel, respectively. The sizes of tumor were recorded and analyzed by growth curve. The number of different types of immune cells was analyzed using flow cytometry. The expressions of Ki67, S100 calcium binding protein A9 (S100A9) and matrix metalloproteinase 9 (MMP9) were detected by immunohistochemistry. The cell cycles of 4T1 cells in paclitaxel group and doxorubicin group were analyzed by flow cytometry. Results The results of CTR_Microarray_75 analysis showed that the immune scores, and the number of cytotoxic lymphocytes, B lineages, CD8+ T cells, dendritic cells (DCs), monocytic lineages and natural killer (NK) cells in chemotherapy-sensitive breast cancer were higher than those in chemotherapy-insensitive breast cancer. Through growth curve analysis in mice with breast cancer, we found that both paclitaxel and doxorubicin could inhibit the increase of the tumor sizes, and the paclitaxel showed a higher inhibitory effect. The results of cytometry displayed that both paclitaxel and doxorubicin could restrain the expression of Ki67 and increase the number of breast cancer cells in G2/M phase, and in the paclitaxel group, the expression of Ki67 was lower and the number of breast cancer cells in G2/M phase was larger. Paclitaxel and doxorubicin enhanced the infiltration of CD45+ immune cells but decreased the infiltration of neutrophils. Additionally, paclitaxel promoted the infiltration of CD3+CD4+ T helper cells, CD3+CD8+ cytotoxic T cells and CD45+CD19+B cells, while doxorubicin increased the infiltration of CD4+CD25+ regulatory T cells (Tregs). The results of immunohistochemistry displayed that the paclitaxel significantly inhibited the expression of S100A9, while the doxorubicin significantly restrained the expression of MMP9. Conclusion Paclitaxel and doxorubicin can effectively inhibit the growth of breast cancer cells and change immune microenvironment of TNBC by regulating the different patterns of cell infiltration and the expression of different extracellular matrix components.
Subject(s)
Animals , Mice , Humans , Paclitaxel/pharmacology , Matrix Metalloproteinase 9 , Triple Negative Breast Neoplasms/drug therapy , CD8-Positive T-Lymphocytes , Ki-67 Antigen , Doxorubicin/pharmacology , Calgranulin B , Tumor MicroenvironmentABSTRACT
Colorectal cancer is a common malignant tumor in gastrointestinal tract. Its onset and development are associated with its own characteristics as well as the tumor microenvironment (TME) in which tumor-associated macrophages (TAMs) are the most abundant immune cells. After being recruited to the tumor site and stimulated by different signals in TME, TAMs can grow into two different subtypes, namely M1 and M2. TAMs are mainly manifested as M1 macrophages in the early stage of colorectal cancer, mediating the immune response to inhibit tumor growth. In the late stage, TAMs mainly grow into M2 macrophages, showing the ability to suppress immunity, stimulate the proliferation of tumor cells and tumor angiogenesis, and promote the invasion and metastasis of tumor cells. It has been found that intervention in TAMs polarization can regulate its relationship with the onset and development of colorectal cancer.
Subject(s)
Humans , Tumor-Associated Macrophages , Macrophages , Tumor Microenvironment , Colorectal NeoplasmsABSTRACT
Objective This study aimed to establish a pre-metastatic niche mouse model utilizing luciferase-labeled Lewis (Luc-Lewis) lung cancer cells and to assess the efficacy of this model employing both qualitative and quantitative methods. Methods C57BL/6 mice were categorized into two groups: a normal control group and a model group, each containing 15 individual mice. The pre-metastatic niche model was established via tail vein injection of Luc-Lewis lung cancer cells. Body mass were measured daily for all groups. Tumor fluorescence signals within the mice were detected using a high-throughput enzyme marker instrument. Lung tissue specimens were harvested to evaluate metastatic progression. HE staining was used to assess histopathological changes. Real-time quantitative PCR and Western blot analysis were used to detect the mRNA and protein expression of lysyl oxidase (LOX), matrix metalloproteinase 9 (MMP9), versican (VCAN), and fibronectin (FN), which are the specific markers for the formation of the microenvironment of lung tissues before metastasis. Results Significant declines in body mass and observable lethargy were noted in the model group when compared to the control group. Distinct fluorescence signals were observed in the lung tissue of the model group, demonstrating a positive correlation with the duration of model establishment. By day 14, elevated mRNA and protein expression levels of LOX, MMP9, VCAN, and FN were significantly evident. In addition, histopathological evaluations revealed augmented interstitial thickness, alveolar atrophy and significant inflammatory cell infiltration within the lung tissues of the model group. By the 21st day, metastatic lesions manifested in the lung tissues of the model group, suggesting an approximate pre-metastatic niche maturation timeline of 14 days. Conclusion A pre-metastatic niche mouse model for Lewis lung cancer is successfully established.
Subject(s)
Mice , Animals , Lung Neoplasms/pathology , Matrix Metalloproteinase 9 , Mice, Inbred C57BL , Carcinoma, Lewis Lung , Disease Models, Animal , RNA, Messenger , Tumor MicroenvironmentABSTRACT
Tumor-derived exosomes play an important role in the tumor micro-environment. The exosome-derived non-coding RNAs are transmitted in the tumor microenvironment in three ways, communication between tumor cells, normal cells affecting tumor cells, and tumor cells affecting normal cells. Through these three ways, exosomal non-coding RNAs are involved in the regulation of tumor progression, affecting tumor angiogenesis, tumor invasiveness, drug resistance, stemness, tumor metabolic repro-gramming and immune escape, resulting in dual roles in promoting or inhibiting tumor development. Exosomes have a membranous structure and their contents are resistant to degradation by extracellular proteases and remain highly stable in body fluids, thus exosome-derived non-coding RNAs are expected to serve as diagnostic and prognostic indicators for a variety of cancers. In addition, exosomes can be used to deliver non-coding RNAs for targeted therapy, or to knock down or modify tumor-promoting non-coding RNAs for tumor therapy. This article reviews the function and communication mechanism of exosomal non-coding RNAs in the tumor microenvironment, including their pathways of action, effects, potential values for tumor biomarkers and treatment targets. This article also points out the issues that need to be further studied in order to promote the progress of extracellular non-coding RNAs in cancer research and their application in tumor diagnosis and treatment.
Subject(s)
Humans , Exosomes , Neoplasms/genetics , Biomarkers, Tumor , Body Fluids , RNA, Untranslated/genetics , Tumor MicroenvironmentABSTRACT
Tumors in which the microenvironment is characterized by lack of immune cell infiltration are referred as "cold tumors" and typically exhibit low responsiveness to immune therapy. Targeting the factors contributing to "cold tumors" formation and converting them into "hot tumors" is a novel strategy for improving the efficacy of immunotherapy. Adenosine, a hydrolysis product of ATP, accumulates with a significantly higher concentration in the tumor microenvironments compared with normal tissue and exerts inhibitory effects on tumor-specific adaptive immunity. Tumor cells, dendritic cells, macrophages, and T cells express abundant adenosine receptors on their surfaces. The binding of adenosine to these receptors initiates downstream signaling pathways that suppress tumor antigen presentation and immune cell activation, consequently dampening adaptive immune responses against tumors. Adenosine down-regulates the expression of major histocompatibility complex Ⅱ and co-stimulatory factors on dendritic cells and macrophages, thereby inhibiting antigen presentation to T cells. Adenosine also inhibits ligand-receptor binding and transmembrane signaling on T cells, concomitantly suppressing the secretion of anti-tumor cytokines and impairing T cell activation. Furthermore, adenosine hinders effector T cell trafficking to tumor sites and infiltration by inhibiting chemokine secretion and KCa3.1 channels. Additionally, adenosine promotes the secretion of immunosuppressive cytokines, increases immune checkpoint protein expression, and enhances the activity of immunosuppressive cells, collectively curbing cytotoxic T cell-mediated tumor cell killing. Given the immunosuppressive role of adenosine in adaptive antitumor immunity, several inhibitors targeting adenosine generation or adenosine receptor blockade are currently in preclinical or clinical development with the aim of enhancing the effectiveness of immunotherapies. This review provides an overview of the inhibitory effects of adenosine on adaptive antitumor immunity, elucidate the molecular mechanisms involved, and summarizes the latest advances in application of adenosine inhibition strategies for antitumor immunotherapy.