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Voluntary exercise sensitizes cancer immunotherapy via collagen degradation-orchestrated inflammatory tumor immune microenvironment

ABSTRACT: Physical activity reduces cancer-associated mortality through multiple mechanisms, including tumor immune microenvironment (TIME) reprogramming. However, whether and how physiological interventions promote anti-tumor immunity and immunotherapy remains elusive. Here we report that clinically relevant voluntary exercise promotes muscle-derived exosomal miR-29a-3p for extracellular matrix (ECM) degradation in patients and mouse models with multiple types of cancer, thereby permitting immune cell infiltration and immunotherapy. Mechanistically, an unbiased screening identified exercise-responsive exosomal miR-29a-3p that targets tumor cell and cancer associated fibroblasts to downregulate COL1A1 and reduce ECM. State-of-the-art techniques including cytometry by time-of-flight (CyTOF) demonstrated miR-29a-3p-induced TIME remodeling and immune cell infiltration. Combining immunotherapy with voluntary exercise or miR-29a-3p further increased the anti-tumor efficacy in preclinical models. Clinically, miR-29a-3p was correlated with degraded ECM and T-cell infiltration in various cancer types in patients, and correlated with immunotherapy responders. Our work reveals the novel predictive value of miR-29a-3p for immunotherapy, provides mechanistic insights into exercise-promoted anti-cancer immunity, and highlights the therapeutic potential of voluntary exercise in immunotherapy.

ORGANISM(S): Homo sapiens

PROVIDER: GSE273436 | GEO | 2024/08/12

REPOSITORIES: GEO

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Voluntary exercise sensitizes cancer immunotherapy via collagen degradation-orchestrated inflammatory tumor immune microenvironment

Project description:Physical activity reduces cancer-associated mortality through multiple mechanisms, including tumor immune microenvironment (TIME) reprogramming. However, whether and how physiological interventions promote anti-tumor immunity and immunotherapy remains elusive. Here we report that clinically relevant voluntary exercise promotes muscle-derived exosomal miR-29a-3p for extracellular matrix (ECM) degradation in patients and mouse models with multiple types of cancer, thereby permitting immune cell infiltration and immunotherapy. Mechanistically, an unbiased screening identified exercise-responsive exosomal miR-29a-3p that targets tumor cell and cancer associated fibroblasts to downregulate COL1A1 and reduce ECM. State-of-the-art techniques including cytometry by time-of-flight (CyTOF) demonstrated miR-29a-3p-induced TIME remodeling and immune cell infiltration. Combining immunotherapy with voluntary exercise or miR-29a-3p further increased the anti-tumor efficacy in preclinical models. Clinically, miR-29a-3p was correlated with degraded ECM and T-cell infiltration in various cancer types in patients, and correlated with immunotherapy responders. Our work reveals the novel predictive value of miR-29a-3p for immunotherapy, provides mechanistic insights into exercise-promoted anti-cancer immunity, and highlights the therapeutic potential of voluntary exercise in immunotherapy.

2024-08-07 | GSE273831 | GEO

miR-29a-3p coordinates the ECM-integrin-adaptor protein axis to regulate focal adhesion in allergic rhinitis [miRNA-Seq]

Project description:MiR-29a-3p plays a crucial role in regulating cell-cell junctions in the nasal mucosa epithelial cells of individuals with allergic rhinitis (AR). However, the impact of miR-29a-3p on focal adhesion (FA) homeostasis or cell-extracellular matrix (ECM) adhesion remains uncertain. This study demonstrates that miR-29a-3p can regulate the expression of LAMC1 and ITGA6, showing a potential correlation with AR pathogenesis in humans. Furthermore, the targeted inhibitory relationship between miR-29a-3p and both LAMC1 and ITGA6 was confirmed through dual-luciferase reporter assays. Analysis of miRNA-seq and mRNA-seq datasets established a differential expression (DE) profile for AR-associated genes, revealing 278 DE-miRNAs and 11,352 DE-mRNAs. Based on this data, we assert that miR-29s are a remarkable example of a single microRNA family exhibiting a consistent upregulation trend in AR. The KEGG analysis showed that AR is significantly associated with FA and ECM-receptor interaction. By integrating online databases for miRNA-target prediction with mRNA-seq data, we identified crucial genes involved in FA (e.g., ITGA6) and cell-ECM adhesion (e.g., LAMC1) as potential targets of miR-29s. Consequently, the role of the entire miRNA transcriptome can be virtually encompassed by miR-29s. In vivo evidence from AR mouse models further supported the role of miR-29a-3p in repressing these proteins' expression. Our findings provide a comprehensive understanding of the significant differential expression of miRNA/mRNA genes in AR, with a specific focus on miR-29a-3p. This particular miRNA appears to hinder the process of FA and cell-ECM adhesion by targeting the ECM-integrins-adaptor protein axis, potentially contributing to the pathogenesis of AR.

2024-10-01 | GSE247294 | GEO

miR-29a-3p coordinates the ECM-integrin-adaptor protein axis to regulate focal adhesion in allergic rhinitis [RNA-Seq]

2024-10-01 | GSE247293 | GEO

Expression of exosomal microRNAs in bovine serum with clinical or subclinical mastitis

Project description:Bovine mastitis causes changes in the serum exosomal miRNAs expression. Serum samples from healthy dairy cows (n = 7) were compared to those of cows with subclinical (n = 7 ) using small RAN sequencing. Three hundred fifty-five miRNAs (341 known and 14 novel ones) were identified. There were 42 miRNAs up-regulated in serum-derived EVs from cows with subclinical mastitis, including bta-miR-1246, bta-miR-2431-3p, bta-miR-126-3p, bta-miR-29a, etc. The MAPK signaling pathway was the most affected pathway by clinical mastitis. Thus, miRNA alterations in mastitis serum-derived EVs support the potential regulator role of specific miRNAs as exosomal cargo in clinical mastitis physiology.

2022-08-31 | GSE202849 | GEO

Identification of miR-16/29 targets in adipocytes by LC-MSMS

Project description:Cancer cachexia is a multifactorial metabolic syndrome defined by the rapid loss of skeletal muscle mass and the loss of fat mass. Up 80% of cancer patients at the late stage with cachexia suffer from progressive atrophy of adipose tissue. Unlike studies on skeletal muscle wasting, there is limited research on fat loss in cachexia. It was noted that most patients suffer from fat loss as cancer progress. Fat loss precedes muscle loss, is associated with shorter survival, and is variable to timing and intensity in various cancer populations. Increased lipolysis may be the leading cause of fat loss in cancer cachexia. miRNAs are a class of non-coding RNAs of 19~25 nucleotides that regulate gene silencing by interacting with the 3’ untranslated region (UTR) of target mRNA to cause mRNA degradation and translational repression. miRNAs play multifaceted roles in pancreatic cancer proliferation, survival, metastasis, and chemoresistance. Aberrant expression of miRNA in circulating exosomes may play potential roles in modulating fat loss in cancer cachexia. We identified 2 miRNAs, miR-16 and miR-29, which have 2-fold higher expression existed in at PDAC cells. To explore which genes in adipogenesis and lipolysis were directly affected by miR-16-5p or/and miR-29a-3p, we analyzed the targets which were down-regulated in both miR-16-5p and miR-29a-3p-transfected 3T3-L1 cells by mass analysis.

2024-06-13 | PXD037998 | Pride

Identification of miR-16/29 targets in adipocytes by LC-MSMS

2024-06-13 | PXD037862 | Pride

Differentially expressed genes after miRNA or siRNA transfection in human cancer cell lines (II)

Project description:To identify differentially expressed genes by anti cancer treatments (microRNAs or siRNAs) in human cancer, several cell lines (bladder cancer, prostate cancer, renal cell carcinoma, oral squamous cell carcinoma and lung squamous cell carcinoma) were subjected to Agilent whole genome microarrays. Human cancer cell lines (SAS, HSC3, BOY, T24, PC3, PC3M, DU145, C4-2, 786-O, A-498 and EBC-1) were treated with miRNAs (miR-205, miR-29a, miR-144-3p, miR-144-5p, miR-451, miR-210, miR-145-5p, miR-145-3p, miR-23b cluster, miR-221, miR-222 and miR-223), siRNAs (si-GOLM1, si-HMGB3, si-CENPF, si-LOXL2, si-TMEM184B and si-CORO1C).

2016-04-13 | E-GEOD-66498 | biostudies-arrayexpress

Voluntary exercise suppresses tumor growth through exercise-directed recruitment and intratumoral infiltration of NK cells

Project description:Voluntary exercise reduces the risk of cancer and lowers the risk of disease recurrence. Yet the mechanisms for this protection remain to be elucidated. Here we demonstrate that exercise halves tumor growth through an exercise-dependent mobilization and intratumoral infiltration of NK cells in malignant melanoma. Using voluntary wheel running, we show that exercise prior to and during B16 tumor challenge reduced tumor growth by 67%, and this reduction was associated with increased inflammation and immune cell infiltrates, especially NK cells, in the tumors from exercising mice. Depletion of NK cells blunted the exercise-dependent reduction in tumor growth. Moreover, during exercise, NK cells were engaged through an epinephrine-dependent mobilization to the circulation and redistributed to peripheral tissues through an IL-6 dependent mechanism. This study highlights the importance of exercise-dependent immune regulation in the control of malignant melanoma Gene expression profile of melanoma tumor tissue from two groups of exercise and non-exercise mice

2016-07-21 | E-GEOD-62628 | biostudies-arrayexpress

Combination of four serum exosomal miRNAs as novel diagnostic biomarkers for early-stage gastric cancer

Project description:The aim of this study was to identify and evaluate exosomal miRNAs in serum as early diagnostic markers for gastric cancer (GC). Methods: Using next-generation sequencing (NGS) and bioinformatics, we identified candidate serum exosomal miRNA markers for early detection of GC in patients. The candidates were further validated by qRT-PCR in 50 newly recruited early-stage GC patients and matched healthy individuals. Results: NGS revealed that the average mappable reads in the RNA libraries were about 6.5 million per patient. A total of 66 up and 13 down-regulated exosomal miRNAs were found in the screened cohort after removal of log2 transformed read counts <5 and p >0.05. In the validation cohort, by comparing candidate exosomal miRNAs levels in early-stage GC patients and healthy individuals, higher levels of miR-92b-3p, let-7g-5p, miR-146b-5p and miR-9-5p were found to be significantly associated with GC. Diagnostic power of the combined panels of the exosomal miRNAs or the combination of exosomal miRNAs and CEA outperformed that of single exosomal miRNA marker for establishing a diagnosis of early-stage GC. In addition, serum levels of exosomal miR-92b-3p were significantly associated with low adhesion, let-7g-5p and miR-146b-5p were significantly correlated with nerve infiltration, and miR146b-5p was statistically correlated with tumor invasion depth in early-stage GC. Conclusions: Serum exosomal miR-92b-3p, -146b-5p, -9-5p, and let-7g-5p may serve as potential noninvasive biomarkers for early diagnosis of GC. Further validation of these candidate exosomal miRNAs in larger experimental cohorts are required in order to confirm the diagnostic values.

2020-02-21 | GSE130654 | GEO

miRNA profiling in camptothecin-treated or untreated hepatoma-derived exosomes

Project description:Totally 1,308 miRNAs were examined. Three miRNAs (hsa-miR-1976, 4728-3p, and 877-3p) were upregulated with fold change excess 0.8 and six miRNAs (hsa-miR-4497, -204-3p, -6126, -5787, -1273e, and -1908-3p) were downregulated in the exosome released from camptothecin-treated hepatoma. Comparing between results of these two samples revealed novel miRNA regulation upon anti-cancer drug treatments exosomal miRNAs from CPT-treated hepatoma and unrteated

2015-11-10 | E-GEOD-74829 | biostudies-arrayexpress

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