Exercise-Induced Engagement of the IL-15/IL15Rα axis Promotes Anti Tumor Immunity
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PROVIDER: PRJNA735753 | ENA |
REPOSITORIES: ENA
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Project description:The advent of immune checkpoint blockade has improved patient outcomes, providing durable disease control by reversing localized tumor-mediated immune-suppression and promoting anti-tumor immunity. Despite successes in melanoma and lung cancer, these therapies have largely failed in pancreatic ductal adenocarcinoma (PDA); a ‘cold’ tumor with the highest mortality rate among all major cancers. PDA is uniquely characterized by multiple intra-pancreatic tumor- and stroma-induced mechanisms of immune-suppression, and there remains a great need to explore creative approaches to improve anti-tumor immune responses in this disease. Herein, we show routine aerobic exercise provides tumor-protective benefits in murine PDA through modulation of both systemic and intra-tumoral immunity. Reversing immune-suppressive properties of both myeloid and T cell populations, we found the anti-tumor benefits of exercise require CD8 T cell activation and expansion in the tumor. Specifically, we report the sub-population of IL15Ra+ CD8 T cells is required for exercise-induced tumor protection and anti-tumor immunity, both of which are abrogated in the context IL-15 blockade. We further show that exercise-induced increases in intra-tumoral T cells are governed by adrenergic signaling and S1P-gradient dependent lymphocyte migration. Finally, we found that combination with aerobic exercise sensitizes pancreatic tumors to anti-PD-1 therapy. Overall, our work highlights the unique mechanisms governing exercise-induced tumor protection in PDA, and uncovers the importance of the interplay between systemic and intra-tumoral immunity to develop innovative strategies to reverse immune-suppression in this devastating disease.
2022-05-11 | GSE176311 | GEO
Project description:Aerobic exercise is associated with decreased cancer incidence and cancer-associated mortality. However, little is known about the effects of exercise on pancreatic ductal adenocarcinoma (PDA), a disease for which current therapeutic options are limited. Herein, we show that aerobic exercise reduces PDA tumor growth, by modulating systemic and intra-tumoral immunity. Mechanistically, exercise promotes immune mobilization and accumulation of tumor-infiltrating IL15Rα+ CD8 T cells, which are responsible for the tumor-protective effects. In clinical samples, an exercise-dependent increase of intra-tumoral CD8 T cells is also observed. Underscoring the translational potential of the interleukin (IL)-15/IL-15Rα axis, IL-15 super-agonist (NIZ985) treatment attenuates tumor growth, prolongs survival, and enhances sensitivity to chemotherapy. Finally, exercise or NIZ985 both sensitize pancreatic tumors to αPD-1, with improved anti-tumor and survival benefits. Collectively, our findings highlight the therapeutic potential of an exercise-oncology axis and identify IL-15 activation as a promising treatment strategy for this deadly disease.
| S-EPMC9280705 | biostudies-literature
Project description:Dissection of obesity-exercise axis in adipose-muscle tissues
| PRJNA759891 | ENA
Project description:We studied the opposing effects of exercise training and high-fat diet at single-cell resolution to reveal changes in cell type abundance, cell-type-specific gene expression/pathway/regulatory network changes, and changes in cell-cell communication both within and across tissues. We profiled scRNA-seq in 204,883 cells, grouped into 53 distinct cell sub-types/states across 22 major cell types, from subcutaneous white adipose tissue, visceral white adipose tissue, and skeletal muscle across 16 lean and 15 obese mice with both diet and exercise interventions. Changes in both cell proportion and transcriptional state were most strongly pronounced in adipose stem cells in fat, consistent with roles of adipogenesis in thermogenesis-vs-lipogenesis and hyperplasia-vs-hypertrophy in obesity. For immune cells, exercise training decreases obesity-associated inflammatory tissue-resident cell populations, including myeloid and regulatory T cells, and promotes beige-cell-inducing populations, including NKT cells. These changes clustered in common pathways across tissues for both exercise and obesity, including extracellular matrix remodelling and circadian rhythm in mesenchymal stem cells and cell activation/migration in immune cells.
2022-10-13 | GSE183288 | GEO
Project description:T-cells redirected for antigen-unrestricted cytokine-initiated killing (TRUCKs) are engineered chimeric antigen receptor (CAR) T-cells that constitutively or inducibly release cytokines upon CAR engagement. Their purpose is to enhance the function of effector cells in the immune-suppressive tumor microenvironment (TME) of particularly solid tumors that is often devoid of pro-inflammatory cytokines. We capitalize on the pleiotropic effects of two γc family cytokines, interleukin (IL)-15 and IL-21, and use them synergistically for TRUCK engineering. We demonstrate that TRUCKs with soluble IL-15/IL-21 eradicate CAR T-cell–resistant neuroblastoma, the most common extra-cranial solid tumor of childhood, but are associated with significant toxicities in mice. These toxicities can be delayed when we constitutively tether the cytokines to the surface of T-cells but are abrogated when we engineer CAR T-cells with NFAT-induced membrane-tethered IL-15/IL-21 expression.
2025-06-17 | GSE243349 | GEO
Project description:10 male subjects performed ~45 min one-legged cycling and 4 x 7 maximal concentric-eccentric knee extensions for each leg 15 min later. Thus, one limb performed aerobic and resistance exercise (AE+RE), while the opposing leg did resistance exercise only (RE). Biopsies were obtained from m. vastus lateralis of each leg 3 h after the resistance exercise bout. Gene expression analysis was carried out on the Affymetrix HuGene-2.1-st platform.
2016-05-24 | GSE74194 | GEO
Project description:Exercise is usually regarded to have short-term beneficial effects on immune health. Here we show that early-life regular exercise exerts long-term beneficial effects on inflammatory immunity. Swimming training for 3 months in male mice starting from 1-month-old curbed cytokine response and mitigated sepsis when exposed to lipopolysaccharide (LPS) challenge, even after 11-month interval of detraining. Metabolomics analysis of serum and liver identified pipecolic acid (a non-encoded amino acid) as a pivotal metabolite responding to early-life regular exercise. We then explored histone epigenetic modifications and observed a significant increase of H3K4me3 expression in the liver of 15-month-old mice exposed to early-life exercise. To further unravel the prolonged increased pipecplic acid production raised by early-life exercise, we conducted ChIP-seq analysis and found H3K4me3 occupancy at Crym (a key enzyme responsible for catalyzing pipecolic acid production) promoter has a significant increase in hepatocytes of early-life exercised mice. Our findings demonstrate that early-life regular exercise enhances anti-inflammatory immunity during middle-aged phase in male mice via epigenetic immunometabolic modulation, in which hepatic pipecolic acid production plays a pivotal role.
2024-03-12 | GSE255161 | GEO
Project description:IL-15 is recognized as a promising candidate for tumor immunotherapy and has been described as both a promoter of cancer and a promoter of anti-cancer immunity. IL-15 was discovered in cells transformed by HTLV-1, the etiologic agent of adult T cell leukemia / lymphoma (ATL) and the human retrovirus that carries the Tax oncogene. We have developed the TAX-LUC mouse model of ATL in which Tax expression drives both malignant transformation and luciferase expression, enabling non-invasive imaging of tumorigenesis in real time. To identify the role of IL-15 in spontaneous development of lymphoma in vivo, an IL-15-/- TAX-LUC strain was developed and examined. The absence of IL-15 resulted in aggressive tumor growth and accelerated mortality and demonstrated that IL-15 was not required for Tax-mediated lymphoma but was essential for anti-tumor immunity. Further analysis revealed a unique transcriptional profile in tumor cells that arise in the absence of IL-15 that included a significant increase in the expression of IL-1α and IL-1α-regulated cytokines. Moreover, anti-IL-1α antibodies and an IL-1 receptor antagonist (Anakinra) were used to interrogate the potential of IL-1α targeted therapies in this model. Taken together, these findings identify IL-15 and IL-1α as therapeutic targets in lymphoma. We used microarrays to compare the gene expression profile of tumors in IL-15-/- TAX-LUC mice to IL-15+/+ TAX-LUC mice
2013-06-11 | GSE46072 | GEO
Project description:The aim of this study was to compare the signaling cascades initiated by the two closely related cytokines IL-2 and IL-15. Considering the relevance of protein tyrosine phosphorylation in signal transduction, in order to quantify changes in protein phosphorylation in response to IL-2 and IL-15, we combined triple SILAClabeling of leukemic T-cells with phosphotyrosine (pY)-specific antibody-based protein enrichment followed by mass spectrometry (MS) analysis. Following the strategy described above, we managed to decipher in detail the complex signaling networks triggered by IL-2 and IL-15. Interestingly, a large number of components of the three main signaling pathways known to be initiated in response to the interleukins (JAK/STAT; RAS/MAPK; PI3K/AKT) were identified.
2014-09-23 | PXD001129 | Pride
Project description:Tissue-level dissection of obesity-exercise axis in adipose-muscle tissues
| PRJNA759774 | ENA