Exercise-Induced Engagement of the IL-15/IL15Rα axis Promotes Anti Tumor Immunity
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ABSTRACT:
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.
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Project description:Exercise activation of muscle p38γ raises blood IL-15, which signal in the brain for a boost on locomotor activity.
2026-03-23 | GSE263912 | 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: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.
2017-03-29 | MSV000080767 | MassIVE
Project description:RNA squencing of human NK cells activated with IL-15 or IL-12, IL-15, and IL-18
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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 RNA was obtained from CD16/32HI and CD16/32LO cells harvested from n=2 IL-15+/+ (control)and n=2 IL-15-/- Tax tumors and was compared to look for alterations in gene expression in malignant and tumor infiltrating cells resulting from loss of IL-15 in vivo
2013-06-11 | E-GEOD-46072 | biostudies-arrayexpress
Project description:Intestinal intraepithelial lymphocytes (IEL) are an abundant population of tissue-resident T cells that protect the gut from pathogens and maintain intestinal homeostasis. The cytokine IL-15 is trans-presented by epithelial cells to IEL in complex with the IL-15 receptor α chain (IL-15Rα) and plays essential roles both in maintaining IEL homeostasis, and in inducing IEL activation in response to epithelial stress. When overproduced, IL-15 is a key driver of the gluten-induced enteropathy Coeliac disease, through cytotoxic activation of IEL. To better understand how IL-15 directly regulates both homeostatic and inflammatory functions of IEL, we performed quantitative proteomics of IL-15/Rα-stimulated murine IEL, sorted into their 3 main subpopulations, TCRγδ CD8αα, TCRαβ CD8αβ and TCRαβ CD8αα expressing IEL. The data reveal that high IL-15/Rα stimulation licenses cell cycle activation, upregulates the biosynthetic machinery in IEL, increases mitochondrial respiratory capacity and induces expression of cell surface immune receptors and adhesion proteins that potentially drive IEL activation.
2021-05-10 | PXD025891 | Pride
Project description:T cell antigen-receptor (TCR) and cytokine receptor engagement trigger large changes in Serine/Threonine kinase signalling networks to drive T cell activation and differentiation. The role of only few kinase signalling pathways have been studied in detail, and in this context, Pim kinases are an interesting, yet understudied, family of Serine/Threonine kinases, with reported roles in key processes including survival, proliferation, metabolism across a range of cell types. T lymphocytes predominantly express PIM1 and PIM2, which are rapidly induced by TCR, costimulation and cytokine signalling. Using high-resolution mass spectrometry and RNAseq we systematically examine the impact of Pim1/Pim2 double deficiency on in vitro differentiated cytotoxic T lymphocytes (CTL) expanded in the cytokines IL-2 and IL-15 to generate effector or memory T cells respectively. We find that Pim kinases are dispensable for IL-15-driven memory cell differentiation, but that Pim1/2-deficiency has a selective impact on the transcriptome and proteome of IL-2 driven effector CD8 T cells. ~75% of Pim kinase-regulated proteins were not predicted by differences in mRNA in IL-2 expanded CTL. These included proteins that are key for effector cell function: glucose transporters SLC2A1 and SLC2A3 and key effector molecules Granzyme A and B. We find that Pim kinases have this effect via control of protein translation. Another key finding was that the mRNA for key T cell homing receptors Ccr7, S1pr1 and CD62L was increased in Pim1/2-deficienct T cells and that this functionally enhancing homing to secondary lymphoid organs.
2024-04-15 | PXD051213 | Pride