IL15

Gene Summary

Gene:IL15; interleukin 15
Aliases: IL-15
Location:4q31.21
Summary:The protein encoded by this gene is a cytokine that regulates T and natural killer cell activation and proliferation. This cytokine and interleukine 2 share many biological activities. They are found to bind common hematopoietin receptor subunits, and may compete for the same receptor, and thus negatively regulate each other's activity. The number of CD8+ memory cells is shown to be controlled by a balance between this cytokine and IL2. This cytokine induces the activation of JAK kinases, as well as the phosphorylation and activation of transcription activators STAT3, STAT5, and STAT6. Studies of the mouse counterpart suggested that this cytokine may increase the expression of apoptosis inhibitor BCL2L1/BCL-x(L), possibly through the transcription activation activity of STAT6, and thus prevent apoptosis. Alternatively spliced transcript variants of this gene have been reported. [provided by RefSeq, Feb 2011]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:interleukin-15
Source:NCBIAccessed: 01 September, 2019

Ontology:

What does this gene/protein do?
Show (36)
Pathways:What pathways are this gene/protein implicaed in?
Show (4)

Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 01 September 2019 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Immunotherapy
  • Genetic Vectors
  • Interferon-gamma
  • Flow Cytometry
  • Vaccination
  • CD8-Positive T-Lymphocytes
  • Biomarkers, Tumor
  • Signal Transduction
  • Mice, Transgenic
  • Messenger RNA
  • Lymphocyte Activation
  • Cytotoxicity, Immunologic
  • Childhood Cancer
  • Lung Cancer
  • RTPCR
  • Acute Lymphocytic Leukaemia
  • Disease Models, Animal
  • Interleukin-15 Receptor alpha Subunit
  • Gene Expression Profiling
  • Cell Proliferation
  • Survival Rate
  • Adolescents
  • Tumor Suppressor Proteins
  • Genotype
  • Cytokines, Interleukin-2
  • Immunologic Memory
  • Gene Expression
  • Receptors, Interleukin-15
  • Single Nucleotide Polymorphism
  • Infant
  • Immunotherapy, Adoptive
  • Skin Cancer
  • Natural Killer Cells
  • Cancer Gene Expression Regulation
  • Genetic Therapy
  • Transplant Recipients
  • Genetic Predisposition
  • Tumor Burden
  • Chromosome 4
  • Interleukin-15
  • Cytokines
  • Breast Cancer
Tag cloud generated 01 September, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (4)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: IL15 (cancer-related)

Gong W, Hoffmann JM, Stock S, et al.
Comparison of IL-2 vs IL-7/IL-15 for the generation of NY-ESO-1-specific T cells.
Cancer Immunol Immunother. 2019; 68(7):1195-1209 [PubMed] Related Publications
The anti-tumor efficacy of TCR-engineered T cells in vivo depends largely on less-differentiated subsets such as T cells with naïve-like T cell (T

Wang Y, Yu W, Zhu J, et al.
Anti-CD166/4-1BB chimeric antigen receptor T cell therapy for the treatment of osteosarcoma.
J Exp Clin Cancer Res. 2019; 38(1):168 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Chimeric antigen receptor (CAR)-engineered T cells have displayed outstanding performance in the treatment of patients with hematological malignancies. However, their efficacy against solid tumors has been largely limited.
METHODS: In this study, human osteosarcoma cell lines were prepared, flow cytometry using antibodies against CD166 was performed on different cell samples. CD166-specific T cells were obtained by viral gene transfer of corresponding DNA plasmids and selectively expanded using IL-2 and IL-15. The ability of CD166.BBζ CAR-T cells to kill CD166
RESULTS: CD166 was selectively expressed on four different human osteosarcoma cell lines, indicating its role as the novel target for CAR-T cell therapy. CD166.BBζ CAR-T cells killed osteosarcoma cell lines in vitro; the cytotoxicity correlated with the level of CD166 expression on the tumor cells. Intravenous injection of CD166.BBζ CAR-T cells into mice resulted in the regression of the tumor with no obvious toxicity.
CONCLUSIONS: Together, the data suggest that CD166.BBζ CAR-T cells may serve as a new therapeutic strategy in the future clinical practice for the treatment of osteosarcoma.

Fantini M, David JM, Wong HC, et al.
An IL-15 Superagonist, ALT-803, Enhances Antibody-Dependent Cell-Mediated Cytotoxicity Elicited by the Monoclonal Antibody NEO-201 Against Human Carcinoma Cells.
Cancer Biother Radiopharm. 2019; 34(3):147-159 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: A major mechanism of action for therapeutic antibodies is antibody-dependent cell-mediated cytotoxicity (ADCC). ALT-803 is an interleukin-15 superagonist complex that enhances ADCC against human carcinoma cells in vitro and exerts an antitumor activity in murine, rat, and human carcinomas in vivo. The authors investigated the ability of ALT-803 to modulate ADCC mediated by the humanized IgG1 monoclonal antibody (mAb) NEO-201 against human carcinoma cells.
MATERIALS AND METHODS: ALT-803 modulating activity on ADCC mediated by NEO-201 was evaluated on several NEO-201 ligand-expressing human carcinoma cells. Purified human natural killer (NK) cells from multiple healthy donors were treated with ALT-803 before their use as effectors in ADCC assay. Modulation of NK cell phenotype and cytotoxic function by exposure to ALT-803 was evaluated by flow cytometry and gene expression analysis.
RESULTS: ALT-803 significantly enhanced ADCC mediated by NEO-201. ALT-803 also upregulated NK activating receptors, antiapoptotic factors, and factors involved in the NK cytotoxicity, as well as downregulated gene expression of NK inhibiting receptors.
CONCLUSIONS: These findings indicate that ALT-803 can enhance ADCC activity mediated by NEO-201, by modulating NK activation and cytotoxicity, suggesting a possible clinical use of ALT-803 in combination with NEO-201 for the treatment of human carcinomas.

Marx M, Zumpe M, Troschke-Meurer S, et al.
Co-expression of IL-15 enhances anti-neuroblastoma effectivity of a tyrosine hydroxylase-directed DNA vaccination in mice.
PLoS One. 2018; 13(11):e0207320 [PubMed] Free Access to Full Article Related Publications
Long-term survival of high-risk neuroblastoma (NB) patients still remains under 50%. Here, we report the generation, in vitro characterization and anti-tumor effectivity of a new bicistronic xenogenic DNA vaccine encoding tyrosine hydroxylase (TH) that is highly expressed in NB tumors, and the immune stimulating cytokine interleukin 15 (IL-15) that induces cytotoxic but not regulatory T cells. The DNA sequences of TH linked to ubiquitin and of IL-15 were integrated into the bicistronic expression vector pIRES. Successful production and bioactivity of the vaccine-derived IL-15- and TH protein were shown by ELISA, bioactivity assay and western blot analysis. Further, DNA vaccine-driven gene transfer to the antigen presenting cells of Peyer's patches using attenuated Salmonella typhimurium that served as oral delivery system was shown by immunofluorescence analysis. The anti-tumor effect of the generated vaccine was evaluated in a syngeneic mouse model (A/J mice, n = 12) after immunization with S. typhimurium (3× prior and 3× after tumor implantation). Importantly, TH-/IL-15-based DNA vaccination resulted in an enhanced tumor remission in 45.5% of mice compared to controls (TH (16.7%), IL-15 (0%)) and reduced spontaneous metastasis (30.0%) compared to controls (TH (63.6%), IL-15 (70.0%)). Interestingly, similar levels of tumor infiltrating CD8+ T cells were observed among all experimental groups. Finally, co-expression of IL-15 did not result in elevated regulatory T cell levels in tumor environment measured by flow cytometry. In conclusion, co-expression of the stimulatory cytokine IL-15 enhanced the NB-specific anti-tumor effectivity of a TH-directed vaccination in mice and may provide a novel immunological approach for NB patients.

Matosevic S
Viral and Nonviral Engineering of Natural Killer Cells as Emerging Adoptive Cancer Immunotherapies.
J Immunol Res. 2018; 2018:4054815 [PubMed] Free Access to Full Article Related Publications
Natural killer (NK) cells are powerful immune effectors whose antitumor activity is regulated through a sophisticated network of activating and inhibitory receptors. As effectors of cancer immunotherapy, NK cells are attractive as they do not attack healthy self-tissues nor do they induce T cell-driven inflammatory cytokine storm, enabling their use as allogeneic adoptive cellular therapies. Clinical responses to adoptive NK-based immunotherapy have been thwarted, however, by the profound immunosuppression induced by the tumor microenvironment, particularly severe in the context of solid tumors. In addition, the short postinfusion persistence of NK cells

Zhenjiang L, Rao M, Luo X, et al.
Cytokine Networks and Survivin Peptide-Specific Cellular Immune Responses Predict Improved Survival in Patients With Glioblastoma Multiforme.
EBioMedicine. 2018; 33:49-56 [PubMed] Free Access to Full Article Related Publications
PURPOSE: We investigated serum cytokine and T-cell responses directed against tumour-associated antigens (TAAs) in association with survival of patients with glioblastoma multiforme (GBM).
PATIENTS AND METHODS: Peripheral blood from 205 treatment-naïve patients with glioma (GBM = 145; non-GBM = 60) was obtained on the day of surgery to measure (i) circulating T-cells reacting to viral antigens and TAAs, in the presence or absence of cytokine conditioning with IL-2/IL-15/IL-21 or IL-2/IL-7, and (ii) serum cytokine levels (IL-4, IL-5, IL-6, TNF-α, IFN-γ and IL-17A). Patients were followed-up for at least 1000 days post-surgery. Survivin protein and gene expression in resected GBM tumour tissue were confirmed by immunohistochemistry and real-time polymerase chain reaction, respectively. Antigen-specific T-cell responses were gauged by ICS (intracellular cytokine production). Associations between patient survival and immunological reactivity patterns were analysed using univariate and multivariate statistics.
RESULTS: Approximately 2% of patients with GBM and 18% of patients with non-GBM glioma, were alive beyond 1000 days of surgery. Univariate analysis indicated that the combination of three cytokines (IL-4/IL-5/IL-6, p = .0022; IFN-γ/TNF-α/IL-17A, p = .0083) but not a 'partial' combination of these cytokines, the IFN-γ immune response to EBV-EBNA-1 (p < .0001) as well as T-cell responses to the survivin
CONCLUSION: Serum cytokine patterns and lymphocyte reactivity to survivin

Liu X, Li Y, Sun X, et al.
Powerful anti-colon cancer effect of modified nanoparticle-mediated IL-15 immunogene therapy through activation of the host immune system.
Theranostics. 2018; 8(13):3490-3503 [PubMed] Free Access to Full Article Related Publications

Hartana CA, Ahlén Bergman E, Broomé A, et al.
Tissue-resident memory T cells are epigenetically cytotoxic with signs of exhaustion in human urinary bladder cancer.
Clin Exp Immunol. 2018; 194(1):39-53 [PubMed] Free Access to Full Article Related Publications
Tissue-resident memory T (T

Jiang W, Zhang C, Tian Z, Zhang J
hIL-15-gene modified human natural killer cells (NKL-IL15) exhibit anti-human leukemia functions.
J Cancer Res Clin Oncol. 2018; 144(7):1279-1288 [PubMed] Related Publications
PURPOSE: Natural killer (NK) cells can kill transformed cells and represent anti-tumor activities for improving the immunotherapy of cancer. In previous works, we established human interleukin-15 (hIL-15) gene-modified NKL cells (NKL-IL15) and demonstrated their efficiency against human hepatocarcinoma cells (HCCs) in vitro and in vivo. To further assess the applicability of NKL-IL15 cells in adoptive cellular immunotherapy for human leukemia, here we report their natural cytotoxicity against leukemia in vitro and in vivo.
METHODS: Flow cytometry, ELISA and MTT methods were performed for molecular expression, cell proliferation and cytotoxicity assays. Leukemia xenograft NOD/SCID mice were established by subcutaneous injection with K562 cells, and then treated with irradiated NKL cells.
RESULTS: We found NKL-IL15 cells displayed a significant high cytolysis activity against both human leukemia cell lines and primary leukemia cells from patients, accompanied with up-regulated expression of molecules related to NK cell cytotoxicity such as perforin, granzyme B and NKp80. Moreover, cytokines secreted by NKL-IL15 cells, including TNF-α and IFN-γ, could induce the expression of NKG2D ligands on target cells, which increased the susceptibility of leukemia cells to NK cell-mediated cytolysis. Encouragingly, NKL-IL15 cells significantly inhibited the growth of leukemia cells in xenografted NOD/SCID mice and prolonged the survival of tumor-bearing mice dramatically. Furthermore, NKL-IL15 cells displayed stimulatory effects on hPBMCs, indicating the immunesuppressive status of leukemia patients could be improved by NKL-IL15 cell treatment.
CONCLUSIONS: These results provided evidence that IL-15 gene-modification could augment NK cell-mediated anti-human leukemia function, which would improve primary NK cell-based immunotherapy for leukemia in future.

Borrelli C, Ricci B, Vulpis E, et al.
Drug-Induced Senescent Multiple Myeloma Cells Elicit NK Cell Proliferation by Direct or Exosome-Mediated IL15
Cancer Immunol Res. 2018; 6(7):860-869 [PubMed] Related Publications
Treatment of multiple myeloma (MM) cells with sublethal doses of genotoxic drugs leads to senescence and results in increased NK cell recognition and effector functions. Herein, we demonstrated that doxorubicin- and melphalan-treated senescent cells display increased expression of IL15, a cytokine involved in NK cell activation, proliferation, and maturation. IL15 upregulation was evident at the mRNA and protein level, both in MM cell lines and malignant plasma cells from patients' bone marrow (BM) aspirates. However, IL15 was detectable as a soluble cytokine only

Rots D, Kreile M, Nikulshin S, et al.
Influence of IL15 gene variations on the clinical features, treatment response and risk of developing childhood acute lymphoblastic leukemia in Latvian population.
Pediatr Hematol Oncol. 2018; 35(1):37-44 [PubMed] Related Publications
Acute lymphoblastic leukemia (ALL) is the most common childhood malignancy. Modern treatment protocols allow achievement of long-term event-free survival rates in up to 85% of cases, although the treatment response varies among different patient groups. It is hypothesized that treatment response is influenced by the IL15 gene variations, although research results are conflicting. To analyze IL15 gene variations influence treatment response, clinical course and the risk of developing ALL we performed a case-control and family-based study. The study included 81 patients with childhood ALL. DNA samples of both or one biological parent were available for 62 of ALL patients and 130 age and gender adjusted healthy samples were used as a control group. Analyzed IL15 gene variations: rs10519612, rs10519613 and rs17007695 were genotyped using PCR-RFLP assay. Our results shows that IL15 gene variations haplotypes are associated with the risk of developing childhood ALL (p < 0.05), although there is no such association for the variations separately. The variations rs10519612 and rs1059613 in a recessive pattern of inheritance were associated with hyperdiploidy (p = 0.048). Analyzed genetic variations had no impact on other clinical features and treatment response (assessed by the minimal residual disease) in our study.

Mathew NR, Baumgartner F, Braun L, et al.
Sorafenib promotes graft-versus-leukemia activity in mice and humans through IL-15 production in FLT3-ITD-mutant leukemia cells.
Nat Med. 2018; 24(3):282-291 [PubMed] Free Access to Full Article Related Publications
Individuals with acute myeloid leukemia (AML) harboring an internal tandem duplication (ITD) in the gene encoding Fms-related tyrosine kinase 3 (FLT3) who relapse after allogeneic hematopoietic cell transplantation (allo-HCT) have a 1-year survival rate below 20%. We observed that sorafenib, a multitargeted tyrosine kinase inhibitor, increased IL-15 production by FLT3-ITD

Cooley S, Parham P, Miller JS
Strategies to activate NK cells to prevent relapse and induce remission following hematopoietic stem cell transplantation.
Blood. 2018; 131(10):1053-1062 [PubMed] Free Access to Full Article Related Publications
Natural killer (NK) cells are lymphocytes of innate immunity that respond to virus infected and tumor cells. After allogeneic transplantation, NK cells are the first reconstituting lymphocytes, but are dysfunctional. Manipulating this first wave of lymphocytes could be instrumental in reducing the 40% relapse rate following transplantation with reduced-intensity conditioning. NK cells express numerous activating and inhibitory receptors. Some recognize classical or nonclassical HLA class I ligands, others recognize class I-like ligands or unrelated ligands. Dominant in the NK-cell transplant literature are killer cell immunoglobulin-like receptors (KIRs), encoded on chromosome 19q. Inhibitory KIR recognition of the cognate HLA class I ligand is responsible for NK-cell education, which makes them tolerant of healthy cells, but responsive to unhealthy cells having reduced expression of HLA class I.

Meraz IM, Majidi M, Cao X, et al.
TUSC2 Immunogene Therapy Synergizes with Anti-PD-1 through Enhanced Proliferation and Infiltration of Natural Killer Cells in Syngeneic
Cancer Immunol Res. 2018; 6(2):163-177 [PubMed] Free Access to Full Article Related Publications
Expression of the multikinase inhibitor encoded by the tumor suppressor gene

Kohnken R, Wen J, Mundy-Bosse B, et al.
Diminished microRNA-29b level is associated with BRD4-mediated activation of oncogenes in cutaneous T-cell lymphoma.
Blood. 2018; 131(7):771-781 [PubMed] Free Access to Full Article Related Publications
MicroRNA (miRNA) dysregulation is a hallmark of cutaneous T-cell lymphoma (CTCL), an often-fatal malignancy of skin-homing CD4

Guo Y, Luan L, Patil NK, Sherwood ER
Immunobiology of the IL-15/IL-15Rα complex as an antitumor and antiviral agent.
Cytokine Growth Factor Rev. 2017; 38:10-21 [PubMed] Free Access to Full Article Related Publications
Interleukin (IL)-15 is essential for natural killer (NK), NKT and memory (m) CD8

Mesiano G, Zini R, Montagner G, et al.
Analytic and Dynamic Secretory Profile of Patient-Derived Cytokine-Induced Killer Cells.
Mol Med. 2017; 23:235-246 [PubMed] Free Access to Full Article Related Publications
Adoptive immunotherapy with Cytokine Induced Killer (CIK) cells has shown antitumor activity against several kinds of cancers in preclinical models and clinical trials. CIK cells are a subset of ex vivo expanded T lymphocytes with T-NK phenotype and MHC-unrestricted antitumor activity. Literature provides scanty information on cytokines, chemokines and growth factors secreted by CIK cells. Therefore, we investigated the secretory profile of CIK cells generated from tumor patients. The secretome analysis was performed at specific time points (day 1, day 14 and day 21) of CIK cells expansion. Mature CIK cells (day 21) produce a great variety of interleukins and secreted proteins that can be divided into 3 groups based on their secretion quantity: high (IL-13, RANTES, MIP-1α and 1β), medium (IL-1Ra, IL-5, IL-8, IL-10, IL-17, IP-10, INF-γ, VEGF and GMCSF) and low (IL-1β, IL-4, IL-6, IL-7, IL-9, IL-12, IL-15, Eotaxin, PDGF-bb, FGF basic, G-CSF and MCP-1) secreted. Moreover, comparing PBMC (day 1) and mature CIK cells (day 14 and 21) secretome, we observed that IL-5, IL-10, IL-13, GM-CSF, VEGF resulted greatly up-regulated, while IL-1β, IL-6, IL-8, IL-15, IL-17, eotaxin, MCP-1, and RANTES were down-regulated. We also performed a gene expression profile analysis of patient-derived CIK cells showing that mRNA for the different cytokines and secreted proteins were modulated during PBMC to CIK differentiation. We highlighted previously unknown secretory properties and provided for the first time a comprehensive molecular characterization of CIK cells. Our findings provide rationale to explore the functional implications and possible therapeutic modulation of CIK secretome.

Liu E, Tong Y, Dotti G, et al.
Cord blood NK cells engineered to express IL-15 and a CD19-targeted CAR show long-term persistence and potent antitumor activity.
Leukemia. 2018; 32(2):520-531 [PubMed] Free Access to Full Article Related Publications
Chimeric antigen receptors (CARs) have been used to redirect the specificity of autologous T cells against leukemia and lymphoma with promising clinical results. Extending this approach to allogeneic T cells is problematic as they carry a significant risk of graft-versus-host disease (GVHD). Natural killer (NK) cells are highly cytotoxic effectors, killing their targets in a non-antigen-specific manner without causing GVHD. Cord blood (CB) offers an attractive, allogeneic, off-the-self source of NK cells for immunotherapy. We transduced CB-derived NK cells with a retroviral vector incorporating the genes for CAR-CD19, IL-15 and inducible caspase-9-based suicide gene (iC9), and demonstrated efficient killing of CD19-expressing cell lines and primary leukemia cells in vitro, with marked prolongation of survival in a xenograft Raji lymphoma murine model. Interleukin-15 (IL-15) production by the transduced CB-NK cells critically improved their function. Moreover, iC9/CAR.19/IL-15 CB-NK cells were readily eliminated upon pharmacologic activation of the iC9 suicide gene. In conclusion, we have developed a novel approach to immunotherapy using engineered CB-derived NK cells, which are easy to produce, exhibit striking efficacy and incorporate safety measures to limit toxicity. This approach should greatly improve the logistics of delivering this therapy to large numbers of patients, a major limitation to current CAR-T-cell therapies.

Zanon V, Pilipow K, Scamardella E, et al.
Curtailed T-cell activation curbs effector differentiation and generates CD8
Eur J Immunol. 2017; 47(9):1468-1476 [PubMed] Free Access to Full Article Related Publications
Human T memory stem (T

Ye JF, Qi WX, Liu MY, Li Y
The combination of NK and CD8+T cells with CCL20/IL15-armed oncolytic adenoviruses enhances the growth suppression of TERT-positive tumor cells.
Cell Immunol. 2017; 318:35-41 [PubMed] Related Publications
Adoptive immunotherapy and targeted gene therapy have been extensively used to eliminate tumor cells. The combination treatment is capable of efficiently generating an effective antitumor immune response and disrupting tumor-induced tolerance. Moreover, effective antitumor immune responses are dependent on coordinate interaction among various effector cells. This study focused on whether the combination of cytotoxic effector cell-based adoptive immunotherapy and CCL20/IL15-armed oncolytic adenoviruses could induce enhanced antitumor activity. The CCL20/IL15-armed oncolytic adenovirus was constructed using homologous recombination with shuttle plasmids and full-length Ad backbones. We chose the telomerase reverse transcriptase promoter (TERTp) to replace the E1A promoter to drive the oncolytic adenoviral E1A gene. Thus, this CRAd-CCL20-IL15 could induce apoptosis in TERTp-positive tumor cells due to viral propagation, but these viruses could not replicate efficiently in normal cells. The combination of cytotoxic effector cells and CRAd-CCL20-IL15 showed greater antitumor potential than that of cytotoxic effector cells or CRAd-CCL20-IL15 alone. Moreover, the combined treatment could induce tumor-specific cytotoxicity of CTLs in vitro. Further analysis demonstrated that this combined treatment resulted in significant tumor regression in mouse models. This study has provided preclinical evidence that combined treatment with cytotoxic effector cells and CRAd-CCL20-IL15 may offer alternative treatment options for tumor therapy.

Heczey A, Louis CU, Savoldo B, et al.
CAR T Cells Administered in Combination with Lymphodepletion and PD-1 Inhibition to Patients with Neuroblastoma.
Mol Ther. 2017; 25(9):2214-2224 [PubMed] Free Access to Full Article Related Publications
Targeting disialoganglioside (GD2) on neuroblastoma (NB) with T cells expressing a first-generation chimeric antigen receptor (CAR) was safe, but the cells had poor expansion and long-term persistence. We developed a third-generation GD2-CAR (GD2-CAR3) and hypothesized that GD2-CAR3 T cells (CARTs) would be safe and effective. This phase 1 study enrolled relapsed or refractory NB patients in three cohorts. Cohort 1 received CART alone, cohort 2 received CARTs plus cyclophosphamide and fludarabine (Cy/Flu), and cohort 3 was treated with CARTs, Cy/Flu, and a programmed death-1 (PD-1) inhibitor. Eleven patients were treated with CARTs. The infusions were safe, and no dose-limiting toxicities occurred. CARTs were detectable in cohort 1, but the lymphodepletion induced by Cy/Flu increased circulating levels of the homeostatic cytokine interleukin (IL)-15 (p = 0.003) and increased CART expansion by up to 3 logs (p = 0.03). PD-1 inhibition did not further enhance expansion or persistence. Antitumor responses at 6 weeks were modest. We observed a striking expansion of CD45/CD33/CD11b/CD163

Krenciute G, Prinzing BL, Yi Z, et al.
Transgenic Expression of IL15 Improves Antiglioma Activity of IL13Rα2-CAR T Cells but Results in Antigen Loss Variants.
Cancer Immunol Res. 2017; 5(7):571-581 [PubMed] Free Access to Full Article Related Publications
Glioblastoma (GBM) is the most aggressive primary brain tumor in adults and is virtually incurable with conventional therapies. Immunotherapy with T cells expressing GBM-specific chimeric antigen receptors (CAR) is an attractive approach to improve outcomes. Although CAR T cells targeting GBM antigens, such as IL13 receptor subunit α2 (IL13Rα2), HER2, and EGFR variant III (EGFRvIII), have had antitumor activity in preclinical models, early-phase clinical testing has demonstrated limited antiglioma activity. Transgenic expression of IL15 is an appealing strategy to enhance CAR T-cell effector function. We tested this approach in our IL13Rα2-positive glioma model in which limited IL13Rα2-CAR T-cell persistence results in recurrence of antigen-positive gliomas. T cells were genetically modified with retroviral vectors encoding IL13Rα2-CARs or IL15 (IL13Rα2-CAR.IL15 T cells). IL13Rα2-CAR.IL15 T cells recognized glioma cells in an antigen-dependent fashion, had greater proliferative capacity, and produced more cytokines after repeated stimulations in comparison with IL13Rα2-CAR T cells. No autonomous IL13Rα2-CAR.IL15 T-cell proliferation was observed; however, IL15 expression increased IL13Rα2-CAR T-cell viability in the absence of exogenous cytokines or antigen.

Rohena-Rivera K, Sánchez-Vázquez MM, Aponte-Colón DA, et al.
IL-15 regulates migration, invasion, angiogenesis and genes associated with lipid metabolism and inflammation in prostate cancer.
PLoS One. 2017; 12(4):e0172786 [PubMed] Free Access to Full Article Related Publications
Prostate cancer (PCa) is the most commonly diagnosed non-cutaneous cancer. In the United States it is second leading cause of cancer related deaths in men. PCa is often treated via radical prostatectomy (RP). However, 15-30% of the patients develop biochemical recurrence (i.e. increased serum prostate specific antigen (PSA) levels). Interleukin-15 (IL-15) is a secreted cytokine found over expressed in patients with recurrence-free survival after RP. In our study, we aim to determine the role of IL-15 in PCa using in vitro and in vivo models, and gene expression analysis. PC3 (androgen-independent) and 22RV1 (androgen-dependent) cell lines were treated with IL-15 at 0.0013 ng/mL and 0.1 ng/mL. Tumor growth was evaluated using an orthotopic xenograft model. The anterior prostate lobes of SCID mice were injected with 250,000 22RV1 cells and IL-15 was administered bi-weekly with intraperitoneal (IP) injections during 4 weeks. Tumor tissue was collected for immunohistochemical and gene expression analysis. To study changes in gene expression, we looked at "Tumor Metastasis" and "PI3K pathway" using commercially available PCR arrays. In addition, we employed a microarray approach using the Affymetrix Hugene 2.0 ST array chip followed by analysis with Ingenuity Pathways Analysis (IPA) software. In vitro studies showed that IL-15 decreased PCa cell motility at both concentrations. In vivo studies showed that IL-15 increased neutrophil infiltration, and the expression of adiponectin, desmin and alpha smooth muscle actin (α-sma) in the tumor tissue. Angiogenesis analysis, using CD31 immunohistochemistry, showed that IL-15 decreased the number of blood vessels. Gene expression analysis identified Cancer, Cell Death, Immune Response and Lipid Metabolism as the major diseases and functions altered in tumors treated with IL-15. This suggests that IL-15 causes inflammation and changes in stroma that can promote decreased tumor cell proliferation.

Xu X, Sun Q, Yu X, Zhao L
Rescue of nonlytic Newcastle Disease Virus (NDV) expressing IL-15 for cancer immunotherapy.
Virus Res. 2017; 233:35-41 [PubMed] Related Publications
In order to test and enhance the antitumor activity against mice melanoma by NDV-modified tumor vaccine, a recombinant NDV expressing IL-15 (LX/(IL-15)) was generated by reverse genetics. Then, the expression level and biological activity of IL-15 were examined. Our results showed that mice tumor cell lines infected with LX/(IL-15) expressed IL-15 at a high level, and that expressed IL-15 was biologically active. Expression kinetics demonstrated that the highest expression level of IL-15 was at 48h post infection. The cytotoxicity assay showed that murine melanoma cells modified with LX/(IL-15) could significantly enhance the antitumor immune response in vitro. In vivo study also showed that murine melanoma cells modified with LX/(IL-15) could prevent melanoma growth in mice. Taken together, our data strongly indicated that recombinant LX/(IL-15) is a promising agent for cancer immunotherapy both for human and animal.

Giannoni P, Cutrona G, Totero D
Survival and Immunosuppression Induced by Hepatocyte Growth Factor in Chronic Lymphocytic Leukemia.
Curr Mol Med. 2017; 17(1):24-33 [PubMed] Related Publications
Chronic lymphocytic leukemia (CLL), the most common leukemia among adults in the western world, is characterized by a progressive accumulation of relatively mature CD5+ B cells in peripheral blood, lymph nodes and bone marrow. Despite much recent advancement in therapy, CLL is still incurable. Lymph nodes and bone marrow represent sanctuary sites preserving leukemic cells from spontaneous or drug-induced apoptosis, and infiltration of leukemic cells in these districts correlates with clinical stages and prognosis. The central role played by the microenvironment in the disease has become increasingly clear. Different chemokines (CXCL12, CXCL13, CCL19, CCL21) may in fact participate in attracting CLL cells into bone marrow and lymph nodes, where various factors, such as IL-15 and CXCL12, enhance leukemic cells survival. Recently, we have suggested that hepatocyte growth factor (HGF), produced by microenvironmental stromal cells, can contribute to CLL pathogenesis. We have demonstrated that HGF exerts a double effect on CLL B cells through the interaction with its receptor c- MET; HGF, infact, protects CLL B cells, which are c-MET+, from apoptosis, and also polarizes mono/macrophages towards the M2 phenotype, thus facilitating the evasion of the CLL clone from immune control. This double effect appears mediated by the activation of two major signaling pathways: STAT3TYR705 and AKT. The aim of this review is to summarize data on HGF and c-MET expression in normal B cells and in B cell malignancies, with a particular emphasis on our results obtained in CLL. Altogether, the observations described here suggest that the HGF/c-MET axis may have a prominent role in malignancy progression further indicating novel potential therapeutic options aimed to block HGF-induced signaling pathways in B lymphoproliferative disorders.

Rady M, Watzl C, Claus M, et al.
Altered expression of miR-181a and miR-146a does not change the expression of surface NCRs in human NK cells.
Sci Rep. 2017; 7:41381 [PubMed] Free Access to Full Article Related Publications
MicroRNAs (miRNAs) play an important role in regulating gene expression and immune responses. Of interest, miR-181a and miR-146a are key players in regulating immune responses and are among the most abundant miRNAs expressed in NK cells. Bioinformatically, we predicted miR-181a to regulate the expression of the natural cytotoxicity receptor NCR2 by seeded interaction with the 3'-untranslated region (3'-UTR). Whereas, miR-146a expression was not significantly different (P = 0.7361), miR-181a expression was, on average 10-fold lower in NK cells from breast cancer patients compared to normal subjects; P < 0.0001. Surface expression of NCR2 was detected in NK cells from breast cancer patients (P = 0.0384). While cytokine receptor-induced NK cell activation triggered overexpression of miR-146a when stimulated with IL-2 (P = 0.0039), IL-15 (P = 0.0078), and IL-12/IL-18 (P = 0.0072), expression of miR-181a was not affected. Overexpression or knockdown of miR-181a or miR-146a in primary cultured human NK cells did not affect the level of expression of any of the three NCRs; NCR1, NCR2 or NCR3 or NK cell cytotoxicity. Expression of miR-181a and miR-146a did not correlate to the expression of the NCRs in NK cells from breast cancer patients or cytokine-stimulated NK cells from healthy subjects.

Whitaker LH, Murray AA, Matthews R, et al.
Selective progesterone receptor modulator (SPRM) ulipristal acetate (UPA) and its effects on the human endometrium.
Hum Reprod. 2017; 32(3):531-543 [PubMed] Free Access to Full Article Related Publications
STUDY QUESTION: What is the impact of administration of the selective progesterone receptor modulator (SPRM), ulipristal acetate (UPA) on the endometrium of women with fibroids?
SUMMARY ANSWER: UPA administration altered expression of sex-steroid receptors and progesterone-regulated genes and was associated with low levels of glandular and stromal cell proliferation.
WHAT IS KNOWN ALREADY: Administration of all SPRM class members results in PAEC (progesterone receptor modulator associated endometrial changes). Data on the impact of the SPRM UPA administration on endometrial sex-steroid receptor expression, progesterone (P)-regulated genes and cell proliferation are currently lacking.
STUDY DESIGN SIZE, DURATION: Observational study with histological and molecular analyses to delineate impact of treatment with UPA on endometrium. Endometrial samples (n = 9) were collected at hysterectomy from women aged 39 to 49 with uterine fibroids treated with UPA (oral 5 mg daily) for 9-12 weeks. Control proliferative (n = 9) and secretory (n = 9) endometrium from women aged 38-52 with fibroids were derived from institutional tissue archives.
PARTICIPANTS/MATERIALS, SETTING, METHODS: Study setting was a University Research Institute. Endometrial biopsies were collected with institutional ethical approval and written informed consent. Concentrations of mRNAs encoded by steroid receptors, P-regulated genes and factors in decidualised endometrium were quantified with qRT-PCR. Immunohistochemistry was employed for localization of progesterone (PR, PRB), androgen (AR), estrogen (ERα) receptors and expression of FOXO1, HAND2, HOXA10, PTEN homologue. Endometrial glandular and stromal cell proliferation was objectively quantified using Ki67.
MAIN RESULTS AND THE ROLE OF CHANCE: UPA induced morphological changes in endometrial tissue consistent with PAEC. A striking change in expression patterns of PR and AR was detected compared with either proliferative or secretory phase samples. There were significant changes in pattern of expression of mRNAs encoded by IGFBP-1, FOXO1, IL-15, HAND2, IHH and HOXA10 compared with secretory phase samples consistent with low agonist activity in endometrium. Expression of mRNA encoded by FOXM1, a transcription factor implicated in cell cycle progression, was low in UPA-treated samples. Cell proliferation (Ki67 positive nuclei) was lower in samples from women treated with UPA compared with those in the proliferative phase.
LARGE SCALE DATA: N/A.
LIMITATIONS REASONS FOR CAUTION: A small number of well-characterized patients were studied in-depth. The impacts on morphology, molecular and cellular changes with SPRM, UPA administration on symptom control remains to be determined.
WIDER IMPLICATIONS OF THE FINDINGS: P plays a pivotal role in endometrial function. P-action is mediated through interaction with the PR. These data provide support for onward development of the SPRM class of compounds as effective long-term medical therapy for heavy menstrual bleeding.
STUDY FUNDING/COMPETING INTEREST(S): H.O.D.C. received has clinical research support for laboratory consumables and staff from Bayer Pharma Ag and provides consultancy advice (no personal remuneration) for Bayer Pharma Ag, PregLem SA, Gedeon Richter, Vifor Pharma UK Ltd, AbbVie Inc.; A.R.W.W. has received consultancy payments from Bayer, Gedeon Richter, Preglem SA, HRA Pharma; L.H.R.W., A.A.M., R.M., G.S. and P.T.K.S. have no conflicts of interest. Study funded in part from each of: Medical Research Council (G1002033; G1100356/1; MR/N022556/1); National Health Institute for Health Research (12/206/520) and TENOVUS Scotland.

Fallahi S, Mohammadi SM, Tayefi Nasrabadi H, et al.
Impact of C-rel inhibition of cord blood-derived B-, T-, and NK cells.
J Immunotoxicol. 2017; 14(1):15-22 [PubMed] Related Publications
The c-Rel transcription factor is a unique member of the nuclear factor (NF)-κB family that has a role in curtailing the proliferation, differentiation, cytokine production, and overall activity of B- and T-cells. In addition, c-Rel is a key regulator of apoptosis in that it influences the expression of anti-apoptotic genes such as Bcl-2 and Bcl-xL; conversely, inhibition of c-Rel increases cell apoptosis. To better understand the relationship between c-Rel expression and effects on B- and T-cell expansion, the current study evaluated c-Rel expression in cord blood mononuclear cells. This particular source was selected as cord blood is an important source of cells used for transplantation and immunotherapy, primarily in treating leukemias. As stem cell factor (SCF) and FLT3 are important agents for hematopoietic stem cell expansion, and cytokines like interleukin (IL)-2, -7, and -15 are essential for T- and B- (and also NK) cell development and proliferation, the current study evaluated c-Rel expression in cord blood mononuclear cells and CD34

Sim GC, Liu C, Wang E, et al.
IL2 Variant Circumvents ICOS+ Regulatory T-cell Expansion and Promotes NK Cell Activation.
Cancer Immunol Res. 2016; 4(11):983-994 [PubMed] Related Publications
Clinical responses to high-dose IL2 therapy are limited due to selective expansion of CD4

Gorges TM, Kuske A, Röck K, et al.
Accession of Tumor Heterogeneity by Multiplex Transcriptome Profiling of Single Circulating Tumor Cells.
Clin Chem. 2016; 62(11):1504-1515 [PubMed] Related Publications
BACKGROUND: Transcriptome analysis of circulating tumor cells (CTCs) holds great promise to unravel the biology of cancer cell dissemination and identify expressed genes and signaling pathways relevant to therapeutic interventions.
METHODS: CTCs were enriched based on their EpCAM expression (CellSearch
RESULTS: Distinct breast and prostate CTC expression signatures could be discriminated from RNA profiles of leukocytes. Some CTCs positive for epithelial transcripts (EpCAM and KRT19) also coexpressed leukocyte/mesenchymal associated markers (PTPRC and VIM). Additional subsets of CTCs within individual patients were characterized by divergent expression of genes involved in epithelial-mesenchymal transition (e.g., CDH2, MMPs, VIM, or ZEB1 and 2), DNA repair (RAD51), resistance to cancer therapy (e.g., AR, AR-V7, ERBB2, EGFR), cancer stemness (e.g., CD24 and CD44), activated signaling pathways involved in tumor progression (e.g., PIK3CA and MTOR) or cross talks between tumors and immune cells (e.g., CCL4, CXCL2, CXCL9, IL15, IL1B, or IL8).
CONCLUSIONS: Multimarker RNA profiling of single CTCs reveals distinct CTC subsets and provides important insights into gene regulatory networks relevant for cancer progression and therapy.

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