Gene Summary

Gene:IL21; interleukin 21
Aliases: Za11, IL-21, CVID11
Summary:This gene encodes a member of the common-gamma chain family of cytokines with immunoregulatory activity. The encoded protein plays a role in both the innate and adaptive immune responses by inducing the differentiation, proliferation and activity of multiple target cells including macrophages, natural killer cells, B cells and cytotoxic T cells. Dysregulation of this gene plays a role in multiple immune-mediated diseases including lupus, psoriasis and chronic inflammatory diseases. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Dec 2011]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Source:NCBIAccessed: 01 September, 2019


What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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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.

  • Interleukins
  • Messenger RNA
  • Cell Movement
  • Chronic Lymphocytic Leukemia
  • Cell Proliferation
  • Case-Control Studies
  • Natural Killer Cells
  • Immunotherapy
  • Cytokines
  • Diffuse Large B-Cell Lymphoma
  • Cytokines, Interleukin-2
  • Single Nucleotide Polymorphism
  • MicroRNAs
  • CD4-Positive T-Lymphocytes
  • CD40 Antigens
  • Cell Differentiation
  • Chromosome 4
  • Lymphocyte Activation
  • Breast Cancer
  • Gene Expression Regulation
  • Genotype
  • T-Lymphocytes
  • NF-kappa B
  • B-Lymphocytes
  • Receptors, Interleukin-21
  • Interferon-gamma
  • Up-Regulation
  • Cytotoxicity, Immunologic
  • CD8-Positive T-Lymphocytes
  • Interleukin-21 Receptor alpha Subunit
  • Gene Expression
  • Promoter Regions
  • Multiple Myeloma
  • Cancer Gene Expression Regulation
  • Gene Expression Profiling
  • Mice, Inbred BALB C
  • Genetic Therapy
  • Ovarian Cancer
  • Genetic Predisposition
  • Apoptosis
  • Odds Ratio
Tag cloud generated 01 September, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (5)

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: IL21 (cancer-related)

Li T, Li M, Xu C, et al.
miR‑146a regulates the function of Th17 cell differentiation to modulate cervical cancer cell growth and apoptosis through NF‑κB signaling by targeting TRAF6.
Oncol Rep. 2019; 41(5):2897-2908 [PubMed] Related Publications
The aim of the present study was to investigate whether miRNA‑146a regulated the function of Th17 cell differentiation to modulate cervical cancer cell growth and apoptosis. miR‑146a expression was increased in human cervical cancer. Both overall survival (OS) and disease‑free survival (DFS) of low miR‑146a expression were higher than those of high miR‑146a expression. Additionally, IL‑17a expression was lower in patients with high miR‑146a expression compared to that of patients with lower miR‑146a expression. In a co‑culture of cervical cancer and CD4+ T cells, downregulation of miR‑146a inhibited cell growth and induced apoptosis of cervical cancer cells, while overexpression of miR‑146a promoted cell growth and reduced apoptosis of cervical cancer cells. Downregulation of miR‑146a induced TRAF6 and NF‑κB protein expression, increased IL‑6, IL‑17A and IL‑21 levels, and enhanced p‑STAT3 protein expression. The inhibition of TRAF6 attenuated the effects of anti‑miR‑146a on the function of Th17 cell differentiation to modulate cervical cancer cell growth and apoptosis. Collectively, miR‑146a regulated the function of Th17 cell differentiation to modulate cervical cancer cell growth and apoptosis through NF‑κB signaling by targeting TRAF6. miR‑146a may function as an oncogene in cervical cancer via Th17 cell differentiation by targeting TRAF6.

Chat V, Ferguson R, Simpson D, et al.
Autoimmune genetic risk variants as germline biomarkers of response to melanoma immune-checkpoint inhibition.
Cancer Immunol Immunother. 2019; 68(6):897-905 [PubMed] Article available free on PMC after 01/06/2020 Related Publications
Immune-checkpoint inhibition (ICI) treatments improve outcomes for metastatic melanoma; however, > 60% of treated patients do not respond to ICI. Current biomarkers do not reliably explain ICI resistance. Given the link between ICI and autoimmunity, we investigated if genetic susceptibility to autoimmunity modulates ICI efficacy. In 436 patients with metastatic melanoma receiving single line ICI or combination treatment, we tested 25 SNPs, associated with > 2 autoimmune diseases in recent genome-wide association studies, for modulation of ICI efficacy. We found that rs17388568-a risk variant for allergy, colitis and type 1 diabetes-was associated with increased anti-PD-1 response, with significance surpassing multiple testing adjustments (OR 0.26; 95% CI 0.12-0.53; p = 0.0002). This variant maps to a locus of established immune-related genes: IL2 and IL21. Our study provides first evidence that autoimmune genetic susceptibility may modulate ICI efficacy, suggesting that systematic testing of autoimmune risk loci could reveal personalized biomarkers of ICI response.

Jiang H, Yang Z, Song Z, et al.
γδ T cells in hepatocellular carcinoma patients present cytotoxic activity but are reduced in potency due to IL-2 and IL-21 pathways.
Int Immunopharmacol. 2019; 70:167-173 [PubMed] Related Publications
Hepatocellular carcinoma (HCC) is the most common primary liver carcinoma and has one of the highest mortality rates of all cancers. The γδ T cells could infiltrate HCC and have demonstrated potent tumor-killing capacity. Here, we found that in peripheral blood, the vast majority of γδ T cells were Vδ2 T cells. In HCC patients, the frequency of Vδ2 T cells was significantly lower than in controls. γδ T cells that were harvested directly ex vivo possessed very limited capacity to eliminate Zol-loaded HCC cell lines, even at a high effector to target ratio. In vitro expansion with Zol could significantly increase the capacity of γδ T cells to eliminate HCC cell lines. But even with in vitro expansion, the γδ T cells from HCC patients presented significantly lower cytotoxic capacity than the γδ T cells from healthy individuals. The expression of IL-2 and IL-21 by γδ T cells was significantly lower in HCC patients than in control volunteers. Supplementing recombinant human IL-2 and IL-21 in the in vitro expansion culture increased the cytotoxic capacity of γδ T cells. In addition, the frequency of PD-1

Wu K, Zhao H, Xiu Y, et al.
IL-21-mediated expansion of Vγ9Vδ2 T cells is limited by the Tim-3 pathway.
Int Immunopharmacol. 2019; 69:136-142 [PubMed] Related Publications
Vγ9Vδ2 T cells are the main γδ T subset in the peripheral blood and lymphoid organs. Previous studies have shown that Vγ9Vδ2 T cells could expand in the presence of phosphoantigens and IL-2 and exert antitumor functions. However, their potency was limited because sustained proliferation could not be achieved, possibly due to exhaustion caused by prolonged antigenic stimulation. In this study, we examined the proliferative response of Vγ9Vδ2 T cells to IL-21, a cytokine previously shown to promote NK cell and CD8 T cell cytotoxicity. We found that IL-21 could significantly improve the proliferation of phosphoantigen-stimulated Vγ9Vδ2 T cells in a dose-dependent manner. However, in acute myeloid leukemia (AML) patients, the efficacy of IL-21 was significantly reduced. Vγ9Vδ2 T cells from AML patients exhibited lower expression of IL-21R, and required higher levels of IL-21 for expansion. IL-21-treated Vγ9Vδ2 T cells from AML patients presented lower increase in STAT1 phosphorylation than Vγ9Vδ2 T cells from healthy volunteers. Interestingly, AML Vγ9Vδ2 T cells presented significantly higher Tim-3 expression than healthy Vγ9Vδ2 T cells. IL-21 treatment further induced Tim-3 upregulation. Blocking Tim-3 increased the proliferation and the STAT phosphorylation in Vγ9Vδ2 T cells in response to IL-21. Together, these results demonstrated that IL-21 could significantly expand the Vγ9Vδ2 T cells, but its efficacy was limited since it also increased the expression of checkpoint molecule Tim-3.

De Silva P, Garaud S, Solinas C, et al.
FOXP1 negatively regulates tumor infiltrating lymphocyte migration in human breast cancer.
EBioMedicine. 2019; 39:226-238 [PubMed] Article available free on PMC after 01/06/2020 Related Publications
BACKGROUND: FOXP1, a transcriptional regulator of lymphocyte development, is abnormally expressed in some human tumors. This study investigated FOXP1-mediated regulation of tumor infiltrating lymphocytes (TIL) in untreated primary breast cancer (BC).
METHODS: FOXP1 expression was analyzed in tissues from primary untreated breast tumors, BC cell lines and the METABRIC gene expression BC dataset. Cytokine and chemokine expression and lymphocyte migration in response to primary tumor supernatants (SN) was compared between FOXP1
FINDING: FOXP1 expression was higher in estrogen receptor positive compared to negative BC. FOXP1
INTERPRETATION: These data identify FOXP1 as an important negative regulator of immune responses in BC via its regulation of cytokine and chemokine expression. FUND: Belgian Fund for Scientific Research (FNRS 3.4513.12F) and Opération Télévie (7.4636.13F and 7.4609.15F), Fonds J.C. Heuson and Fonds Lambeau-Marteaux.

Li S, Wang Z, Zhang G, et al.
Interleukin-7 promotes lung-resident CD14
Int Immunopharmacol. 2019; 67:202-210 [PubMed] Related Publications
Interleukin (IL)-7 enhances cytokines secretion by CD14

Yan L, Zhang J, Guo D, et al.
IL-21R functions as an oncogenic factor and is regulated by the lncRNA MALAT1/miR-125a-3p axis in gastric cancer.
Int J Oncol. 2019; 54(1):7-16 [PubMed] Article available free on PMC after 01/06/2020 Related Publications
Interleukin-21 receptor (IL-21R) is involved in the immunological regulation of immune cells and tumor progression in multiple malignancies. However, the potential molecular mechanisms through which non-coding RNAs (ncRNAs) modulate IL-21R signaling in gastric cancer (GC) remain elusive. In this study, the expression of IL-21R was detected by RT-qPCR and western blot analysis in GC cell lines. The association between IL-21R expression and clinicopathological characteristics and the prognosis of patients with GC was analyzed by immunohistochemistry and Kaplan-Meier plotter analysis. The biological functions of IL-21R were analyzed by a series of in vitro and in vivo experiments, and its regulation by ncRNAs was predicted by bioinformatics analysis and confirmed by luciferase assays and rescue experiments. As a result, the expression of IL-21R was found to be significantly increased in GC cell lines and tissues as compared with normal tissues, and was associated with tumor size and lymphatic metastasis, acting as an independent prognostic factor of poor survival and recurrence in patients with GC. The knockdown of IL-21R markedly suppressed GC cell proliferation and invasion, and IL-21R expression was further validated to be negatively regulated by miR-125a-3p (miR-125a). The overexpression of IL-21R reversed the tumor suppressive effects of miR-125a in vitro and in vivo. Moreover, lncRNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) acted as a sponge of miR-125a to modulate the IL-21R signaling pathway in GC cells and represented a risk factor for survival and recurrence in patients with GC. Taken together, the findings of this study reveal an oncogenic role for IL-21R in gastric tumorigenesis and verify that its activation is partly due to the dysregulation of the lncRNA MALAT1/miR-125a axis. These findings may provide a potential prognostic marker for patients with GC.

Ngai H, Tian G, Courtney AN, et al.
IL-21 Selectively Protects CD62L
J Immunol. 2018; 201(7):2141-2153 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
T cells expressing CD19-specific chimeric Ag receptors (CARs) produce high remission rates in B cell lymphoma, but frequent disease recurrence and challenges in generating sufficient numbers of autologous CAR T cells necessitate the development of alternative therapeutic effectors. Vα24-invariant NKTs have intrinsic antitumor properties and are not alloreactive, allowing for off-the-shelf use of CAR-NKTs from healthy donors. We recently reported that CD62L

Jalali S, Price-Troska T, Paludo J, et al.
Soluble PD-1 ligands regulate T-cell function in Waldenstrom macroglobulinemia.
Blood Adv. 2018; 2(15):1985-1997 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
Although immune checkpoint molecules regulate the progression of certain cancers, their significance in malignant development of Waldenstrom macroglobulinemia (WM), an incurable low-grade B-cell lymphoma, remains unknown. Recently, cytokines in the bone marrow (BM) microenvironment are shown to contribute to the pathobiology of WM. Here, we investigated the impact of cytokines, including interleukin-6 (IL-6) and IL-21, on immune regulation and particularly on the programmed death-1 (PD-1) and its ligands PD-L1 and PD-L2. We showed that IL-21, interferon γ, and IL-6 significantly induced PD-L1 and PD-L2 gene expression in WM cell lines. Increased PD-L1 and PD-L2 messenger RNA was also detected in patients' BM cells. Patients' nonmalignant BM cells, including T cells and monocytes, showed increased PD-L1, but minimal or undetectable PD-L2 surface expression. There was also very modest PD-L1 and PD-L2 surface expression by malignant WM cells, suggesting that ligands are cleaved from the cell surface. Levels of soluble ligands were higher in patients' BM plasma and blood serum than controls. Furthermore, IL-21 and IL-6 increased secreted PD-L1 in the culture media of WM cell lines, implying that elevated levels of soluble PD-1 ligands are cytokine mediated. Soluble PD-1 ligands reduced T-cell proliferation, phosphorylated extracellular signal-regulated kinase and cyclin A levels, mitochondrial adenosine triphosphate production, and spare respiratory capacity. In conclusion, we identify that soluble PD-1 ligands are elevated in WM patients and, in addition to surface-bound ligands in WM BM, could regulate T-cell function. Given the capability of secreted forms to be bioactive at distant sites, soluble PD-1 ligands have the potential to promote disease progression in WM.

Le KS, Amé-Thomas P, Tarte K, et al.
CXCR5 and ICOS expression identifies a CD8 T-cell subset with T
Blood Adv. 2018; 2(15):1889-1900 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
A better characterization of T-cell subsets in the microenvironment of classical Hodgkin lymphoma (cHL) would help to develop immunotherapies. Using multicolor flow cytometry, we identified in 6 of 43 cHL tissue samples a previously unrecognized subset of CD8 T cells coexpressing CXCR5 and inducible T-cell costimulator (ICOS) molecules (CD8

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] Article available free on PMC after 01/10/2019 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

Fu ZQ, Zhou Q, Zhu S, Liu W
Anti-tumor mechanism of IL-21 used alone and in combination with 5-fluorouracil in vitro on human gastric cancer cells.
J Biol Regul Homeost Agents. 2018 May-Jun; 32(3):619-625 [PubMed] Related Publications
To study the effect and related mechanism of IL-21 alone and in combination with 5-Fluorouracil on the proliferation and growth, transferability, and apoptosis of gastric cancer cells, we cultivated gastric cancer cell SGC-7901 and created four experimental groups with varying concentrations of IL-21 and 5-Fluorouracil: IL-21 group (IL-21 100ng/ml), semi-combination group (5-Fluorouracil 25μg/ml+IL-21 100ng/ml), 5-Fluorouracil group (5-Fluorouracil 50μg/ml), and combination group (5-Fluorouracil 50μg/ml+IL-21 100ng/ml). The MTT (3-(4, 5)-dimethylthiahiazo (-z-y1)-3, 5-di- phenytetrazoliumromide) assay was used to detect the inhibitory effect of each group on the proliferation and growth of gastric cancer cells. A scratch-wound assay was carried out to detect the inhibitory effect of each group on transferability. TUNEL assay was used to detect the effect of each group on the apoptosis of the gastric cancer cells, and Western blot was used to detect the expression of caspase-3, caspase-8, bcl-2, and c-myc, which are the proteins related to apoptosis, after the drug effect in each group. The results show that, compared to the 5-Fluorouracil group, the inhibitory effects after 24 h of the IL-21 group and the semi-combination group on SGC-7901 were weaker (P less than 0.001). However, if the effect lasted 48 h, then the inhibition in the semi-combination group had no significant difference compared to the 5-Fluorouracil group (P>0.05). The scarification test showed that all groups could inhibit the transferability of SGC-7901 and that the effect increased successively from the IL-21 group, the semicombination group, the 5-Fluorouracil group, to the combination group. The TUNEL assay indicated that all groups could promote the apoptosis of SGC-7901. The percentage of cell apoptosis increased, and the Western blot showed that the expression of caspase-3, caspase-8, and c-myc, respectively, in the semi-combination group, the 5-Fluorouracil group, and the combination group increased successively and that the successive increasing of c-myc was the most significant. The expression of bc1-2 tended to decrease. In conclusion, IL-21 used alone and in combination with 5-Fluorouracil are anti-tumor mechanisms in SGC-7901.

Seo H, Kim BS, Bae EA, et al.
IL21 Therapy Combined with PD-1 and Tim-3 Blockade Provides Enhanced NK Cell Antitumor Activity against MHC Class I-Deficient Tumors.
Cancer Immunol Res. 2018; 6(6):685-695 [PubMed] Related Publications
Increased expression of coinhibitory molecules such as PD-1 and Tim-3 on NK cells has been demonstrated in advanced cancer patients who harbor MHC class I-deficient tumors. However, even in preclinical models, the antitumor effects of checkpoint blockade on NK cells have not been clearly elucidated. Here, we show that anti-PD-1/anti-Tim-3 treatment suppressed tumor progression in mice bearing MHC class I-deficient tumors, and the suppression was further enhanced by recombinant IL21 (rIL21) treatments through an NK-cell-dependent mechanism. We also show that the intratumoral delivery of rIL21 attracted NK cells to the tumor site in a CXCR3-dependent fashion. A combination of IL21 and checkpoint blockade facilitated the effector function of exhausted NK cells in cancer patients. Given the effects of the checkpoint blockade and rIL21 combination on NK cells infiltrating into MHC class I-deficient tumors, we suggest that the efficacy of checkpoint blockade can be enhanced through the administration of IL21 for advanced cancer patients with MHC class I-low/deficient tumors.

Li L, Ma Y, Xu Y, Maerkeya K
TIM-3 expression identifies a distinctive PD-1
Int Immunopharmacol. 2018; 57:139-146 [PubMed] Related Publications
Follicular helper T (Tfh) cells are critical regulators of immune responses in several human malignancies. Their characteristics in ovarian cancer (OC) patients remain unclear. In this study, the circulating CD4

You FP, Zhang J, Cui T, et al.
Th9 cells promote antitumor immunity via IL-9 and IL-21 and demonstrate atypical cytokine expression in breast cancer.
Int Immunopharmacol. 2017; 52:163-167 [PubMed] Related Publications
Breast cancer is a major cause of cancer-related death in women. Antitumor T cell responses play critical therapeutic roles, including direct cytotoxicity mediated by CD8

Cui G, Yuan A, Zhu L, et al.
Increased expression of interleukin-21 along colorectal adenoma-carcinoma sequence and its predicating significance in patients with sporadic colorectal cancer.
Clin Immunol. 2017; 183:266-272 [PubMed] Related Publications
The role and significance of interleukin (IL)-21 in the development of sporadic CRC have not been well defined. The aim of this study is therefore to investigate the dynamics of the IL-21 along colorectal adenoma-carcinoma sequence and to evaluate the impact of IL-21 on clinicopathological parameters and CRC prognosis. The real-time PCR results showed that the level of IL-21 in adenomas (n=50) and sporadic CRC (n=50) were significantly higher than that in normal controls (n=18), which were predominately observed in the adenoma/CRC stroma. Analysis revealed that IL-21 level was correlated with the overall survival time in CRC patients. Double immunofluorescence observations confirmed that IL-21 positive cells were mostly natural killer cells and T lymphocytes in the tumor stroma. These results indicate that significant increased IL-21 expression present within the adenoma/CRC microenvironment might have a potential predicating significance for survival time in patients with CRC.

Streltsova MA, Barsov E, Erokhina SA, Kovalenko EI
Retroviral gene transfer into primary human NK cells activated by IL-2 and K562 feeder cells expressing membrane-bound IL-21.
J Immunol Methods. 2017; 450:90-94 [PubMed] Related Publications
Natural killer (NK) cells are capable of rapidly recognizing and efficiently killing tumor cells. This makes them a potentially promising agent for cancer immunotherapy. Additional genetic modifications of NK cells may further improve their anti-tumor efficacy. Numerous technical challenges associated with gene delivery into NK cells have significantly tempered this approach. We achieved efficient retroviral vector transduction of primary human NK cells that were stimulated by a combination of IL-2 and engineered K562 cells expressing membrane-bound IL-21. The activated NK cells were in less differentiated state and expressed NK cell activation receptors NKG2D, NKp30, CD16, and were highly HLA-DR-positive. This NK cell population was highly susceptible to the transduction by both GFP- and NGFR-expressing retroviral vectors, with transduction efficiency exceeding 50%. More mature CD57

Wu L, Ehlin-Henriksson B, Zhou X, et al.
Epstein-Barr virus (EBV) provides survival factors to EBV
Immunology. 2017; 152(4):562-573 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
Diffuse large B-cell lymphoma (DLBCL), the most common type of malignant lymphoma, accounts for 30% of adult non-Hodgkin lymphomas. Epstein-Barr virus (EBV) -positive DLBCL of the elderly is a newly recognized subtype that accounts for 8-10% of DLBCLs in Asian countries, but is less common in Western populations. Five DLBCL-derived cell lines were employed to characterize patterns of EBV latent gene expression, as well as response to cytokines and chemotaxis. Interleukin-4 and interleukin-21 modified LMP1, EBNA1 and EBNA2 expression depending on cell phenotype and type of EBV latent programme (type I, II or III). These cytokines also affected CXCR4- or CCR7-mediated chemotaxis in two of the cell lines, Farage (type III) and Val (type II). Further, we investigated the effect of EBV by using dominant-negative EBV nuclear antigen 1(dnEBNA1) to eliminate EBV genomes. This resulted in decreased chemotaxis. By employing an alternative way to eliminate EBV genomes, Roscovitine, we show an increase of apoptosis in the EBV-positive lines. These results show that EBV plays an important role in EBV-positive DLBCL lines with regard to survival and chemotactic response. Our findings provide evidence for the impact of microenvironment on EBV-carrying DLBCL cells and might have therapeutic implications.

Seo H, Jeon I, Kim BS, et al.
IL-21-mediated reversal of NK cell exhaustion facilitates anti-tumour immunity in MHC class I-deficient tumours.
Nat Commun. 2017; 8:15776 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
During cancer immunoediting, loss of major histocompatibility complex class I (MHC-I) in neoplasm contributes to the evasion of tumours from host immune system. Recent studies have demonstrated that most natural killer (NK) cells that are found in advanced cancers are defective, releasing the malignant MHC-I-deficient tumours from NK-cell-dependent immune control. Here, we show that a natural killer T (NKT)-cell-ligand-loaded tumour-antigen expressing antigen-presenting cell (APC)-based vaccine effectively eradicates these advanced tumours. During this process, we find that the co-expression of Tim-3 and PD-1 marks functionally exhausted NK cells in advanced tumours and that MHC-I downregulation in tumours is closely associated with the induction of NK-cell exhaustion in both tumour-bearing mice and cancer patients. Furthermore, the recovery of NK-cell function by IL-21 is critical for the anti-tumour effects of the vaccine against advanced tumours. These results reveal the process involved in the induction of NK-cell dysfunction in advanced cancers and provide a guidance for the development of strategies for cancer immunotherapy.

Ye X, Wang R, Bhattacharya R, et al.
Cancer Prev Res (Phila). 2017; 10(7):398-409 [PubMed] Related Publications
Chronic infection and associated inflammation have long been suspected to promote human carcinogenesis. Recently, certain gut bacteria, including some in the

Bhat S, Gardi N, Hake S, et al.
Impact of intra-tumoral IL17A and IL32 gene expression on T-cell responses and lymph node status in breast cancer patients.
J Cancer Res Clin Oncol. 2017; 143(9):1745-1756 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
PURPOSE: Pro-inflammatory cytokines such as Interleukin-17A (IL17A) and Interleukin-32 (IL32), known to enhance natural killer and T cell responses, are also elevated in human malignancies and linked to poor clinical outcomes. To address this paradox, we evaluated relation between IL17A and IL32 expression and other inflammation- and T cell response-associated genes in breast tumors.
METHODS: TaqMan-based gene expression analysis was carried out in seventy-eight breast tumors. The association between IL17A and IL32 transcript levels and T cell response genes, ER status as well as lymph node status was also examined in breast tumors from TCGA dataset.
RESULTS: IL17A expression was detected in 32.7% ER-positive and 84.6% ER-negative tumors, with higher expression in the latter group (26.2 vs 7.1-fold, p < 0.01). ER-negative tumors also showed higher expression of IL32 as opposed to ER-positive tumors (8.7 vs 2.5-fold, p < 0.01). Expression of both IL17A and IL32 genes positively correlated with CCL5, GNLY, TBX21, IL21 and IL23 transcript levels (p < 0.01). Amongst ER-positive tumors, higher IL32 expression significantly correlated with lymph node metastases (p < 0.05). Conversely, in ER-negative subtype, high IL17A and IL32 expression was seen in patients with negative lymph node status (p < 0.05). Tumors with high IL32 and IL17A expression showed higher expression of TH1 response genes studied, an observation validated by similar analysis in the TCGA breast tumors (n=1041). Of note, these tumors were characterized by low expression of a potentially immunosuppressive isoform of IL32 (IL32γ).
CONCLUSION: These results suggest that high expression of both IL17A and IL32 leads to enhancement of T cell responses. Our study, thus, provides basis for the emergence of strong T cell responses in an inflammatory milieu that have been shown to be associated with better prognosis in ER-negative breast cancer.

Tan L, Han S, Ding S, et al.
Chitosan nanoparticle-based delivery of fused NKG2D-IL-21 gene suppresses colon cancer growth in mice.
Int J Nanomedicine. 2017; 12:3095-3107 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
Nanoparticles can be loaded with exogenous DNA for the potential expression of cytokines with immune-stimulatory function. NKG2D identifies major histocompatibility complex class I chain-related protein in human and retinoic acid early induced transcript-1 in mouse, which acts as tumor-associated antigens. Biologic agents based on interleukin 21 (IL-21) have displayed antitumor activities through lymphocyte activation. The NKG2D-IL-21 fusion protein theoretically identifies tumor cells through NKG2D moiety and activates T cells through IL-21 moiety. In this study, double-gene fragments that encode the extracellular domains of NKG2D and IL-21 genes were connected and then inserted into the pcDNA3.1(-) plasmid. PcDNA3.1-dsNKG2D-IL-21 plasmid nanoparticles based on chitosan were generated. Tumor cells pretransfected with dsNKG2D-IL-21 gene nanoparticles can activate natural killer (NK) and CD8

Bhatt S, Parvin S, Zhang Y, et al.
Anti-CD20-interleukin-21 fusokine targets malignant B cells via direct apoptosis and NK-cell-dependent cytotoxicity.
Blood. 2017; 129(16):2246-2256 [PubMed] Related Publications
In spite of newly emerging therapies and the improved survival of patients with non-Hodgkin lymphoma (NHL), relapses or primary refractory disease are commonly observed and associated with dismal prognosis. Although discovery of the anti-CD20 antibody rituximab has markedly improved outcomes in B-cell NHL, rituximab resistance remains an important obstacle to successful treatment of these tumors. To improve the efficacy of CD20-targeted therapy, we fused interleukin 21 (IL-21), which induces direct lymphoma cytotoxicity and activates immune effector cells, to the anti-CD20 antibody (αCD20-IL-21 fusokine). We observed substantially enhanced IL-21R-mediated signaling by the fusokine compared with native IL-21 at equimolar concentrations. Fusokine treatment led to direct apoptosis of lymphoma cell lines and primary tumors that otherwise were resistant to native IL-21 treatment. In addition to direct cytotoxicity, the fusokine enhanced NK cell activation, effector functions, and interferon γ production, resulting in greater antibody-dependent cell-mediated cytotoxicity compared with IL-21 and/or anti-CD20 antibody treatments. Further, the αCD20-IL-21 fusokine stabilizes IL-21 and prolongs its half-life. In vivo αCD20-IL-21 therapy resulted in a significant tumor control in the rituximab-resistant A20-huCD20 tumors. Collectively, the dual functional ability of the αCD20-IL-21 fusokine to induce direct apoptosis and activate immune effector cells may provide benefit over existing treatments for NHL.

Bolzoni M, Ronchetti D, Storti P, et al.
Haematologica. 2017; 102(4):773-784 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
Bone marrow monocytes are primarily committed to osteoclast formation. It is, however, unknown whether potential primary alterations are specifically present in bone marrow monocytes from patients with multiple myeloma, smoldering myeloma or monoclonal gammopathy of undetermined significance. We analyzed the immunophenotypic and transcriptional profiles of bone marrow CD14

Yang Y, Weng W, Peng J, et al.
Fusobacterium nucleatum Increases Proliferation of Colorectal Cancer Cells and Tumor Development in Mice by Activating Toll-Like Receptor 4 Signaling to Nuclear Factor-κB, and Up-regulating Expression of MicroRNA-21.
Gastroenterology. 2017; 152(4):851-866.e24 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
BACKGROUND & AIMS: Nearly 20% of the global cancer burden can be linked to infectious agents. Fusobacterium nucleatum promotes tumor formation by epithelial cells via unclear mechanisms. We aimed to identify microRNAs (miRNAs) induced by F nucleatum and evaluate their ability to promote colorectal carcinogenesis in mice.
METHODS: Colorectal cancer (CRC) cell lines were incubated with F nucleatum or control reagents and analyzed in proliferation and would healing assays. HCT116, HT29, LoVo, and SW480 CRC cell lines were incubated with F nucleatum or phosphate-buffered saline (PBS [control]) and analyzed for miRNA expression patterns and in chromatin immunoprecipitation assays. Cells were incubated with miRNAs mimics, control sequences, or small interfering RNAs; expression of reporter constructs was measured in luciferase assays. CRC cells were incubated with F nucleatum or PBS and injected into BALB/C nude mice; growth of xenograft tumors was measured. C57BL adenomatous polyposis coli
RESULTS: Fusobacterium nucleatum increased proliferation and invasive activities of CRC cell lines compared with control cells. CRC cell lines infected with F nucleatum formed larger tumors, more rapidly, in nude mice than uninfected cells. Adenomatous polyposis coli
CONCLUSIONS: We found infection of CRC cells with F nucleatum to increase their proliferation, invasive activity, and ability to form xenograft tumors in mice. Fusobacterium nucleatum activates Toll-like receptor 4 signaling to MYD88, leading to activation of the nuclear factor-κB and increased expression of miR21; this miRNA reduces levels of the RAS GTPase RASA1. Patients with both high amount of tissue F nucleatum DNA and miR21 demonstrated a higher risk for poor outcomes.

Moyes KW, Lieberman NA, Kreuser SA, et al.
Genetically Engineered Macrophages: A Potential Platform for Cancer Immunotherapy.
Hum Gene Ther. 2017; 28(2):200-215 [PubMed] Related Publications
In spite of their successes against hematologic malignancies, immunotherapeutic interventions for the treatment of patients with glioblastoma (GBM) have thus far been unsuccessful. This is in part due to the presence of a tumor microenvironment that fosters neoplastic growth and protects the tumor from destruction by the immune system. A novel genetically engineered macrophage-based platform has been developed with the potential to minimize the effects of the suppressive tumor microenvironment and improve innate and adaptive antitumor immune responses. A newly described lentiviral expression system was validated for the generation of transduced monocytes and monocyte-derived macrophages, and transgene expression was shown to be stable over the course of weeks to months, both in vitro and in a mouse xenograft model of GBM. Furthermore, the genetically engineered macrophages (GEMs) neither caused morbidity in animals nor contributed to accelerated tumor growth. The versatility of GEMs is also highlighted by showing that they can be engineered to secrete proteins that either reduce immune suppression, such as the soluble transforming growth factor beta receptor II, or promote immune cell activation, by expressing interleukin 21. There is also the potential to prevent GEM-mediated immune suppression by using the CRISPR system to knock out genes responsible for dysfunction of cytotoxic cells, including interleukin 10 and programmed death-ligand 1. Together, these results suggest that GEMs are an ideal cell type for transforming the tumor microenvironment and enhancing antitumor immunity. Importantly, it is anticipated that these findings will have broad applicability to other types of tumors with microenvironments that currently preclude successful immunotherapeutic approaches.

Gu YZ, Fan CW, Lu R, et al.
Forced co-expression of IL-21 and IL-7 in whole-cell cancer vaccines promotes antitumor immunity.
Sci Rep. 2016; 6:32351 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
Genetic modification of whole-cell cancer vaccines to augment their efficacies has a history of over two and a half decades. Various genes and gene combinations, targeting different aspects of immune responses have been tested in pursuit of potent adjuvant effects. Here we show that co-expression of two cytokine members of the common cytokine receptor γ-chain family, IL-21 and IL-7, in whole-cell cancer vaccines boosts antitumor immunity in a CD4(+) and CD8(+) T cell-dependent fashion. It also generates effective immune memory. The vaccine-elicited short-term effects positively correlated with enhanced infiltration of CD4(+) and CD8(+) effector T cells, and the long-term effects positively correlated with enhanced infiltration of effector memory T cells, especially CD8(+) effector memory T cells. Preliminary data suggested that the vaccine exhibited good safety profile in murine models. Taken together, the combination of IL-21 and IL-7 possesses potent adjuvant efficacy in whole-cell vaccines. This finding warrants future development of IL-21 and IL-7 co-expressing whole-cell cancer vaccines and their relevant combinatorial regimens.

Chen MM, Xiao X, Lao XM, et al.
Polarization of Tissue-Resident TFH-Like Cells in Human Hepatoma Bridges Innate Monocyte Inflammation and M2b Macrophage Polarization.
Cancer Discov. 2016; 6(10):1182-1195 [PubMed] Related Publications
The existence, regulation, and functions of IL21
SIGNIFICANCE: We identified a novel protumorigenic IL21

Panjwani MK, Smith JB, Schutsky K, et al.
Feasibility and Safety of RNA-transfected CD20-specific Chimeric Antigen Receptor T Cells in Dogs with Spontaneous B Cell Lymphoma.
Mol Ther. 2016; 24(9):1602-14 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
Preclinical murine models of chimeric antigen receptor (CAR) T cell therapy are widely applied, but are greatly limited by their inability to model the complex human tumor microenvironment and adequately predict safety and efficacy in patients. We therefore sought to develop a system that would enable us to evaluate CAR T cell therapies in dogs with spontaneous cancers. We developed an expansion methodology that yields large numbers of canine T cells from normal or lymphoma-diseased dogs. mRNA electroporation was utilized to express a first-generation canine CD20-specific CAR in expanded T cells. The canine CD20 (cCD20) CAR expression was efficient and transient, and electroporated T cells exhibited antigen-specific interferon-gamma (IFN-γ) secretion and lysed cCD20+ targets. In a first-in-canine study, autologous cCD20-ζ CAR T cells were administered to a dog with relapsed B cell lymphoma. Treatment was well tolerated and led to a modest, but transient, antitumor activity, suggesting that stable CAR expression will be necessary for durable clinical remissions. Our study establishes the methodologies necessary to evaluate CAR T cell therapy in dogs with spontaneous malignancies and lays the foundation for use of outbred canine cancer patients to evaluate the safety and efficacy of next-generation CAR therapies and their optimization prior to translation into humans.

Lindahl LM, Fredholm S, Joseph C, et al.
STAT5 induces miR-21 expression in cutaneous T cell lymphoma.
Oncotarget. 2016; 7(29):45730-45744 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
In cutaneous T cell lymphomas (CTCL), miR-21 is aberrantly expressed in skin and peripheral blood and displays anti-apoptotic properties in malignant T cells. It is, however, unclear exactly which cells express miR-21 and what mechanisms regulate miR-21. Here, we demonstrate miR-21 expression in situ in both malignant and reactive lymphocytes as well as stromal cells. qRT-PCR analysis of 47 patients with mycosis fungoides (MF) and Sezary Syndrome (SS) confirmed an increased miR-21 expression that correlated with progressive disease. In cultured malignant T cells miR-21 expression was inhibited by Tofacitinib (CP-690550), a clinical-grade JAK3 inhibitor. Chromatin immunoprecipitation (ChIP) analysis showed direct binding of STAT5 to the miR-21 promoter. Cytokine starvation ex vivo triggered a decrease in miR-21 expression, whereas IL-2 induced an increased miR-21 expression in primary SS T cells and cultured cytokine-dependent SS cells (SeAx). siRNA-mediated depletion of STAT5 inhibited constitutive- and IL-2-induced miR-21 expression in cytokine-independent and dependent T cell lines, respectively. IL-15 and IL-2 were more potent than IL-21 in inducing miR-21 expression in the cytokine-dependent T cells. In conclusion, we provide first evidence that miR-21 is expressed in situ in CTCL skin lesions, induced by IL-2 and IL-15 cytokines, and is regulated by STAT5 in malignant T cells. Thus, our data provide novel evidence for a pathological role of IL-2Rg cytokines in promoting expression of the oncogenic miR-21 in CTCL.

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