Gene Summary

Gene:IL7R; interleukin 7 receptor
Aliases: ILRA, CD127, IL7RA, CDW127, IL-7R-alpha
Summary:The protein encoded by this gene is a receptor for interleukin 7 (IL7). The function of this receptor requires the interleukin 2 receptor, gamma chain (IL2RG), which is a common gamma chain shared by the receptors of various cytokines, including interleukins 2, 4, 7, 9, and 15. This protein has been shown to play a critical role in V(D)J recombination during lymphocyte development. Defects in this gene may be associated with severe combined immunodeficiency (SCID). Alternatively spliced transcript variants have been found. [provided by RefSeq, Dec 2015]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:interleukin-7 receptor subunit alpha
Source:NCBIAccessed: 01 September, 2019


What does this gene/protein do?
Show (25)
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.

  • Case-Control Studies
  • Leukemic Gene Expression Regulation
  • Genetic Predisposition
  • Adolescents
  • Chromosome 5
  • Exons
  • Staging
  • Mutation
  • Antineoplastic Agents
  • Translocation
  • Apoptosis
  • Receptors, Cytokine
  • Risk Factors
  • Disease-Free Survival
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma
  • Oligonucleotide Array Sequence Analysis
  • Transcription
  • Biomarkers, Tumor
  • Cancer Gene Expression Regulation
  • Signal Transduction
  • Infant
  • Smoking
  • Transcriptome
  • NOTCH1 Receptor
  • Interleukin-7 Receptor alpha Subunit
  • Precursor B-Cell Lymphoblastic Leukemia-Lymphoma
  • DNA Mutational Analysis
  • Single Nucleotide Polymorphism
  • Flow Cytometry
  • Childhood Cancer
  • Down-Regulation
  • Heterografts
  • Gene Expression Profiling
  • Molecular Sequence Data
  • Protein Kinase Inhibitors
  • Xenograft Models
  • Acute Lymphocytic Leukaemia
  • Philadelphia Chromosome
  • T-Lymphocytes
  • Receptors, Interleukin-7
Tag cloud generated 01 September, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (3)

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: IL7R (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

Sharma ND, Nickl CK, Kang H, et al.
Epigenetic silencing of SOCS5 potentiates JAK-STAT signaling and progression of T-cell acute lymphoblastic leukemia.
Cancer Sci. 2019; 110(6):1931-1946 [PubMed] Free Access to Full Article Related Publications
Activating mutations in cytokine receptors and transcriptional regulators govern aberrant signal transduction in T-cell lineage acute lymphoblastic leukemia (T-ALL). However, the roles played by suppressors of cytokine signaling remain incompletely understood. We examined the regulatory roles of suppressor of cytokine signaling 5 (SOCS5) in T-ALL cellular signaling networks and leukemia progression. We found that SOCS5 was differentially expressed in primary T-ALL and its expression levels were lowered in HOXA-deregulated leukemia harboring KMT2A gene rearrangements. Here, we report that SOCS5 expression is epigenetically regulated by DNA methyltransferase-3A-mediated DNA methylation and methyl CpG binding protein-2-mediated histone deacetylation. We show that SOCS5 negatively regulates T-ALL cell growth and cell cycle progression but has no effect on apoptotic cell death. Mechanistically, SOCS5 silencing induces activation of JAK-STAT signaling, and negatively regulates interleukin-7 and interleukin-4 receptors. Using a human T-ALL murine xenograft model, we show that genetic inactivation of SOCS5 accelerates leukemia engraftment and progression, and leukemia burden. We postulate that SOCS5 is epigenetically deregulated in T-ALL and serves as an important regulator of T-ALL cell proliferation and leukemic progression. Our results link aberrant downregulation of SOCS5 expression to the enhanced activation of the JAK-STAT and cytokine receptor-signaling cascade in T-ALL.

Park Y, Kim J
Regulation of IL-6 signaling by miR-125a and let-7e in endothelial cells controls vasculogenic mimicry formation of breast cancer cells.
BMB Rep. 2019; 52(3):214-219 [PubMed] Free Access to Full Article Related Publications
The role of tumor-proximal factors in tumor plasticity during chemoresistance and metastasis following chemotherapy is well studied. However, the role of endothelial cell (EC) derived paracrine factors in tumor plasticity, their effect on chemotherapeutic outcome, and the mechanism by which these paracrine factors modulate the tumor microenvironment are not well understood. In this study, we report a novel mechanism by which endothelial miR-125a and let-7e-mediated regulation of interleukin-6 (IL-6) signaling can manipulate vasculogenic mimicry (VM) formation of MDA-MB-231 breast cancer cells. We found that endothelial IL-6 levels were significantly higher in response to cisplatin treatment, whereas levels of IL-6 upon cisplatin exposure remained unchanged in MDA-MB-231 breast cancer cells. We additionally found an inverse correlation between IL-6 and miR-125a/let-7e expression levels in cisplatin treated ECs. Interestingly, IL-6, IL-6 receptor (IL-6R), and signal transducer and activator of transcription 3 (STAT3) genes in the IL-6 pathway are closely regulated by miR-125a and let-7e, which directly target its 3' untranslated region. Functional analyses revealed that endothelial miR-125a and let-7e inhibit IL-6-induced adhesion of monocytes to ECs. Furthermore, conditioned medium from cisplatin treated ECs induced a significantly higher formation of VM in MDA-MB-231 breast cancer cells as compared to that from intact ECs; this effect of cisplatin treatment was abrogated by concurrent overexpression of miR-125a and let-7e. Overall, this study reveals a novel EC-tumor cell crosstalk mediated by the endothelial miR-125a/let-7e-IL-6 signaling axis, which might improve chemosensitivity and provide potential therapeutic targets for the treatment of cancer. [BMB Reports 2019; 52(3): 214-219].

Baldan F, Allegri L, Lazarevic M, et al.
Biological and molecular effects of bromodomain and extra-terminal (BET) inhibitors JQ1, IBET-151, and IBET-762 in OSCC cells.
J Oral Pathol Med. 2019; 48(3):214-221 [PubMed] Related Publications
BACKGROUND: Despite improvements in oral squamous cell carcinoma (OSCC) management, survival rates remain relatively low and novel anti-neoplastic agents are needed. Bromodomain and extra-terminal (BET) inhibitors proved to be promising agents for cancer treatment. We investigated the effects of three BET inhibitors (JQ1, IBET-151, IBET-762) on SCC-25 cell line and primary oral cancer cell culture.
METHODS: Cell viability was evaluated by MTT. Protein levels of MCM5 and cleaved-PARP were estimated by Western blot. Clonogenic and migratory abilities were determined by colony forming and scratch assays. BET inhibitors effects on mRNA levels of E-Cadherin, Vimentin, SNAI1, SNAI2, CLU, SERPINI1, MCM5, c-Myc, E2F, IL7R, and PPARg were analyzed by qPCR.
RESULTS: BET inhibitors significantly reduced oral cancer cell viability. JQ1 showed the greatest effect reducing cell viability to 10%, both in SCC-25 and primary OSCC cultures (P < 0.001), compared to control cells. Cells treated with BET inhibitors displayed a reduction to 50% in colony forming capacity compared to control cells (P < 0.0001) and the colonies were smaller; they also had a 50%-60% reduction in migratory capacity (P < 0.05) compared to untreated cells. BET inhibitors had a significant impact on genes related to epithelial to mesenchymal transition and other cancer cell markers, notably on MCM5, a gene related to cell cycle control.
CONCLUSIONS: BET inhibitors induce both OSCC cell death and reduction of tumor aggressiveness. Molecular mechanisms of BET inhibition involve among others, MCM5 downregulation. Importantly, this study demonstrates for the first time the anti-tumoral effect of IBET-151 and IBET-762 in oral cancer.

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

Jian M, Yunjia Z, Zhiying D, et al.
Interleukin 7 receptor activates PI3K/Akt/mTOR signaling pathway via downregulation of Beclin-1 in lung cancer.
Mol Carcinog. 2019; 58(3):358-365 [PubMed] Related Publications
Interleukin-7(IL-7) can regulate proliferation and apoptosis of cell and also regulate tumor lymphangiogenesis, but whether it regulating autophagy of tumor cells is not well known. We study the relationship between IL-7 and some autophagy-related markers, Beclin 1 and mammalian target of rapamycin (mTOR) and the mechanism of IL-7 in regulating autophagy of human lung cancer cells. We detected expression of Beclin 1 and mTOR in lung cancer cells and their impact on the prognosis of lung cancer patients. Using Western blot and Reverse Transcription PCR, we found that IL-7 activates PI3 K/Akt/mTOR signaling pathway by downregulated the expression of Beclin 1 in lung cancer cell lines. In addition, the expressions of Beclin 1 and mTOR were well correlated with clinical stages and survival of human non-small cell lung cancer (NSCLC) patients. IL-7R, mTOR, and tumor stage were the independent prognosticators in lung cancer. Taken together, our results provided evidence that IL-7 activates PI3 K/Akt/mTOR signaling pathway via Beclin 1 to regulate autophagy in lung cancer cells.

Kim HD, Song GW, Park S, et al.
Association Between Expression Level of PD1 by Tumor-Infiltrating CD8
Gastroenterology. 2018; 155(6):1936-1950.e17 [PubMed] Related Publications
BACKGROUND & AIMS: T-cell exhaustion, or an impaired capacity to secrete cytokines and proliferate with overexpression of immune checkpoint receptors, occurs during chronic viral infections but has also been observed in tumors, including hepatocellular carcinomas (HCCs). We investigated features of exhaustion in CD8
METHODS: We obtained HCC specimens, along with adjacent nontumor tissues and blood samples, from 90 patients who underwent surgical resection at Asan Medical Center (Seoul, Korea) from April 2016 through April 2018. Intrahepatic lymphocytes and tumor-infiltrating T cells were analyzed by flow cytometry. Tumor-infiltrating CD8
RESULTS: PD1-high, PD1-intermediate, and PD1-negative CD8
CONCLUSIONS: We found HCC specimens to contain CD8

Barve A, Casson L, Krem M, et al.
Comparative utility of NRG and NRGS mice for the study of normal hematopoiesis, leukemogenesis, and therapeutic response.
Exp Hematol. 2018; 67:18-31 [PubMed] Article available free on PMC after 01/11/2019 Related Publications
Cell-line-derived xenografts (CDXs) or patient-derived xenografts (PDXs) in immune-deficient mice have revolutionized our understanding of normal and malignant human hematopoiesis. Transgenic approaches further improved in vivo hematological research, allowing the development of human-cytokine-producing mice, which show superior human cell engraftment. The most popular mouse strains used in research, the NOG (NOD.Cg-Prkdc

Stock S, Hoffmann JM, Schubert ML, et al.
Influence of Retronectin-Mediated T-Cell Activation on Expansion and Phenotype of CD19-Specific Chimeric Antigen Receptor T Cells.
Hum Gene Ther. 2018; 29(10):1167-1182 [PubMed] Related Publications
Enhanced in vivo expansion, long-term persistence of chimeric antigen receptor T (CART) cells, and efficient tumor eradication through these cells are linked to the proportion of less-differentiated cells in the CART cell product. Retronectin is well established as an adjuvant for improved retroviral transduction, while its property to enrich less-differentiated T cells is less known. In order to increase these subsets, this study investigated the effects of retronectin-mediated T-cell activation for CD19-specific CART cell production. Peripheral blood mononuclear cells of healthy donors and untreated chronic lymphocytic leukemia (CLL) patients without or with positive selection for CD3+ T cells were transduced with a CD19.CAR.CD28.CD137zeta third-generation retroviral vector. Activation of peripheral blood mononuclear cells was performed by CD3/CD28, CD3/CD28/retronectin, or CD3/retronectin. Interleukin-7 and -15 were supplemented to all cultures. Retronectin was used in all three activation protocols for retroviral transduction. Expansion was assessed by trypan blue staining. Viability, transduction efficiency, immune phenotype, and cytokine production were longitudinally analyzed by flow cytometry. Cytotoxic capacity of generated CART cells was evaluated using a classical chromium-51 release assay. Retronectin-mediated activation resulted in an enrichment of CD8+ cytotoxic CART cells and less-differentiated naïve-like T cells (CD45RA+CCR7+). Retronectin-activated CART cells showed increased cytotoxic activity. However, activation with retronectin decreased viability, expansion, transduction efficiency, and cytokine production, particularly of CLL patient-derived CART cells. Both retronectin-mediated activation protocols promoted a less-differentiated CART cell phenotype without comprising cytotoxic properties of healthy donor-derived CART cells. However, up-front retronectin resulted in reduced viability and expansion in CLL patients. This effect is probably attributed to the retronectin-mediated activation of B cells with prolonged CLL persistence. Consequently, CART cell expansion and generation failed. In summary, activation with retronectin should be performed with caution and may be limited to patients without a higher percentage of tumor cells in the peripheral blood.

Roberts KG, Reshmi SC, Harvey RC, et al.
Genomic and outcome analyses of Ph-like ALL in NCI standard-risk patients: a report from the Children's Oncology Group.
Blood. 2018; 132(8):815-824 [PubMed] Article available free on PMC after 01/11/2019 Related Publications
Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL;

Studd JB, Yang M, Li Z, et al.
Genetic predisposition to B-cell acute lymphoblastic leukemia at 14q11.2 is mediated by a CEBPE promoter polymorphism.
Leukemia. 2019; 33(1):1-14 [PubMed] Article available free on PMC after 01/11/2019 Related Publications
Acute lymphoblastic leukaemia (ALL) is the most common paediatric malignancy. Genome-wide association studies have shown variation at 14q11.2 influences ALL risk. We sought to decipher causal variant(s) at 14q11.2 and the mechanism of tumorigenesis. We show rs2239630 G>A resides in the promoter of the CCAT enhancer-binding protein epsilon (CEBPE) gene. The rs2239630-A risk allele is associated with increased promotor activity and CEBPE expression. Depletion of CEBPE in ALL cells reduces cell growth, correspondingly CEBPE binds to the promoters of electron transport and energy generation genes. RNA-seq in CEBPE depleted cells demonstrates CEBPE regulates the expression of genes involved in B-cell development (IL7R), apoptosis (BCL2), and methotrexate resistance (RASS4L). CEBPE regulated genes significantly overlapped in CEBPE depleted cells, ALL blasts and IGH-CEBPE translocated ALL. This suggests CEBPE regulates a similar set of genes in each, consistent with a common biological mechanism of leukemogenesis for rs2239630 associated and CEBPE translocated ALL. Finally, we map IGH-CEBPE translocation breakpoints in two cases, implicating RAG recombinase activity in their formation.

Sharapova TN, Romanova EA, Sashchenko LP, Yashin DV
Tag7 (PGLYRP1) Can Induce an Emergence of the CD3+CD4+CD25+CD127+ Cells with Antitumor Activity.
J Immunol Res. 2018; 2018:4501273 [PubMed] Article available free on PMC after 01/11/2019 Related Publications
We have shown that in the human peripheral blood cells, the innate immunity protein Tag7 can activate a subpopulation of CD3+CD4+CD25+ cells, which have antitumor activity. These cells can induce lysis of HLA-negative tumor cell lines. The Hsp70 stress molecule on the surface of the tumor cells is used as a recognition target, while the Tag7 protein on the lymphocyte membrane acts as a receptor for Hsp70. We have also demonstrated that this subpopulation of the CD4+CD25+ cells is CD127 positive and hence is not the Treg cells. Our data suggest that this subpopulation of cells is identical to the CD4+CD25+ lymphocytes, which are activated in the leukocyte pool by the IL-2 cytokine.

Leung CS
Analysis of ROR1 Protein Expression in Mice with Reconstituted Human Immune System Components.
J Immunol Res. 2018; 2018:2480931 [PubMed] Article available free on PMC after 01/11/2019 Related Publications
Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is an oncofetal antigen expressed on multiple tumors and has no significant expression on normal human tissues. ROR1 is highly upregulated in chronic lymphocytic leukemia (CLL) B cells. NOD-scid IL2rg

Kim MJ, Choi SK, Hong SH, et al.
Oncogenic IL7R is downregulated by histone deacetylase inhibitor in esophageal squamous cell carcinoma via modulation of acetylated FOXO1.
Int J Oncol. 2018; 53(1):395-403 [PubMed] Related Publications
The interleukin-7 receptor (IL7R) is generally expressed in immune cells and is critical in survival, development and homeostasis in the immune system. Advanced genome-wide cancer studies have reported that IL7R is genetically amplified in human esophageal squamous cell carcinoma (ESCC), however, the exact role of IL7R in ESCC has not been investigated. In the present study, it was found that IL7R was overexpressed in ESCC cohorts and the loss of IL7R induced anti-oncogenic effects in ESCC cell lines. A small panel of epigenetic drugs were screened for their ability to downregulate the expression of IL7R. Unexpectedly, apicidin, a histone deacetylase (HDAC) inhibitor, effectively downregulated the expression of IL7R in a dose-dependent manner at an early time-point, as determined by quantitative polymerase chain reaction and IL7R immunostaining, and did not require de novo protein synthesis. Of note, apicidin induced the acetylation of Forkhead box-containing protein, O subfamily 1, which acts as a repressor at the IL7R promoter, accompanied with depleted active histone modifications based on chromatin immunoprecipitation assay. Taken together, these results demonstrated that targeting oncogenic IL7R in ESCC by HDAC inhibitors may be a valuable therapeutic approach.

Fan Y, Nan Y, Huang J, et al.
Up-regulation of inflammation-related LncRNA-IL7R predicts poor clinical outcome in patients with cervical cancer.
Biosci Rep. 2018; 38(3) [PubMed] Article available free on PMC after 01/11/2019 Related Publications
The long-term chronic inflammation of cervical intraepithelial neoplasia (CIN) induces the initiation and progression of cervical cancer. Long non-coding RNAs (LncRNAs) are being identified to be involved into inflammation and carcinogenesis and could function as cancer biomarkers in clinical. However, the significance of inflammation-related LncRNA (e.g.

Böiers C, Richardson SE, Laycock E, et al.
A Human IPS Model Implicates Embryonic B-Myeloid Fate Restriction as Developmental Susceptibility to B Acute Lymphoblastic Leukemia-Associated ETV6-RUNX1.
Dev Cell. 2018; 44(3):362-377.e7 [PubMed] Article available free on PMC after 01/11/2019 Related Publications
ETV6-RUNX1 is associated with childhood acute B-lymphoblastic leukemia (cALL) functioning as a first-hit mutation that initiates a clinically silent pre-leukemia in utero. Because lineage commitment hierarchies differ between embryo and adult, and the impact of oncogenes is cell-context dependent, we hypothesized that the childhood affiliation of ETV6-RUNX1 cALL reflects its origins in a progenitor unique to embryonic life. We characterize the first emerging B cells in first-trimester human embryos, identifying a developmentally restricted CD19

Adurthi S, Kumar MM, Vinodkumar HS, et al.
Oestrogen Receptor-α binds the FOXP3 promoter and modulates regulatory T-cell function in human cervical cancer.
Sci Rep. 2017; 7(1):17289 [PubMed] Article available free on PMC after 01/11/2019 Related Publications
Oestrogen controls Foxp3 expression in regulatory T cells (T

Melsted WN, Matzen SH, Andersen MH, Hviid TVF
The choriocarcinoma cell line JEG-3 upregulates regulatory T cell phenotypes and modulates pro-inflammatory cytokines through HLA-G.
Cell Immunol. 2018; 324:14-23 [PubMed] Related Publications
An understanding of the interactions between immune cells and trophoblast cells, as well as choriocarcinoma cells, are of extreme importance in reproductive immunology and cancer immunology. In this study, we found that the human HLA-G-positive choriocarcinoma cell line JEG-3 upregulates CD4

Sikandar SS, Kuo AH, Kalisky T, et al.
Role of epithelial to mesenchymal transition associated genes in mammary gland regeneration and breast tumorigenesis.
Nat Commun. 2017; 8(1):1669 [PubMed] Article available free on PMC after 01/11/2019 Related Publications
Previous studies have proposed that epithelial to mesenchymal transition (EMT) in breast cancer cells regulates metastasis, stem cell properties and chemo-resistance; most studies were based on in vitro culture of cell lines and mouse transgenic cancer models. However, the identity and function of cells expressing EMT-associated genes in normal murine mammary gland homeostasis and human breast cancer still remains under debate. Using in vivo lineage tracing and triple negative breast cancer (TNBC) patient derived xenografts we demonstrate that the repopulating capacity in normal mammary epithelial cells and tumorigenic capacity in TNBC is independent of expression of EMT-associated genes. In breast cancer, while a subset of cells with epithelial and mesenchymal phenotypes have stem cell activity, in many cells that have lost epithelial characteristics with increased expression of mesenchymal genes, have decreased tumor-initiating capacity and plasticity. These findings have implications for the development of effective therapeutic agents targeting tumor-initiating cells.

Cany J, Roeven MWH, Hoogstad-van Evert JS, et al.
Decitabine enhances targeting of AML cells by CD34
Blood. 2018; 131(2):202-214 [PubMed] Article available free on PMC after 01/11/2019 Related Publications
Combining natural killer (NK) cell adoptive transfer with hypomethylating agents (HMAs) is an attractive therapeutic approach for patients with acute myeloid leukemia (AML). However, data regarding the impact of HMAs on NK cell functionality are mostly derived from in vitro studies with high nonclinical relevant drug concentrations. In the present study, we report a comparative study of azacitidine (AZA) and decitabine (DAC) in combination with allogeneic NK cells generated from CD34

Di Pascale F, Nama S, Muhuri M, et al.
C/EBPβ mediates RNA polymerase III-driven transcription of oncomiR-138 in malignant gliomas.
Nucleic Acids Res. 2018; 46(1):336-349 [PubMed] Article available free on PMC after 01/11/2019 Related Publications
MicroRNA-138 (miR-138) is a pro-survival oncomiR for glioma stem cells. In malignant gliomas, dysregulated expression of microRNAs, such as miR-138, promotes Tumour initiation and progression. Here, we identify the ancillary role of the CCAAT/enhancer binding protein β (C/EBPβ) as a transcriptional activator of miR-138. We demonstrate that a short 158 bp DNA sequence encoding the precursor of miR-138-2 is essential and sufficient for transcription of miR-138. This short sequence includes the A-box and B-box elements characteristic of RNA Polymerase III (Pol III) promoters, and is also directly bound by C/EBPβ via an embedded 'C/EBPβ responsive element' (CRE). CRE and the Pol III B-box element overlap, suggesting that C/EBPβ and transcription factor 3C (TFIIIC) interact at the miR-138-2 locus. We propose that this interaction is essential for the recruitment of the RNA Pol III initiation complex and associated transcription of the oncomiR, miR-138 in malignant gliomas.

Vitiello GAF, Losi Guembarovski R, Amarante MK, et al.
Interleukin 7 receptor alpha Thr244Ile genetic polymorphism is associated with susceptibility and prognostic markers in breast cancer subgroups.
Cytokine. 2018; 103:121-126 [PubMed] Related Publications
Interleukin-7 (IL-7) exerts crucial functions on lymphoid cells' development and maintenance. In breast cancer (BC), IL-7 promotes growth of tumor cells in culture through the activation of JAK1/3-STAT5 and PI3K/AKT pathways, and expression of IL-7 signaling components was associated with worst prognosis. AC>T polymorphism (rs6897932; Thr244Ile) at exon 6 of IL-7 receptor alpha (IL-7Rα) gene (IL7RA) shifts the balance between the membrane-bound and soluble IL-7Rα splicing variants and was previously associated with autoimmune diseases, but has not been studied in cancer, including BC, so far. Therefore, the present study aimed to investigate the possible association of this polymorphism with the susceptibility and clinicopathological parameters of BC subgroups. IL7RA Thr244Ile was genotyped through PCR-RFLP in 403 women without neoplasia, no personal history of malignancy or family history of BC and in 338 BC patients with clinicopathological data available. BC patients were stratified according to their positivity for estrogen (ER) and/or progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2). Age-adjusted logistic regression was performed for case-control analyses, and correlations with clinicopathological parameters were assessed through Kendall's Tau-b coefficient. All analyses were two-tailed and had 95% confidence interval. In ER

Goods BA, Hernandez AL, Lowther DE, et al.
Functional differences between PD-1+ and PD-1- CD4+ effector T cells in healthy donors and patients with glioblastoma multiforme.
PLoS One. 2017; 12(9):e0181538 [PubMed] Article available free on PMC after 01/11/2019 Related Publications
Immune checkpoint inhibitors targeting programmed cell death protein 1 (PD-1) have been highly successful in the treatment of cancer. While PD-1 expression has been widely investigated, its role in CD4+ effector T cells in the setting of health and cancer remains unclear, particularly in the setting of glioblastoma multiforme (GBM), the most aggressive and common form of brain cancer. We examined the functional and molecular features of PD-1+CD4+CD25-CD127+Foxp3-effector cells in healthy subjects and in patients with GBM. In healthy subjects, we found that PD-1+CD4+ effector cells are dysfunctional: they do not proliferate but can secrete large quantities of IFNγ. Strikingly, blocking antibodies against PD-1 did not rescue proliferation. RNA-sequencing revealed features of exhaustion in PD-1+ CD4 effectors. In the context of GBM, tumors were enriched in PD-1+ CD4+ effectors that were similarly dysfunctional and unable to proliferate. Furthermore, we found enrichment of PD-1+TIM-3+ CD4+ effectors in tumors, suggesting that co-blockade of PD-1 and TIM-3 in GBM may be therapeutically beneficial. RNA-sequencing of blood and tumors from GBM patients revealed distinct differences between CD4+ effectors from both compartments with enrichment in multiple gene sets from tumor infiltrating PD-1-CD4+ effectors cells. Enrichment of these gene sets in tumor suggests a more metabolically active cell state with signaling through other co-receptors. PD-1 expression on CD4 cells identifies a dysfunctional subset refractory to rescue with PD-1 blocking antibodies, suggesting that the influence of immune checkpoint inhibitors may involve recovery of function in the PD-1-CD4+ T cell compartment. Additionally, co-blockade of PD-1 and TIM-3 in GBM may be therapeutically beneficial.

Yasunaga M, Manabe S, Matsumura Y
Immunoregulation by IL-7R-targeting antibody-drug conjugates: overcoming steroid-resistance in cancer and autoimmune disease.
Sci Rep. 2017; 7(1):10735 [PubMed] Article available free on PMC after 01/11/2019 Related Publications
Steroid-resistance is a common complication in the treatment of malignancies and autoimmune diseases. IL-7/IL-7R signaling, which regulates lymphocyte growth and survival, has been implicated in the development of malignancies and autoimmune diseases. However, the biological significance of IL-7/IL-7R signaling in steroid treatment is poorly understood. Here, we identified a novel relationship between IL-7R signaling and steroid-resistance, and showed that an anti-IL-7R antibody conjugated with SN-38 (A7R-ADC-SN-38) has strong anti-tumor effects against both parental and steroid-resistant malignant cells. Furthermore, inflammation in the mouse autoimmune arthritis model was suppressed to greater extent by A7R-ADC conjugated to MMAE than by A7R-ADC-SN-38. Given that an increased proportion of IL-7R-positive cells is a common mechanism underlying the pathogenesis of autoimmunity, we found that specific depletion of this cell population abrogated the progression of disease. This suggests that the cytotoxicity and immunosuppressive capacity of A7R-ADC could be modulated to treat specific malignancies or autoimmune diseases through the introduction of different payloads, and represents a novel alternative to steroid therapy.

Shum T, Omer B, Tashiro H, et al.
Constitutive Signaling from an Engineered IL7 Receptor Promotes Durable Tumor Elimination by Tumor-Redirected T Cells.
Cancer Discov. 2017; 7(11):1238-1247 [PubMed] Article available free on PMC after 01/11/2019 Related Publications
Successful adoptive T-cell immunotherapy of solid tumors will require improved expansion and cytotoxicity of tumor-directed T cells within tumors. Providing recombinant or transgenic cytokines may produce the desired benefits but is associated with significant toxicities, constraining clinical use. To circumvent this limitation, we constructed a constitutively signaling cytokine receptor, C7R, which potently triggers the IL7 signaling axis but is unresponsive to extracellular cytokine. This strategy augments modified T-cell function following antigen exposure, but avoids stimulating bystander lymphocytes. Coexpressing the C7R with a tumor-directed chimeric antigen receptor (CAR) increased T-cell proliferation, survival, and antitumor activity during repeated exposure to tumor cells, without T-cell dysfunction or autonomous T-cell growth. Furthermore, C7R-coexpressing CAR T cells were active against metastatic neuroblastoma and orthotopic glioblastoma xenograft models even at cell doses that had been ineffective without C7R support. C7R may thus be able to enhance antigen-specific T-cell therapies against cancer.

Forero-Castro M, Robledo C, Benito R, et al.
Mutations in TP53 and JAK2 are independent prognostic biomarkers in B-cell precursor acute lymphoblastic leukaemia.
Br J Cancer. 2017; 117(2):256-265 [PubMed] Article available free on PMC after 01/11/2019 Related Publications
BACKGROUND: In B-cell precursor acute lymphoblastic leukaemia (B-ALL), the identification of additional genetic alterations associated with poor prognosis is still of importance. We determined the frequency and prognostic impact of somatic mutations in children and adult cases with B-ALL treated with Spanish PETHEMA and SEHOP protocols.
METHODS: Mutational status of hotspot regions of TP53, JAK2, PAX5, LEF1, CRLF2 and IL7R genes was determined by next-generation deep sequencing in 340 B-ALL patients (211 children and 129 adults). The associations between mutation status and clinicopathological features at the time of diagnosis, treatment outcome and survival were assessed. Univariate and multivariate survival analyses were performed to identify independent prognostic factors associated with overall survival (OS), event-free survival (EFS) and relapse rate (RR).
RESULTS: A mutation rate of 12.4% was identified. The frequency of adult mutations was higher (20.2% vs 7.6%, P=0.001). TP53 was the most frequently mutated gene (4.1%), followed by JAK2 (3.8%), CRLF2 (2.9%), PAX5 (2.4%), LEF1 (0.6%) and IL7R (0.3%). All mutations were observed in B-ALL without ETV6-RUNX1 (P=0.047) or BCR-ABL1 fusions (P<0.0001). In children, TP53mut was associated with lower OS (5-year OS: 50% vs 86%, P=0.002) and EFS rates (5-year EFS: 50% vs 78.3%, P=0.009) and higher RR (5-year RR: 33.3% vs 18.6% P=0.037), and was independently associated with higher RR (hazard ratio (HR)=4.5; P=0.04). In adults, TP53mut was associated with a lower OS (5-year OS: 0% vs 43.3%, P=0.019) and a higher RR (5-year RR: 100% vs 61.4%, P=0.029), whereas JAK2mut was associated with a lower EFS (5-year EFS: 0% vs 30.6%, P=0.035) and a higher RR (5-year RR: 100% vs 60.4%, P=0.002). TP53mut was an independent risk factor for shorter OS (HR=2.3; P=0.035) and, together with JAK2mut, also were independent markers of poor prognosis for RR (TP53mut: HR=5.9; P=0.027 and JAK2mut: HR=5.6; P=0.036).
CONCLUSIONS: TP53mut and JAK2mut are potential biomarkers associated with poor prognosis in B-ALL patients.

Kruth KA, Fang M, Shelton DN, et al.
Suppression of B-cell development genes is key to glucocorticoid efficacy in treatment of acute lymphoblastic leukemia.
Blood. 2017; 129(22):3000-3008 [PubMed] Article available free on PMC after 01/11/2019 Related Publications
Glucocorticoids (GCs), including dexamethasone (dex), are a central component of combination chemotherapy for childhood B-cell precursor acute lymphoblastic leukemia (B-ALL). GCs work by activating the GC receptor (GR), a ligand-induced transcription factor, which in turn regulates genes that induce leukemic cell death. Which GR-regulated genes are required for GC cytotoxicity, which pathways affect their regulation, and how resistance arises are not well understood. Here, we systematically integrate the transcriptional response of B-ALL to GCs with a next-generation short hairpin RNA screen to identify GC-regulated "effector" genes that contribute to cell death, as well as genes that affect the sensitivity of B-ALL cells to dex. This analysis reveals a pervasive role for GCs in suppression of B-cell development genes that is linked to therapeutic response. Inhibition of phosphatidylinositol 3-kinase δ (PI3Kδ), a linchpin in the pre-B-cell receptor and interleukin 7 receptor signaling pathways critical to B-cell development (with CAL-101 [idelalisib]), interrupts a double-negative feedback loop, enhancing GC-regulated transcription to synergistically kill even highly resistant B-ALL with diverse genetic backgrounds. This work not only identifies numerous opportunities for enhanced lymphoid-specific combination chemotherapies that have the potential to overcome treatment resistance, but is also a valuable resource for understanding GC biology and the mechanistic details of GR-regulated transcription.

Reshmi SC, Harvey RC, Roberts KG, et al.
Targetable kinase gene fusions in high-risk B-ALL: a study from the Children's Oncology Group.
Blood. 2017; 129(25):3352-3361 [PubMed] Article available free on PMC after 01/11/2019 Related Publications
Philadelphia chromosome-like (Ph-like) acute lymphoblastic leukemia (ALL) is a high-risk subtype characterized by genomic alterations that activate cytokine receptor and kinase signaling. We examined the frequency and spectrum of targetable genetic lesions in a retrospective cohort of 1389 consecutively diagnosed patients with childhood B-lineage ALL with high-risk clinical features and/or elevated minimal residual disease at the end of remission induction therapy. The Ph-like gene expression profile was identified in 341 of 1389 patients, 57 of whom were excluded from additional analyses because of the presence of

Giraldo NA, Becht E, Vano Y, et al.
Tumor-Infiltrating and Peripheral Blood T-cell Immunophenotypes Predict Early Relapse in Localized Clear Cell Renal Cell Carcinoma.
Clin Cancer Res. 2017; 23(15):4416-4428 [PubMed] Related Publications

Ren J, Zhang X, Liu X, et al.
A versatile system for rapid multiplex genome-edited CAR T cell generation.
Oncotarget. 2017; 8(10):17002-17011 [PubMed] Article available free on PMC after 01/11/2019 Related Publications
The therapeutic potential of CRISPR system has already been demonstrated in many instances and begun to overlap with the rapidly expanding field of cancer immunotherapy, especially on the production of genetically modified T cell receptor or chimeric antigen receptor (CAR) T cells. Efficient genomic disruption of multiple gene loci to generate universal donor cells, as well as potent effector T cells resistant to multiple inhibitory pathways such as PD-1 and CTLA4 is an attractive strategy for cell therapy. In this study, we accomplished rapid and efficient multiplex genomic editing, and re-directing T cells with antigen specific CAR via a one-shot CRISPR protocol by incorporation of multiple gRNAs in a CAR lentiviral vector. High efficient double knockout of endogenous TCR and HLA class I could be easily achieved to generate allogeneic universal CAR T cells. We also generated Fas-resistant universal CAR T cells by triple gene disruption. Simultaneous gene editing of four gene loci using the one-shot CRISPR protocol to generate allogeneic universal T cells deficient of both PD1 and CTLA-4 was also attempted.

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