TISIDB

Summary
Symbol	IL21
Name	interleukin 21
Aliases	Za11; CVID11; interleukin-21 isoform; Interleukin-21
Chromosomal Location	4q26-q27
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Basic function annotation. > Subcellular Location, Domain and Function > Gene Ontology > KEGG and Reactome Pathway

> Subcellular Location, Domain and Function [ TOP ]
Subcellular Location	Secreted
Domain	PF02372 Interleukin 15
Function	Cytokine with immunoregulatory activity. May promote the transition between innate and adaptive immunity. Induces the production of IgG(1) and IgG(3) in B-cells (By similarity). May play a role in proliferation and maturation of natural killer (NK) cells in synergy with IL15. May regulate proliferation of mature B- and T-cells in response to activating stimuli. In synergy with IL15 and IL18 stimulates interferon gamma production in T-cells and NK cells. During T-cell mediated immune response may inhibit dendritic cells (DC) activation and maturation.

> Gene Ontology [ TOP ]
Biological Process	GO:0001819 positive regulation of cytokine production GO:0001906 cell killing GO:0001909 leukocyte mediated cytotoxicity GO:0001910 regulation of leukocyte mediated cytotoxicity GO:0001912 positive regulation of leukocyte mediated cytotoxicity GO:0002228 natural killer cell mediated immunity GO:0002443 leukocyte mediated immunity GO:0002449 lymphocyte mediated immunity GO:0002694 regulation of leukocyte activation GO:0002696 positive regulation of leukocyte activation GO:0002697 regulation of immune effector process GO:0002699 positive regulation of immune effector process GO:0002703 regulation of leukocyte mediated immunity GO:0002705 positive regulation of leukocyte mediated immunity GO:0002706 regulation of lymphocyte mediated immunity GO:0002708 positive regulation of lymphocyte mediated immunity GO:0002715 regulation of natural killer cell mediated immunity GO:0002717 positive regulation of natural killer cell mediated immunity GO:0007159 leukocyte cell-cell adhesion GO:0007259 JAK-STAT cascade GO:0007260 tyrosine phosphorylation of STAT protein GO:0018108 peptidyl-tyrosine phosphorylation GO:0018212 peptidyl-tyrosine modification GO:0021700 developmental maturation GO:0022407 regulation of cell-cell adhesion GO:0022409 positive regulation of cell-cell adhesion GO:0030888 regulation of B cell proliferation GO:0030890 positive regulation of B cell proliferation GO:0031341 regulation of cell killing GO:0031343 positive regulation of cell killing GO:0031349 positive regulation of defense response GO:0032103 positive regulation of response to external stimulus GO:0032609 interferon-gamma production GO:0032620 interleukin-17 production GO:0032649 regulation of interferon-gamma production GO:0032660 regulation of interleukin-17 production GO:0032729 positive regulation of interferon-gamma production GO:0032740 positive regulation of interleukin-17 production GO:0032943 mononuclear cell proliferation GO:0032944 regulation of mononuclear cell proliferation GO:0032946 positive regulation of mononuclear cell proliferation GO:0034103 regulation of tissue remodeling GO:0034105 positive regulation of tissue remodeling GO:0042035 regulation of cytokine biosynthetic process GO:0042089 cytokine biosynthetic process GO:0042095 interferon-gamma biosynthetic process GO:0042098 T cell proliferation GO:0042100 B cell proliferation GO:0042102 positive regulation of T cell proliferation GO:0042107 cytokine metabolic process GO:0042108 positive regulation of cytokine biosynthetic process GO:0042110 T cell activation GO:0042113 B cell activation GO:0042129 regulation of T cell proliferation GO:0042267 natural killer cell mediated cytotoxicity GO:0042269 regulation of natural killer cell mediated cytotoxicity GO:0042503 tyrosine phosphorylation of Stat3 protein GO:0042508 tyrosine phosphorylation of Stat1 protein GO:0042509 regulation of tyrosine phosphorylation of STAT protein GO:0042510 regulation of tyrosine phosphorylation of Stat1 protein GO:0042511 positive regulation of tyrosine phosphorylation of Stat1 protein GO:0042516 regulation of tyrosine phosphorylation of Stat3 protein GO:0042517 positive regulation of tyrosine phosphorylation of Stat3 protein GO:0042531 positive regulation of tyrosine phosphorylation of STAT protein GO:0045072 regulation of interferon-gamma biosynthetic process GO:0045078 positive regulation of interferon-gamma biosynthetic process GO:0045088 regulation of innate immune response GO:0045089 positive regulation of innate immune response GO:0045785 positive regulation of cell adhesion GO:0045954 positive regulation of natural killer cell mediated cytotoxicity GO:0046425 regulation of JAK-STAT cascade GO:0046427 positive regulation of JAK-STAT cascade GO:0046651 lymphocyte proliferation GO:0048469 cell maturation GO:0048771 tissue remodeling GO:0050670 regulation of lymphocyte proliferation GO:0050671 positive regulation of lymphocyte proliferation GO:0050727 regulation of inflammatory response GO:0050729 positive regulation of inflammatory response GO:0050730 regulation of peptidyl-tyrosine phosphorylation GO:0050731 positive regulation of peptidyl-tyrosine phosphorylation GO:0050863 regulation of T cell activation GO:0050864 regulation of B cell activation GO:0050865 regulation of cell activation GO:0050867 positive regulation of cell activation GO:0050870 positive regulation of T cell activation GO:0050871 positive regulation of B cell activation GO:0051249 regulation of lymphocyte activation GO:0051251 positive regulation of lymphocyte activation GO:0070486 leukocyte aggregation GO:0070489 T cell aggregation GO:0070661 leukocyte proliferation GO:0070663 regulation of leukocyte proliferation GO:0070665 positive regulation of leukocyte proliferation GO:0071593 lymphocyte aggregation GO:0097696 STAT cascade GO:1903037 regulation of leukocyte cell-cell adhesion GO:1903039 positive regulation of leukocyte cell-cell adhesion GO:1904892 regulation of STAT cascade GO:1904894 positive regulation of STAT cascade
Molecular Function	GO:0005125 cytokine activity GO:0005126 cytokine receptor binding GO:0005134 interleukin-2 receptor binding GO:0070851 growth factor receptor binding
Cellular Component	-

> KEGG and Reactome Pathway [ TOP ]
KEGG	hsa04060 Cytokine-cytokine receptor interaction hsa04630 Jak-STAT signaling pathway
Reactome	-

Summary
Symbol	IL21
Name	interleukin 21
Aliases	Za11; CVID11; interleukin-21 isoform; Interleukin-21
Chromosomal Location	4q26-q27
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Literatures that report relations between IL21 and anti-tumor immunity. The specific mechanism were also collected if the literature reports that a gene specifically promotes or inhibits the infiltration or function of T/NK cells.

> Text Mining

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Literatures describing the relation between IL21 and anti-tumor immunity in human cancer.

PMID	Cancer type	Relation to immunity	Evidence sentences
26194763	Mantle Cell Lymphoma	Promote immunity (T/NK cell function)	Together, these data indicate that IL-21 has potent antitumor activity against MCL cells via direct cytotoxic and indirect, immune-mediated effects.
18413772	Melanoma; Renal Cell Carcinoma	Promote immunity (T cell function); increase the efficacy of immunotherapy	Interleukin 21 enhances antibody-mediated tumor rejection. Interleukin-21 (IL-21) is a cytokine with structural and sequence homology to IL-2 and IL-15 that has antitumor activity alone in mouse experimental tumor models and a tolerable safety profile in phase I trials in patients with metastatic melanoma and renal cell carcinoma. Herein, we show that sequentially combining TrimAb with recombinant IL-21 can significantly improve the antitumor activity of this combination against very advanced disease. These data further support the use of IL-21 in adjuvant settings where strong T cell-mediated immune responses to tumors can be generated.
18281483	Primary Cutaneous T-Cell Non-Hodgkin Lymphoma	Promote immunity	They also suggest two novel therapeutic approaches to CTCL and, possibly, other CD4+ T-cell lymphomas: inhibition of the Jak1/Jak3 kinase complex and, given the known strong immunostimulatory properties of IL-21 on CD8+ T, natural killer, and B cells, application of this cytokine to boost an immune response against malignant CD4+ T cells.
18276844	Melanoma; Kidney Carcinoma	Inhibit immunity (T cell function)	Furthermore, IL-21 repressed expression of IL-2Ra and inhibited IL-2-mediated acquisition of a cytolytic CD8(+) T-cell phenotype.
16424205	Breast Adenocarcinoma	Promote immunity	CD25+ regulatory T cell depletion augments immunotherapy of micrometastases by an IL-21-secreting cellular vaccine. In conclusion, immunotherapy of micrometastases by an IL-21-based cellular vaccine is strongly potentiated by CD25+ cell depletion.
28585539	Colorectal Carcinoma; Melanoma; Bladder Carcinoma	Promote immunity (T cell function)	IL-21-mediated reversal of NK cell exhaustion facilitates anti-tumour immunity in MHC class I-deficient tumours.
19915059	Lymphoma	Inhibit immunity (T cell function)	Surprisingly, host IL-21 significantly restricted the expansion of Ag-specific CD8(+) T cells and inhibited primary CD8(+) T cell immunity against OVA-expressing EG7 lymphomas, as well as the secondary expansion of memory CD8(+) T cells.
20039320	Stage 4 Neuroblastoma	Promote immunity (T cell function); essential for immunotherapy	Transient depletion of CD4(+) T cells augments IL-21-based immunotherapy of disseminated neuroblastoma in syngeneic mice. Neuro2a/IL-21 vaccination showed increased expression of IFN-alpha2, -beta1 and -gamma mRNA. In conclusion, anti-CD4 mAb potentiated IL-21-based IT by removing Treg cells and/or their precursors and other potentially immune-suppressive CD4+ cell subsets, thus allowing the development of an IL-21-driven CD8+ T cell response, which mediates NB rejection.
19949105	Melanoma	Promote immunity	An analysis of different supportive cytokine mixtures during the REP found that a combination of IL-15 and IL-21 facilitated comparable expansion of CD8(+) TILs as IL-2, but prevented the loss of CD28 expression with improved responsiveness to antigenic restimulation post-REP. A REP protocol using IL-15 and IL-21 may greatly increase the number of CD28(+) TILs capable of long-term persistence.
19949105	Melanoma	Promote immunity	An analysis of different supportive cytokine mixtures during the REP found that a combination of IL-15 and IL-21 facilitated comparable expansion of CD8(+) TILs as IL-2, but prevented the loss of CD28 expression with improved responsiveness to antigenic restimulation post-REP. A REP protocol using IL-15 and IL-21 may greatly increase the number of CD28(+) TILs capable of long-term persistence.
18684866	Hodgkin Lymphoma	Inhibit immunity (T cell function)	Aberrant expression of the Th2 cytokine IL-21 in Hodgkin lymphoma cells regulates STAT3 signaling and attracts Treg cells via regulation of MIP-3alpha. We demonstrate that IL-21 activates STAT3 in HRS cells, up-regulates STAT3 target genes, and protects HRS cells from CD95 death receptor-induced apoptosis. Furthermore, IL-21 is involved in up-regulation of the CC chemokine macrophage-inflammatory protein-3alpha (MIP-3alpha) in HRS cells.
16081794	Melanoma	Promote immunity	We demonstrate that exposure to IL-21 increased the total number of MART-1-specific CD8+ T cells that could be elicited by >20-fold and, at the clonal level, enriched for a population of high-affinity CD8+ T cells with a peptide dose requirement more than 1 log(10)-fold less than their untreated counterparts. Our studies demonstrate a significant role for IL-21 in the primary Ag-specific human CTL response and support the use of IL-21 in the ex vivo generation of potent Ag-specific CTLs for adoptive therapy or as an adjuvant cytokine during in vivo immunization against tumor Ags.
16081783	Breast Carcinoma; Lung Carcinoma; Prostate Carcinoma	Promote immunity	IL-21 is a cytokine that can promote the anti-tumor responses of the innate and adaptive immune system. Collectively, these findings suggest that IL-21 therapy may work optimally against tumors that can elicit a NKG2D-mediated immune response.
17582604	Glioma	Promote immunity	Most notably 100% of the animals receiving a primary implant of IL-21-transduced cells rejected the implant, and 76% of these animals survived to a subsequent rechallenge with GL261 parental cells. More importantly, IL-21-secreting GL D2-60 cells or 1 microg of rIL-21 protein stereotactically injected into established GL D2-60 tumors were able to trigger glioblastoma rejection in 90 and 77% of mice, respectively.
25200249	melanoma	Promote immunity	This is consistent with the observations by us and others that IL-21 alone did not drive a large expansion of CD8+ T cells but synergized with IL-7 or IL-15 to promote CD8+ T cell proliferation while curtailing acquisition of a hypo-proliferative terminally-differentiated phenotype [101,102].
23384943	Pan-Cancer	Inhibit immunity	Our findings show for the first time that IL-21 induces GrB(+) human Bregs. They also establish the existence of human B cells with a regulatory phenotype in solid tumor infiltrates, where they may contribute to the suppression of antitumor immune responses.

Summary
Symbol	IL21
Name	interleukin 21
Aliases	Za11; CVID11; interleukin-21 isoform; Interleukin-21
Chromosomal Location	4q26-q27
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	High-throughput screening data (e.g. CRISPR-Cas9, shRNA and RNAi) for T cell-mediated killing. Genetic screen techniques can identify mechanisms of tumor cell resistance (e.g., PTPN2) and sensitivity (e.g., APLNR) to killing by cytotoxic T cells, the central effectors of anti-tumor immunity. After comprehensively searching, eight groups of screening data sets were collected in the current database. In this tab, users can check whether their selected genes cause resistance or increase sensitivity to T cell-mediated killing in various data sets.

> High-throughput Screening

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Statistical results of IL21 in screening data sets for detecting immune reponses.

PMID	Screening System	Cancer Type	Cell Line	Data Set	Statistical Results	Relation to immunity
29301958	CRISPR-Cas9	melanoma	B16F10	Pmel-1 T cell	NA/NS	NA/NS
29301958	CRISPR-Cas9	melanoma	B16F10	OT-1 T cell	NA/NS	NA/NS
28783722	CRISPR-Cas9	melanoma	Mel624	2CT-CRISPR	NA/NS	NA/NS
28723893	CRISPR-Cas9	melanoma	B16	GVAX+Anti-PD1	NA/NS	NA/NS
28723893	CRISPR-Cas9	melanoma	B16	GVAX	NA/NS	NA/NS
25691366	RNAi	Breast cancer	MCF7	Luc-CTL assay	NA/NS	NA/NS
24476824	shRNA	melanoma	B16	Primary screen	NA/NS	NA/NS
24476824	shRNA	melanoma	B16	Secondary screen	NA/NS	NA/NS

Summary
Symbol	IL21
Name	interleukin 21
Aliases	Za11; CVID11; interleukin-21 isoform; Interleukin-21
Chromosomal Location	4q26-q27
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Transcriptomic and genomic profiling of pre-treated tumor biopsies from responders and non-responders to immunotherapy. These data were used to identify signatures and mechanisms of response to checkpoint blockade (e.g., anti-PDL1 and anti-PD1). One example is that mutations in the gene PBRM1 benefit clinical survival of patients with clear cell renal cell carcinoma. After comprehensively searching, we collected 5 and 6 of transcriptomic and genomic data sets, respectively. In this tab, users can check whether their selected genes have significant difference of expression or mutation between responders and non-responders in various data sets. > Expression difference between responders and non-responders > Mutation difference between responders and non-responders

> Expression difference between responders and non-responders

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Points in the above scatter plot represent the expression difference of IL21 in various data sets.

No	PMID	Cancer type	Group	Drug	# Res	# NRes	Log2 (Fold Change)	P value
1	26997480	Melanoma	all	Anti-PD-1 (pembrolizumab and nivolumab)	14	12	0	1
2	26997480	Melanoma	MAPKi	Anti-PD-1 (pembrolizumab and nivolumab)	6	5	0	1
3	26997480	Melanoma	non-MAPKi	Anti-PD-1 (pembrolizumab and nivolumab)	8	7	0	1
4	28552987	Urothelial cancer	all	Anti-PD-L1 (atezolizumab)	9	16	-2.281	0.0295
5	28552987	Urothelial cancer	smoking	Anti-PD-L1 (atezolizumab)	5	9	-2.424	0.14
6	28552987	Urothelial cancer	non-smoking	Anti-PD-L1 (atezolizumab)	4	7	-2.105	0.294
7	29033130	Melanoma	all	Anti-PD-1 (nivolumab)	26	23	0	1
8	29033130	Melanoma	NIV3-PROG	Anti-PD-1 (nivolumab)	15	11	0	1
9	29033130	Melanoma	NIV3-NAIVE	Anti-PD-1 (nivolumab)	11	12	0	1
10	29301960	Clear cell renal cell carcinoma (ccRCC)	all	Anti-PD-1 (nivolumab)	4	8	0	1
11	29301960	Clear cell renal cell carcinoma (ccRCC)	VEGFRi	Anti-PD-1 (nivolumab)	2	0	0	1
12	29301960	Clear cell renal cell carcinoma (ccRCC)	non-VEGFRi	Anti-PD-1 (nivolumab)	2	8	0	1
13	29443960	Urothelial cancer	all	Anti-PD-L1 (atezolizumab)	68	230	0.792	0.000663

> Mutation difference between responders and non-responders

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Points in the above scatter plot represent the mutation difference of IL21 in various data sets.

No	PMID	Cancer type	Group	Drug	# Res	# NRes	% Mut/Res	% Diff (R vs NR)	Pval
1	25765070	Non-small cell lung cancer (NSCLC)	all	Anti-PD-1 (pembrolizumab)	14	17	0	0	1
2	25765070	Non-small cell lung cancer (NSCLC)	smoking	Anti-PD-1 (pembrolizumab)	10	3	0	0	1
3	25765070	Non-small cell lung cancer (NSCLC)	non-smoking	Anti-PD-1 (pembrolizumab)	4	14	0	0	1
4	26359337	Melanoma	all	Anti-CTLA-4 (ipilimumab)	27	73	7.4	7.4	0.0709
5	26359337	Melanoma	BRAFi	Anti-CTLA-4 (ipilimumab)	0	14	0	0	1
6	26359337	Melanoma	non-BRAFi	Anti-CTLA-4 (ipilimumab)	27	59	7.4	7.4	0.096
7	26997480	Melanoma	all	Anti-PD-1 (pembrolizumab and nivolumab)	21	17	0	0	1
8	26997480	Melanoma	MAPKi	Anti-PD-1 (pembrolizumab and nivolumab)	8	6	0	0	1
9	26997480	Melanoma	non-MAPKi	Anti-PD-1 (pembrolizumab and nivolumab)	13	11	0	0	1
10	28552987	Urothelial cancer	all	Anti-PD-L1 (atezolizumab)	9	16	0	0	1
11	28552987	Urothelial cancer	smoking	Anti-PD-L1 (atezolizumab)	5	9	0	0	1
12	28552987	Urothelial cancer	non-smoking	Anti-PD-L1 (atezolizumab)	4	7	0	0	1
13	29033130	Melanoma	all	Anti-PD-1 (nivolumab)	38	27	0	0	1
14	29033130	Melanoma	NIV3-PROG	Anti-PD-1 (nivolumab)	22	13	0	0	1
15	29033130	Melanoma	NIV3-NAIVE	Anti-PD-1 (nivolumab)	16	14	0	0	1
16	29301960	Clear cell renal cell carcinoma (ccRCC)	all	Anti-PD-1 (nivolumab)	11	13	0	0	1
17	29301960	Clear cell renal cell carcinoma (ccRCC)	VEGFRi	Anti-PD-1 (nivolumab)	6	1	0	0	1
18	29301960	Clear cell renal cell carcinoma (ccRCC)	non-VEGFRi	Anti-PD-1 (nivolumab)	5	12	0	0	1

Summary
Symbol	IL21
Name	interleukin 21
Aliases	Za11; CVID11; interleukin-21 isoform; Interleukin-21
Chromosomal Location	4q26-q27
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Relations between abundance of tumor-infiltrating lymphocytes (TILs) and expression, copy number, methylation, or mutation of IL21. The immune-related signatures of 28 TIL types from Charoentong's study, which can be viewed in the download page. For each cancer type, the relative abundance of TILs were inferred by using gene set variation analysis (GSVA) based on gene expression profile. In this tab, users can examine which kinds of TILs might be regulated by the current gene.

> Lymphocyte [ TOP ]

Summary
Symbol	IL21
Name	interleukin 21
Aliases	Za11; CVID11; interleukin-21 isoform; Interleukin-21
Chromosomal Location	4q26-q27
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Relations between three kinds of immunomodulators and expression, copy number, methylation, or mutation of IL21. These immunomo-dulators were collected from Charoentong's study. In this tab, users can examine which immunomodulators might be regulated by IL21. > Immunoinhibitor > Immunostimulator > MHC molecule

> Immunoinhibitor [ TOP ]

> Immunostimulator [ TOP ]

> MHC molecule [ TOP ]

Summary
Symbol	IL21
Name	interleukin 21
Aliases	Za11; CVID11; interleukin-21 isoform; Interleukin-21
Chromosomal Location	4q26-q27
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Relations between chemokines (or receptors) and expression, copy number, methylation, or mutation of IL21. In this tab, users can examine which chemokines (or receptors) might be regulated by the current gene. > Chemokine > Receptor

> Chemokine [ TOP ]

> Receptor [ TOP ]

Summary
Symbol	IL21
Name	interleukin 21
Aliases	Za11; CVID11; interleukin-21 isoform; Interleukin-21
Chromosomal Location	4q26-q27
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Distribution of IL21 expression across immune and molecular subtypes. > Immune subtype > Molecular subtype

> Immune subtype [ TOP ]

> Molecular subtype [ TOP ]

Summary
Symbol	IL21
Name	interleukin 21
Aliases	Za11; CVID11; interleukin-21 isoform; Interleukin-21
Chromosomal Location	4q26-q27
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Associations between IL21 and clinical features. > Overall survival analysis > Cancer stage > Tumor grade

> Overall survival [ TOP ]

> Stage [ TOP ]

> Grade [ TOP ]

Summary
Symbol	IL21
Name	interleukin 21
Aliases	Za11; CVID11; interleukin-21 isoform; Interleukin-21
Chromosomal Location	4q26-q27
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Drugs targeting IL21 collected from DrugBank database.

> Drugs from DrugBank database [ TOP ]
There is no record.

Browse IL21