TISIDB

Summary
Symbol	IL15
Name	interleukin 15
Aliases	IL-15; MGC9721; Interleukin-15
Chromosomal Location	4q31
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	Isoform IL15-S48AA: Secreted.; SUBCELLULAR LOCATION: Isoform IL15-S21AA: Cytoplasm. Nucleus. Note=IL15-S21AA is not secreted, but rather is stored intracellularly, appearing in the nucleus and cytoplasmic components.
Domain	PF02372 Interleukin 15
Function	Cytokine that stimulates the proliferation of T-lymphocytes. Stimulation by IL-15 requires interaction of IL-15 with components of IL-2R, including IL-2R beta and probably IL-2R gamma but not IL-2R alpha.

> Gene Ontology [ TOP ]
Biological Process	GO:0001779 natural killer cell differentiation GO:0001787 natural killer cell proliferation GO:0001819 positive regulation of cytokine production GO:0001866 NK T cell proliferation GO:0002521 leukocyte differentiation GO:0002694 regulation of leukocyte activation GO:0002696 positive regulation of leukocyte activation GO:0002697 regulation of immune effector process GO:0002831 regulation of response to biotic stimulus GO:0003012 muscle system process GO:0006022 aminoglycan metabolic process GO:0006486 protein glycosylation GO:0006493 protein O-linked glycosylation GO:0007159 leukocyte cell-cell adhesion GO:0007259 JAK-STAT cascade GO:0007260 tyrosine phosphorylation of STAT protein GO:0007568 aging GO:0007584 response to nutrient GO:0009100 glycoprotein metabolic process GO:0009101 glycoprotein biosynthetic process GO:0009615 response to virus GO:0009991 response to extracellular stimulus GO:0010559 regulation of glycoprotein biosynthetic process GO:0010560 positive regulation of glycoprotein biosynthetic process GO:0014732 skeletal muscle atrophy GO:0014888 striated muscle adaptation GO:0014889 muscle atrophy GO:0014891 striated muscle atrophy 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:0030098 lymphocyte differentiation GO:0030101 natural killer cell activation GO:0030203 glycosaminoglycan metabolic process GO:0030212 hyaluronan metabolic process GO:0030217 T cell differentiation GO:0031349 positive regulation of defense response GO:0031667 response to nutrient levels GO:0031668 cellular response to extracellular stimulus GO:0031669 cellular response to nutrient levels GO:0031670 cellular response to nutrient GO:0032103 positive regulation of response to external stimulus GO:0032620 interleukin-17 production GO:0032660 regulation of interleukin-17 production GO:0032740 positive regulation of interleukin-17 production GO:0032814 regulation of natural killer cell activation GO:0032816 positive regulation of natural killer cell activation GO:0032817 regulation of natural killer cell proliferation GO:0032819 positive regulation of natural killer cell proliferation GO:0032823 regulation of natural killer cell differentiation GO:0032825 positive regulation of natural killer cell differentiation GO:0032943 mononuclear cell proliferation GO:0032944 regulation of mononuclear cell proliferation GO:0032946 positive regulation of mononuclear cell proliferation GO:0033002 muscle cell proliferation GO:0033078 extrathymic T cell differentiation GO:0033273 response to vitamin GO:0033280 response to vitamin D GO:0034103 regulation of tissue remodeling GO:0034105 positive regulation of tissue remodeling GO:0042098 T cell proliferation GO:0042102 positive regulation of T cell proliferation GO:0042110 T cell activation GO:0042129 regulation of T cell proliferation GO:0042503 tyrosine phosphorylation of Stat3 protein GO:0042506 tyrosine phosphorylation of Stat5 protein GO:0042509 regulation of tyrosine phosphorylation of STAT 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:0043413 macromolecule glycosylation GO:0043500 muscle adaptation GO:0043501 skeletal muscle adaptation GO:0043900 regulation of multi-organism process GO:0043903 regulation of symbiosis, encompassing mutualism through parasitism GO:0045058 T cell selection GO:0045062 extrathymic T cell selection GO:0045580 regulation of T cell differentiation GO:0045619 regulation of lymphocyte differentiation GO:0045621 positive regulation of lymphocyte differentiation GO:0045785 positive regulation of cell adhesion GO:0046425 regulation of JAK-STAT cascade GO:0046427 positive regulation of JAK-STAT cascade GO:0046631 alpha-beta T cell activation GO:0046633 alpha-beta T cell proliferation GO:0046651 lymphocyte proliferation GO:0048469 cell maturation GO:0048535 lymph node development GO:0048659 smooth muscle cell proliferation GO:0048660 regulation of smooth muscle cell proliferation GO:0048662 negative regulation of smooth muscle cell proliferation GO:0048771 tissue remodeling GO:0050670 regulation of lymphocyte proliferation GO:0050671 positive regulation of lymphocyte proliferation GO:0050688 regulation of defense response to virus GO:0050691 regulation of defense response to virus by host 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:0050792 regulation of viral process GO:0050863 regulation of T cell activation GO:0050865 regulation of cell activation GO:0050867 positive regulation of cell activation GO:0050870 positive regulation of T cell activation GO:0051132 NK T cell activation GO:0051249 regulation of lymphocyte activation GO:0051251 positive regulation of lymphocyte activation GO:0051607 defense response to virus GO:0060049 regulation of protein glycosylation GO:0060050 positive regulation of protein glycosylation GO:0070085 glycosylation 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:0071295 cellular response to vitamin GO:0071305 cellular response to vitamin D GO:0071396 cellular response to lipid GO:0071407 cellular response to organic cyclic compound GO:0071496 cellular response to external stimulus GO:0071593 lymphocyte aggregation GO:0097696 STAT cascade GO:0098542 defense response to other organism GO:1902105 regulation of leukocyte differentiation GO:1902107 positive regulation of leukocyte differentiation GO:1903018 regulation of glycoprotein metabolic process GO:1903020 positive regulation of glycoprotein metabolic process GO:1903037 regulation of leukocyte cell-cell adhesion GO:1903039 positive regulation of leukocyte cell-cell adhesion GO:1903510 mucopolysaccharide metabolic process GO:1903706 regulation of hemopoiesis GO:1903708 positive regulation of hemopoiesis GO:1904098 regulation of protein O-linked glycosylation GO:1904100 positive regulation of protein O-linked glycosylation GO:1904892 regulation of STAT cascade GO:1904894 positive regulation of STAT cascade
Molecular Function	GO:0005125 cytokine activity GO:0005126 cytokine receptor binding
Cellular Component	-

> KEGG and Reactome Pathway [ TOP ]
KEGG	hsa04060 Cytokine-cytokine receptor interaction hsa04630 Jak-STAT signaling pathway hsa04668 TNF signaling pathway hsa04672 Intestinal immune network for IgA production
Reactome	R-HSA-1280215: Cytokine Signaling in Immune system R-HSA-168256: Immune System R-HSA-449147: Signaling by Interleukins

Summary
Symbol	IL15
Name	interleukin 15
Aliases	IL-15; MGC9721; Interleukin-15
Chromosomal Location	4q31
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Literatures that report relations between IL15 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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PMID	Cancer type	Relation to immunity	Evidence sentences
26511282	Melanoma; Colon Carcinoma	Promote immunity (T cell function)	IL15, a potent stimulant of CD8(+) T cells and natural killer (NK) cells, is a promising cancer immunotherapeutic.
27213690	Melanoma; Prostate Carcinoma; Breast Carcinoma	Inhibit immunity (NK cell function)	We identified cytokine-inducible SH2-containing protein (CIS, encoded by Cish) as a critical negative regulator of IL-15 signaling in NK cells. Cish was rapidly induced in response to IL-15, and deletion of Cish rendered NK cells hypersensitive to IL-15, as evidenced by enhanced proliferation, survival, IFN-γ production and cytotoxicity toward tumors.
26423796	Lymphoma	Promote immunity (NK cell function)	ALT-803 is a superagonist IL-15 mutant and IL-15Rα-Fc fusion complex that activates the IL-15 receptor constitutively expressed on natural killer (NK) cells. ALT-803 augmented cytotoxicity and the expression of granzyme B and perforin, providing one potential mechanism for this enhanced functionality.
26174883	Glioblastoma	Promote immunity (infiltration); increase the efficacy of immunotherapy	We show that an IL-15 superagonist complex ALT-803, as a single treatment as well as in combination with anti-PD-1 antibody or stereotactic radiosurgery, exhibits a robust antitumor immune response resulting in a prolonged survival including complete remission in tumor bearing mice.
25601928	Colon Adenocarcinoma	Promote immunity (T cell function)	In vivo 4-1BB deficiency in myeloid cells enhances peripheral T cell proliferation by increasing IL-15.
25403209	Melanoma	Promote immunity (T cell function)	Interleukin-15 (IL-15) has significant potential in cancer immunotherapy as an activator of antitumor CD8 T and natural killer (NK) cells.
22585684	Melanoma	Promote immunity (NK cell function)	Analysis of different NK-cell-activating cytokines indicated that IL-15 can partially overcome this novel tumor escape mechanism suggesting that IL-15, rather than IL-2, may be eligible for NK-cell-based immunotherapy.
22565311	Neuroblastoma	Promote immunity (T cell function)	Thus, tumor-induced chemokine production in hypoxic TAMs and consequent chemoattraction and inhibition of NKT cells represents a mechanism of immune escape that can be reversed by adoptive immunotherapy with IL-15-transduced NKT cells.
22532287	Small Cell Lung Carcinoma	Inhibit immunity	Our data suggest that IL-15 and Treg cells are potential new therapeutic targets to improve immune response and patient survival in SCLC.
22474386	Prostate Carcinoma	Promote immunity	Combining the immune stimulatory properties of IL-15 with simultaneous removal of two critical immune inhibitory checkpoints, we showed enhancement of immune responses, leading to increased antitumor activity.

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Summary
Symbol	IL15
Name	interleukin 15
Aliases	IL-15; MGC9721; Interleukin-15
Chromosomal Location	4q31
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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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	IL15
Name	interleukin 15
Aliases	IL-15; MGC9721; Interleukin-15
Chromosomal Location	4q31
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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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	0.167	0.679
2	26997480	Melanoma	MAPKi	Anti-PD-1 (pembrolizumab and nivolumab)	6	5	-0.083	0.918
3	26997480	Melanoma	non-MAPKi	Anti-PD-1 (pembrolizumab and nivolumab)	8	7	0.354	0.569
4	28552987	Urothelial cancer	all	Anti-PD-L1 (atezolizumab)	9	16	-0.409	0.478
5	28552987	Urothelial cancer	smoking	Anti-PD-L1 (atezolizumab)	5	9	-0.488	0.615
6	28552987	Urothelial cancer	non-smoking	Anti-PD-L1 (atezolizumab)	4	7	-0.308	0.782
7	29033130	Melanoma	all	Anti-PD-1 (nivolumab)	26	23	0.136	0.757
8	29033130	Melanoma	NIV3-PROG	Anti-PD-1 (nivolumab)	15	11	0.546	0.474
9	29033130	Melanoma	NIV3-NAIVE	Anti-PD-1 (nivolumab)	11	12	-0.365	0.669
10	29301960	Clear cell renal cell carcinoma (ccRCC)	all	Anti-PD-1 (nivolumab)	4	8	1.074	0.446
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	0.965	0.635
13	29443960	Urothelial cancer	all	Anti-PD-L1 (atezolizumab)	68	230	-0.007	0.962

> Mutation difference between responders and non-responders

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No	PMID	Cancer type	Group	Drug	# Res	# NRes	% Mut/NRes	% 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	0	0	1
5	26359337	Melanoma	BRAFi	Anti-CTLA-4 (ipilimumab)	0	14	0	0	1
6	26359337	Melanoma	non-BRAFi	Anti-CTLA-4 (ipilimumab)	27	59	0	0	1
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	3.7	-3.7	0.415
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	7.1	-7.1	0.467
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	IL15
Name	interleukin 15
Aliases	IL-15; MGC9721; Interleukin-15
Chromosomal Location	4q31
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Relations between abundance of tumor-infiltrating lymphocytes (TILs) and expression, copy number, methylation, or mutation of IL15. 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	IL15
Name	interleukin 15
Aliases	IL-15; MGC9721; Interleukin-15
Chromosomal Location	4q31
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Relations between three kinds of immunomodulators and expression, copy number, methylation, or mutation of IL15. These immunomo-dulators were collected from Charoentong's study. In this tab, users can examine which immunomodulators might be regulated by IL15. > Immunoinhibitor > Immunostimulator > MHC molecule

> Immunoinhibitor [ TOP ]

> Immunostimulator [ TOP ]

> MHC molecule [ TOP ]

Summary
Symbol	IL15
Name	interleukin 15
Aliases	IL-15; MGC9721; Interleukin-15
Chromosomal Location	4q31
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Relations between chemokines (or receptors) and expression, copy number, methylation, or mutation of IL15. 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	IL15
Name	interleukin 15
Aliases	IL-15; MGC9721; Interleukin-15
Chromosomal Location	4q31
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Distribution of IL15 expression across immune and molecular subtypes. > Immune subtype > Molecular subtype

> Immune subtype [ TOP ]

> Molecular subtype [ TOP ]

Summary
Symbol	IL15
Name	interleukin 15
Aliases	IL-15; MGC9721; Interleukin-15
Chromosomal Location	4q31
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Associations between IL15 and clinical features. > Overall survival analysis > Cancer stage > Tumor grade

> Overall survival [ TOP ]

> Stage [ TOP ]

> Grade [ TOP ]

Summary
Symbol	IL15
Name	interleukin 15
Aliases	IL-15; MGC9721; Interleukin-15
Chromosomal Location	4q31
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Drugs targeting IL15 collected from DrugBank database.

> Drugs from DrugBank database

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ID	Name	Drug Type	Targets	#Targets
DB01327	Cefazolin	Small Molecule	IL15, IL2, PON1	3

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