TISIDB

Summary
Symbol	HLA-G
Name	major histocompatibility complex, class I, G
Aliases	b2 microglobulin; HLA-G histocompatibility antigen, class I, G; MHC-G; HLA G antigen; MHC class I antigen G; ......
Chromosomal Location	6p21.3
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 1: Cell membrane Single-pass type I membrane protein ; SUBCELLULAR LOCATION: Isoform 2: Cell membrane Single-pass type I membrane protein ; SUBCELLULAR LOCATION: Isoform 3: Cell membrane Single-pass type I membrane protein ; SUBCELLULAR LOCATION: Isoform 4: Cell membrane Single-pass type I membrane protein ; SUBCELLULAR LOCATION: Isoform 5: Secreted ; SUBCELLULAR LOCATION: Isoform 6: Secreted ; SUBCELLULAR LOCATION: Isoform 7: Secreted
Domain	PF07654 Immunoglobulin C1-set domain PF00129 Class I Histocompatibility antigen
Function	Involved in the presentation of foreign antigens to the immune system. Plays a role in maternal tolerance of the fetus by mediating protection from the deleterious effects of natural killer cells, cytotoxic T-lymphocytes, macrophages and mononuclear cells.

> Gene Ontology [ TOP ]
Biological Process	GO:0001819 positive regulation of cytokine production GO:0002474 antigen processing and presentation of peptide antigen via MHC class I GO:0002478 antigen processing and presentation of exogenous peptide antigen GO:0002479 antigen processing and presentation of exogenous peptide antigen via MHC class I, TAP-dependent GO:0002480 antigen processing and presentation of exogenous peptide antigen via MHC class I, TAP-independent GO:0002507 tolerance induction GO:0002517 T cell tolerance induction GO:0002521 leukocyte differentiation GO:0002643 regulation of tolerance induction GO:0002645 positive regulation of tolerance induction GO:0002664 regulation of T cell tolerance induction GO:0002666 positive regulation of T cell tolerance induction GO:0002683 negative regulation of immune system process GO:0002694 regulation of leukocyte activation GO:0002695 negative regulation of leukocyte activation GO:0002696 positive regulation of leukocyte activation GO:0002764 immune response-regulating signaling pathway GO:0002765 immune response-inhibiting signal transduction GO:0002767 immune response-inhibiting cell surface receptor signaling pathway GO:0002768 immune response-regulating cell surface receptor signaling pathway GO:0006968 cellular defense response GO:0007159 leukocyte cell-cell adhesion GO:0007162 negative regulation of cell adhesion GO:0019882 antigen processing and presentation GO:0019884 antigen processing and presentation of exogenous antigen GO:0022407 regulation of cell-cell adhesion GO:0022408 negative regulation of cell-cell adhesion GO:0022409 positive regulation of cell-cell adhesion GO:0030098 lymphocyte differentiation GO:0030217 T cell differentiation GO:0032615 interleukin-12 production GO:0032655 regulation of interleukin-12 production GO:0032735 positive regulation of interleukin-12 production GO:0032943 mononuclear cell proliferation GO:0032944 regulation of mononuclear cell proliferation GO:0032945 negative regulation of mononuclear cell proliferation GO:0034340 response to type I interferon GO:0034341 response to interferon-gamma GO:0042098 T cell proliferation GO:0042110 T cell activation GO:0042129 regulation of T cell proliferation GO:0042130 negative regulation of T cell proliferation GO:0042590 antigen processing and presentation of exogenous peptide antigen via MHC class I GO:0045066 regulatory T cell differentiation GO:0045580 regulation of T cell differentiation GO:0045582 positive regulation of T cell differentiation GO:0045589 regulation of regulatory T cell differentiation GO:0045591 positive regulation of regulatory T cell differentiation GO:0045619 regulation of lymphocyte differentiation GO:0045621 positive regulation of lymphocyte differentiation GO:0045785 positive regulation of cell adhesion GO:0046651 lymphocyte proliferation GO:0048002 antigen processing and presentation of peptide antigen GO:0050670 regulation of lymphocyte proliferation GO:0050672 negative regulation of lymphocyte proliferation GO:0050777 negative regulation of immune response GO:0050863 regulation of T cell activation GO:0050865 regulation of cell activation GO:0050866 negative regulation of cell activation GO:0050867 positive regulation of cell activation GO:0050868 negative regulation of T cell activation GO:0050870 positive regulation of T cell activation GO:0051249 regulation of lymphocyte activation GO:0051250 negative regulation of lymphocyte activation GO:0051251 positive regulation of lymphocyte activation GO:0060333 interferon-gamma-mediated signaling pathway GO:0060337 type I interferon signaling pathway GO:0070486 leukocyte aggregation GO:0070489 T cell aggregation GO:0070661 leukocyte proliferation GO:0070663 regulation of leukocyte proliferation GO:0070664 negative regulation of leukocyte proliferation GO:0071346 cellular response to interferon-gamma GO:0071357 cellular response to type I interferon GO:0071593 lymphocyte aggregation GO:0097028 dendritic cell differentiation GO:1902105 regulation of leukocyte differentiation GO:1902106 negative regulation of leukocyte differentiation GO:1902107 positive regulation of leukocyte differentiation GO:1903037 regulation of leukocyte cell-cell adhesion GO:1903038 negative regulation of leukocyte cell-cell adhesion GO:1903039 positive regulation of leukocyte cell-cell adhesion GO:1903706 regulation of hemopoiesis GO:1903707 negative regulation of hemopoiesis GO:1903708 positive regulation of hemopoiesis GO:2001198 regulation of dendritic cell differentiation GO:2001199 negative regulation of dendritic cell differentiation
Molecular Function	GO:0003823 antigen binding
Cellular Component	GO:0005769 early endosome GO:0010008 endosome membrane GO:0012507 ER to Golgi transport vesicle membrane GO:0030133 transport vesicle GO:0030134 ER to Golgi transport vesicle GO:0030135 coated vesicle GO:0030139 endocytic vesicle GO:0030176 integral component of endoplasmic reticulum membrane GO:0030658 transport vesicle membrane GO:0030659 cytoplasmic vesicle membrane GO:0030662 coated vesicle membrane GO:0030666 endocytic vesicle membrane GO:0030670 phagocytic vesicle membrane GO:0031227 intrinsic component of endoplasmic reticulum membrane GO:0031901 early endosome membrane GO:0042611 MHC protein complex GO:0042612 MHC class I protein complex GO:0044440 endosomal part GO:0045335 phagocytic vesicle GO:0071556 integral component of lumenal side of endoplasmic reticulum membrane GO:0098552 side of membrane GO:0098553 lumenal side of endoplasmic reticulum membrane

> KEGG and Reactome Pathway [ TOP ]
KEGG	hsa04144 Endocytosis hsa04145 Phagosome hsa04514 Cell adhesion molecules (CAMs) hsa04612 Antigen processing and presentation hsa04650 Natural killer cell mediated cytotoxicity
Reactome	R-HSA-1280218: Adaptive Immune System R-HSA-983170: Antigen Presentation R-HSA-1236975: Antigen processing-Cross presentation R-HSA-983169: Class I MHC mediated antigen processing & presentation R-HSA-1280215: Cytokine Signaling in Immune system R-HSA-1236974: ER-Phagosome pathway R-HSA-1236977: Endosomal/Vacuolar pathway R-HSA-168256: Immune System R-HSA-198933: Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell R-HSA-913531: Interferon Signaling R-HSA-909733: Interferon alpha/beta signaling R-HSA-877300: Interferon gamma signaling

> KEGG and Reactome Pathway

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KEGG

hsa04144 Endocytosis
hsa04145 Phagosome
hsa04514 Cell adhesion molecules (CAMs)
hsa04612 Antigen processing and presentation
hsa04650 Natural killer cell mediated cytotoxicity

Reactome

R-HSA-1280218: Adaptive Immune System
R-HSA-983170: Antigen Presentation
R-HSA-1236975: Antigen processing-Cross presentation
R-HSA-983169: Class I MHC mediated antigen processing & presentation
R-HSA-1280215: Cytokine Signaling in Immune system
R-HSA-1236974: ER-Phagosome pathway
R-HSA-1236977: Endosomal/Vacuolar pathway
R-HSA-168256: Immune System
R-HSA-198933: Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell
R-HSA-913531: Interferon Signaling
R-HSA-909733: Interferon alpha/beta signaling
R-HSA-877300: Interferon gamma signaling

Summary
Symbol	HLA-G
Name	major histocompatibility complex, class I, G
Aliases	b2 microglobulin; HLA-G histocompatibility antigen, class I, G; MHC-G; HLA G antigen; MHC class I antigen G; ......
Chromosomal Location	6p21.3
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Literatures that report relations between HLA-G 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 HLA-G and anti-tumor immunity in human cancer.

PMID	Cancer type	Relation to immunity	Evidence sentences
22678912	Melanoma	Inhibit immunity	These data emphasize the impact of HLA-G conformation on its efficiency at inhibiting the antitumor response and thus favoring tumor progression.
18288133	Chronic Lymphocytic Leukemia	Inhibit immunity (NK cell function); immunotherapy target	HLA-G1 surface expression was observed in CLL and was very low or undetectable in MM. Notably, blocking of HLA-G1 with specific antibody on CLL samples increased their susceptibility to NK-mediated killing, demonstrating that HLA-G participates in protecting CLL cells from NK-mediated killing and may thus contribute to their immune escape in vivo.
28470686	Pancreatic Carcinoma; Ampulla of Vater Carcinoma	Inhibit immunity (T cell function)	Our aim was to examine the expression of the immune inhibiting molecules PD-L1, Galectin-9, HVEM, IDO and HLA-G, as well as CD8+ and FoxP3+ tumor infiltrating lymphocytes (TIL), in pancreatic and ampullary cancers, and to relate their individual, as well as their combined expression, to cancer survival. Expression of immune inhibitory molecules and TIL was examined by immunohistochemistry. We show that immune inhibitory molecules are prevalently expressed. Moreover, high tumor expression of PD-L1 (p?=?0.002), Gal-9 (p?=?0.003), HVEM (p?=?0.001), IDO (p?=?0.049), HLA-G (p?=?0.004) and high CD8/FoxP3 TIL ratio (p?=?0.006) were associated with improved cancer-specific survival.
29464090	Ewing Sarcoma	Inhibit immunity (T cell function)	We hypothesized that the non-classical, immune-inhibitory HLA-molecule HLA-G contributes to immune escape of EwS. HLA-G expression was not associated with risk-related patient variables or response to standard chemotherapy, but with significantly increased numbers of tumor-infiltrating CD3+ T cells compared to HLA-Gneg EwS biopsies. In a mouse model, EwS xenografts after adoptive therapy with tumor antigen-specific CAR T cells strongly expressed HLA-G whereas untreated control tumors were HLA-Gneg.
16045815	Melanoma	Inhibit immunity (T/NK cell function)	The non-classical HLA class I antigen HLA-G is an immune modulator which inhibits the functions of T cells, NK cells, and the Dendritic cells (DC). As a result, HLA-G expression in malignant cells may provide them with a mechanism to escape the immune surveillance. Our data strongly suggest that HLA-G is silenced as a result of CpG hypermethylation within a 5' regulatory region encompassing 220 bp upstream of the start codon.
24362551	Chronic Lymphocytic Leukemia	Inhibit immunity	In line with its role in immunomodulation, the percentage of regulatory T lymphocytes is higher in del/del patients than in patients with the other genotypes and correlates with the amounts of surface or soluble HLA-G. Furthermore, addition of sHLA-G-rich plasma from patients with chronic lymphocytic leukemia induces natural killer cell apoptosis and impairs natural killer cell lysis, with effects proportional to the amount of soluble HLA-G added. Lastly, the presence of an HLA-G 14 base pair polymorphism is of prognostic value, with del/del patients showing reduced overall survival, as compared to those with other genotypes. These results suggest that: (i) the HLA-G 14 base pair polymorphism influences the levels of surface and soluble HLA-G expression, and (ii) the over-expression of HLA-G molecules contributes to creating tolerogenic conditions.
17616704	Neuroblastoma	Inhibit immunity	Human neuroblastoma cells trigger an immunosuppressive program in monocytes by stimulating soluble HLA-G release. Neuroblastoma patient sera selected according to high sHLA-G concentrations inhibited natural killer (NK) cell and CTL-mediated neuroblastoma cell lysis. Such lysis was partially restored by serum depletion of sHLA-G.
25228695	Pan-Cancer	Inhibit immunity (NK/T cell function)	miR-152 regulates HLA-G and HLA-C, which act inhibitory to NK and T cells, thereby altering the immunogenicity of tumors. Because HLA-G and HLA-C are both ligands for inhibitory NK cell receptors (9, 10), the miR-148 family is an important regulator of an effective immune response against tumor cells and also against viral infections.

Summary
Symbol	HLA-G
Name	major histocompatibility complex, class I, G
Aliases	b2 microglobulin; HLA-G histocompatibility antigen, class I, G; MHC-G; HLA G antigen; MHC class I antigen G; ......
Chromosomal Location	6p21.3
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 HLA-G 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	HLA-G
Name	major histocompatibility complex, class I, G
Aliases	b2 microglobulin; HLA-G histocompatibility antigen, class I, G; MHC-G; HLA G antigen; MHC class I antigen G; ......
Chromosomal Location	6p21.3
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 HLA-G 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	0.331	0.567
2	26997480	Melanoma	MAPKi	Anti-PD-1 (pembrolizumab and nivolumab)	6	5	0.876	0.344
3	26997480	Melanoma	non-MAPKi	Anti-PD-1 (pembrolizumab and nivolumab)	8	7	-0.08	0.925
4	28552987	Urothelial cancer	all	Anti-PD-L1 (atezolizumab)	9	16	-1.383	0.0725
5	28552987	Urothelial cancer	smoking	Anti-PD-L1 (atezolizumab)	5	9	-1.328	0.26
6	28552987	Urothelial cancer	non-smoking	Anti-PD-L1 (atezolizumab)	4	7	-1.459	0.3
7	29033130	Melanoma	all	Anti-PD-1 (nivolumab)	26	23	0.43	0.326
8	29033130	Melanoma	NIV3-PROG	Anti-PD-1 (nivolumab)	15	11	0.874	0.445
9	29033130	Melanoma	NIV3-NAIVE	Anti-PD-1 (nivolumab)	11	12	-0.117	0.93
10	29301960	Clear cell renal cell carcinoma (ccRCC)	all	Anti-PD-1 (nivolumab)	4	8	0.136	0.934
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	-0.21	0.921
13	29443960	Urothelial cancer	all	Anti-PD-L1 (atezolizumab)	68	230	0.396	0.144

> Mutation difference between responders and non-responders

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Points in the above scatter plot represent the mutation difference of HLA-G in various data sets.

No	PMID	Cancer type	Group	Drug	# Res	# NRes	% Mut/Res	% Mut/NRes	% Diff (R vs NR)	Pval
1	25765070	Non-small cell lung cancer (NSCLC)	all	Anti-PD-1 (pembrolizumab)	14	17	0	0	0	1
2	25765070	Non-small cell lung cancer (NSCLC)	smoking	Anti-PD-1 (pembrolizumab)	10	3	0	0	0	1
3	25765070	Non-small cell lung cancer (NSCLC)	non-smoking	Anti-PD-1 (pembrolizumab)	4	14	0	0	0	1
4	26359337	Melanoma	all	Anti-CTLA-4 (ipilimumab)	27	73	7.4	4.1	3.3	0.61
5	26359337	Melanoma	BRAFi	Anti-CTLA-4 (ipilimumab)	0	14	0	0	0	1
6	26359337	Melanoma	non-BRAFi	Anti-CTLA-4 (ipilimumab)	27	59	7.4	5.1	2.3	0.647
7	26997480	Melanoma	all	Anti-PD-1 (pembrolizumab and nivolumab)	21	17	0	0	0	1
8	26997480	Melanoma	MAPKi	Anti-PD-1 (pembrolizumab and nivolumab)	8	6	0	0	0	1
9	26997480	Melanoma	non-MAPKi	Anti-PD-1 (pembrolizumab and nivolumab)	13	11	0	0	0	1
10	28552987	Urothelial cancer	all	Anti-PD-L1 (atezolizumab)	9	16	0	0	0	1
11	28552987	Urothelial cancer	smoking	Anti-PD-L1 (atezolizumab)	5	9	0	0	0	1
12	28552987	Urothelial cancer	non-smoking	Anti-PD-L1 (atezolizumab)	4	7	0	0	0	1
13	29033130	Melanoma	all	Anti-PD-1 (nivolumab)	38	27	5.3	0	5.3	0.507
14	29033130	Melanoma	NIV3-PROG	Anti-PD-1 (nivolumab)	22	13	4.5	0	4.5	1
15	29033130	Melanoma	NIV3-NAIVE	Anti-PD-1 (nivolumab)	16	14	6.2	0	6.2	1
16	29301960	Clear cell renal cell carcinoma (ccRCC)	all	Anti-PD-1 (nivolumab)	11	13	0	0	0	1
17	29301960	Clear cell renal cell carcinoma (ccRCC)	VEGFRi	Anti-PD-1 (nivolumab)	6	1	0	0	0	1
18	29301960	Clear cell renal cell carcinoma (ccRCC)	non-VEGFRi	Anti-PD-1 (nivolumab)	5	12	0	0	0	1

Summary
Symbol	HLA-G
Name	major histocompatibility complex, class I, G
Aliases	b2 microglobulin; HLA-G histocompatibility antigen, class I, G; MHC-G; HLA G antigen; MHC class I antigen G; ......
Chromosomal Location	6p21.3
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Relations between abundance of tumor-infiltrating lymphocytes (TILs) and expression, copy number, methylation, or mutation of HLA-G. 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	HLA-G
Name	major histocompatibility complex, class I, G
Aliases	b2 microglobulin; HLA-G histocompatibility antigen, class I, G; MHC-G; HLA G antigen; MHC class I antigen G; ......
Chromosomal Location	6p21.3
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Relations between three kinds of immunomodulators and expression, copy number, methylation, or mutation of HLA-G. These immunomo-dulators were collected from Charoentong's study. In this tab, users can examine which immunomodulators might be regulated by HLA-G. > Immunoinhibitor > Immunostimulator > MHC molecule

> Immunoinhibitor [ TOP ]

> Immunostimulator [ TOP ]

> MHC molecule [ TOP ]

Summary
Symbol	HLA-G
Name	major histocompatibility complex, class I, G
Aliases	b2 microglobulin; HLA-G histocompatibility antigen, class I, G; MHC-G; HLA G antigen; MHC class I antigen G; ......
Chromosomal Location	6p21.3
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Relations between chemokines (or receptors) and expression, copy number, methylation, or mutation of HLA-G. 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	HLA-G
Name	major histocompatibility complex, class I, G
Aliases	b2 microglobulin; HLA-G histocompatibility antigen, class I, G; MHC-G; HLA G antigen; MHC class I antigen G; ......
Chromosomal Location	6p21.3
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Distribution of HLA-G expression across immune and molecular subtypes. > Immune subtype > Molecular subtype

> Immune subtype [ TOP ]

> Molecular subtype [ TOP ]

Summary
Symbol	HLA-G
Name	major histocompatibility complex, class I, G
Aliases	b2 microglobulin; HLA-G histocompatibility antigen, class I, G; MHC-G; HLA G antigen; MHC class I antigen G; ......
Chromosomal Location	6p21.3
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Associations between HLA-G and clinical features. > Overall survival analysis > Cancer stage > Tumor grade

> Overall survival [ TOP ]

> Stage [ TOP ]

> Grade [ TOP ]

Summary
Symbol	HLA-G
Name	major histocompatibility complex, class I, G
Aliases	b2 microglobulin; HLA-G histocompatibility antigen, class I, G; MHC-G; HLA G antigen; MHC class I antigen G; ......
Chromosomal Location	6p21.3
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Drugs targeting HLA-G collected from DrugBank database.

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

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