TISIDB

Summary
Symbol	HLA-DRA
Name	major histocompatibility complex, class II, DR alpha
Aliases	HLA-DRA1; MLRW; MHC cell surface glycoprotein; MHC class II antigen DRA; histocompatibility antigen HLA-DR a ......
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	Cell membrane; Single-pass type I membrane protein. Endoplasmic reticulum membrane; Single-pass type I membrane protein. Golgi apparatus, trans-Golgi network membrane; Single-pass type I membrane protein. Endosome membrane; Single-pass type I membrane protein. Lysosome membrane; Single-pass type I membrane protein. Late endosome membrane; Single-pass type I membrane protein. Note=The MHC class II complex transits through a number of intracellular compartments in the endocytic pathway until it reaches the cell membrane for antigen presentation.
Domain	PF07654 Immunoglobulin C1-set domain PF00993 Class II histocompatibility antigen
Function	Binds peptides derived from antigens that access the endocytic route of antigen presenting cells (APC) and presents them on the cell surface for recognition by the CD4 T-cells. The peptide binding cleft accommodates peptides of 10-30 residues. The peptides presented by MHC class II molecules are generated mostly by degradation of proteins that access the endocytic route, where they are processed by lysosomal proteases and other hydrolases. Exogenous antigens that have been endocytosed by the APC are thus readily available for presentation via MHC II molecules, and for this reason this antigen presentation pathway is usually referred to as exogenous. As membrane proteins on their way to degradation in lysosomes as part of their normal turn-over are also contained in the endosomal/lysosomal compartments, exogenous antigens must compete with those derived from endogenous components. Autophagy is also a source of endogenous peptides, autophagosomes constitutively fuse with MHC class II loading compartments. In addition to APCs, other cells of the gastrointestinal tract, such as epithelial cells, express MHC class II molecules and CD74 and act as APCs, which is an unusual trait of the GI tract. To produce a MHC class II molecule that presents an antigen, three MHC class II molecules (heterodimers of an alpha and a beta chain) associate with a CD74 trimer in the ER to form a heterononamer. Soon after the entry of this complex into the endosomal/lysosomal system where antigen processing occurs, CD74 undergoes a sequential degradation by various proteases, including CTSS and CTSL, leaving a small fragment termed CLIP (class-II-associated invariant chain peptide). The removal of CLIP is facilitated by HLA-DM via direct binding to the alpha-beta-CLIP complex so that CLIP is released. HLA-DM stabilizes MHC class II molecules until primary high affinity antigenic peptides are bound. The MHC II molecule bound to a peptide is then transported to the cell membrane surface. In B-cells, the interaction between HLA-DM and MHC class II molecules is regulated by HLA-DO. Primary dendritic cells (DCs) also to express HLA-DO. Lysosomal microenvironment has been implicated in the regulation of antigen loading into MHC II molecules, increased acidification produces increased proteolysis and efficient peptide loading.

> Gene Ontology [ TOP ]
Biological Process	GO:0002396 MHC protein complex assembly GO:0002399 MHC class II protein complex assembly GO:0002429 immune response-activating cell surface receptor signaling pathway GO:0002478 antigen processing and presentation of exogenous peptide antigen GO:0002495 antigen processing and presentation of peptide antigen via MHC class II GO:0002501 peptide antigen assembly with MHC protein complex GO:0002503 peptide antigen assembly with MHC class II protein complex GO:0002504 antigen processing and presentation of peptide or polysaccharide antigen via MHC class II GO:0002505 antigen processing and presentation of polysaccharide antigen via MHC class II GO:0002506 polysaccharide assembly with MHC class II protein complex GO:0002694 regulation of leukocyte activation GO:0002696 positive regulation of leukocyte activation GO:0002757 immune response-activating signal transduction GO:0002764 immune response-regulating signaling pathway GO:0002768 immune response-regulating cell surface receptor signaling pathway GO:0007159 leukocyte cell-cell adhesion GO:0019882 antigen processing and presentation GO:0019884 antigen processing and presentation of exogenous antigen GO:0019886 antigen processing and presentation of exogenous peptide antigen via MHC class II GO:0022407 regulation of cell-cell adhesion GO:0022409 positive regulation of cell-cell adhesion GO:0031294 lymphocyte costimulation GO:0031295 T cell costimulation GO:0034341 response to interferon-gamma GO:0042110 T cell activation GO:0045785 positive regulation of cell adhesion GO:0048002 antigen processing and presentation of peptide antigen GO:0050851 antigen receptor-mediated signaling pathway GO:0050852 T cell receptor signaling pathway 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:0050890 cognition GO:0051249 regulation of lymphocyte activation GO:0051251 positive regulation of lymphocyte activation GO:0060333 interferon-gamma-mediated signaling pathway GO:0065006 protein-carbohydrate complex assembly GO:0070486 leukocyte aggregation GO:0070489 T cell aggregation GO:0071346 cellular response to interferon-gamma GO:0071593 lymphocyte aggregation GO:0071823 protein-carbohydrate complex subunit organization GO:1903037 regulation of leukocyte cell-cell adhesion GO:1903039 positive regulation of leukocyte cell-cell adhesion
Molecular Function	GO:0003823 antigen binding GO:0023023 MHC protein complex binding GO:0023026 MHC class II protein complex binding GO:0032395 MHC class II receptor activity GO:0033218 amide binding GO:0042277 peptide binding GO:0042605 peptide antigen binding
Cellular Component	GO:0005765 lysosomal membrane GO:0005770 late endosome GO:0005802 trans-Golgi network 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:0030136 clathrin-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:0030665 clathrin-coated vesicle membrane GO:0030666 endocytic vesicle membrane GO:0030669 clathrin-coated endocytic vesicle membrane GO:0031227 intrinsic component of endoplasmic reticulum membrane GO:0031902 late endosome membrane GO:0031984 organelle subcompartment GO:0032588 trans-Golgi network membrane GO:0042611 MHC protein complex GO:0042613 MHC class II protein complex GO:0044440 endosomal part GO:0045334 clathrin-coated endocytic 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 GO:0098791 Golgi subcompartment GO:0098852 lytic vacuole membrane

> KEGG and Reactome Pathway [ TOP ]
KEGG	hsa04145 Phagosome hsa04514 Cell adhesion molecules (CAMs) hsa04612 Antigen processing and presentation hsa04640 Hematopoietic cell lineage hsa04672 Intestinal immune network for IgA production
Reactome	R-HSA-1280218: Adaptive Immune System R-HSA-388841: Costimulation by the CD28 family R-HSA-1280215: Cytokine Signaling in Immune system R-HSA-202424: Downstream TCR signaling R-HSA-202433: Generation of second messenger molecules R-HSA-168256: Immune System R-HSA-913531: Interferon Signaling R-HSA-877300: Interferon gamma signaling R-HSA-2132295: MHC class II antigen presentation R-HSA-389948: PD-1 signaling R-HSA-202427: Phosphorylation of CD3 and TCR zeta chains R-HSA-202403: TCR signaling R-HSA-202430: Translocation of ZAP-70 to Immunological synapse

> KEGG and Reactome Pathway

[ TOP ]

KEGG

hsa04145 Phagosome
hsa04514 Cell adhesion molecules (CAMs)
hsa04612 Antigen processing and presentation
hsa04640 Hematopoietic cell lineage
hsa04672 Intestinal immune network for IgA production

Reactome

R-HSA-1280218: Adaptive Immune System
R-HSA-388841: Costimulation by the CD28 family
R-HSA-1280215: Cytokine Signaling in Immune system
R-HSA-202424: Downstream TCR signaling
R-HSA-202433: Generation of second messenger molecules
R-HSA-168256: Immune System
R-HSA-913531: Interferon Signaling
R-HSA-877300: Interferon gamma signaling
R-HSA-2132295: MHC class II antigen presentation
R-HSA-389948: PD-1 signaling
R-HSA-202427: Phosphorylation of CD3 and TCR zeta chains
R-HSA-202403: TCR signaling
R-HSA-202430: Translocation of ZAP-70 to Immunological synapse

Summary
Symbol	HLA-DRA
Name	major histocompatibility complex, class II, DR alpha
Aliases	HLA-DRA1; MLRW; MHC cell surface glycoprotein; MHC class II antigen DRA; histocompatibility antigen HLA-DR a ......
Chromosomal Location	6p21.3
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Literatures that report relations between HLA-DRA 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-DRA and anti-tumor immunity in human cancer.

PMID	Cancer type	Relation to immunity	Evidence sentences
26500140	Diffuse Large B-Cell Lymphoma	Promote immunity	FOXP1 knockdown in ABC-DLBCL cells led to increased cell-surface expression of HLA-DRA and CD74. We propose that FOXP1 represents a novel regulator of genes targeted by the class II MHC transactivator CIITA (MHC II and CD74) and therapeutically targeting the FOXP1 pathway may improve antigen presentation and immune surveillance in high-risk DLBCL patients.
26183926	Melanoma	Inhibit immunity (T cell function)	Taken together, our results illustrate a novel immune escape mechanism that can be activated by aberrant expression of MHC class II molecules, which by attracting tumor-specific CD4(+) T cells elicit a local inflammatory response dominated by TNF that, in turn, inhibits cytotoxic CD8(+) T-cell responses.
27496866	Head and Neck Carcinoma	Promote immunity (T cell function); essential for immunotherapy	CD137 agonist mAb urelumab enhanced cetuximab-activated NK-cell survival, DC maturation, and tumor antigen cross-presentation. Urelumab boosted DC maturation markers, CD86 and HLA DR, and antigen-processing machinery (APM) components TAP1/2, leading to increased tumor antigen cross-presentation. These results suggest a beneficial effect of combination immunotherapy using cetuximab and CD137 agonist in HNC.
25229656	Cervical Carcinoma	Promote immunity (NK cell function)	Indeed, in the presence of HPV-VLPs, DCs further activated NK cells by inducing the upregulation of cell surface activation markers (CD69 and HLADR). The function of NK cells was also improved as shown by an increase in IFN-γ secretion and cytotoxic activity against an HPV+ cell line

Summary
Symbol	HLA-DRA
Name	major histocompatibility complex, class II, DR alpha
Aliases	HLA-DRA1; MLRW; MHC cell surface glycoprotein; MHC class II antigen DRA; histocompatibility antigen HLA-DR a ......
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-DRA 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-DRA
Name	major histocompatibility complex, class II, DR alpha
Aliases	HLA-DRA1; MLRW; MHC cell surface glycoprotein; MHC class II antigen DRA; histocompatibility antigen HLA-DR a ......
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-DRA 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	-0.177	0.819
2	26997480	Melanoma	MAPKi	Anti-PD-1 (pembrolizumab and nivolumab)	6	5	-0.781	0.726
3	26997480	Melanoma	non-MAPKi	Anti-PD-1 (pembrolizumab and nivolumab)	8	7	0.282	0.851
4	28552987	Urothelial cancer	all	Anti-PD-L1 (atezolizumab)	9	16	0.913	0.206
5	28552987	Urothelial cancer	smoking	Anti-PD-L1 (atezolizumab)	5	9	0.133	0.953
6	28552987	Urothelial cancer	non-smoking	Anti-PD-L1 (atezolizumab)	4	7	1.909	0.544
7	29033130	Melanoma	all	Anti-PD-1 (nivolumab)	26	23	0.451	0.499
8	29033130	Melanoma	NIV3-PROG	Anti-PD-1 (nivolumab)	15	11	0.827	0.754
9	29033130	Melanoma	NIV3-NAIVE	Anti-PD-1 (nivolumab)	11	12	-0.04	0.99
10	29301960	Clear cell renal cell carcinoma (ccRCC)	all	Anti-PD-1 (nivolumab)	4	8	1.049	0.755
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	1.237	0.82
13	29443960	Urothelial cancer	all	Anti-PD-L1 (atezolizumab)	68	230	-0.055	0.772

> Mutation difference between responders and non-responders

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Points in the above scatter plot represent the mutation difference of HLA-DRA 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	0	5.5	-5.5	0.572
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	0	6.8	-6.8	0.304
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	2.6	0	2.6	1
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	0	0	0	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-DRA
Name	major histocompatibility complex, class II, DR alpha
Aliases	HLA-DRA1; MLRW; MHC cell surface glycoprotein; MHC class II antigen DRA; histocompatibility antigen HLA-DR a ......
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-DRA. 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-DRA
Name	major histocompatibility complex, class II, DR alpha
Aliases	HLA-DRA1; MLRW; MHC cell surface glycoprotein; MHC class II antigen DRA; histocompatibility antigen HLA-DR a ......
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-DRA. These immunomo-dulators were collected from Charoentong's study. In this tab, users can examine which immunomodulators might be regulated by HLA-DRA. > Immunoinhibitor > Immunostimulator > MHC molecule

> Immunoinhibitor [ TOP ]

> Immunostimulator [ TOP ]

> MHC molecule [ TOP ]

Summary
Symbol	HLA-DRA
Name	major histocompatibility complex, class II, DR alpha
Aliases	HLA-DRA1; MLRW; MHC cell surface glycoprotein; MHC class II antigen DRA; histocompatibility antigen HLA-DR a ......
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-DRA. 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-DRA
Name	major histocompatibility complex, class II, DR alpha
Aliases	HLA-DRA1; MLRW; MHC cell surface glycoprotein; MHC class II antigen DRA; histocompatibility antigen HLA-DR a ......
Chromosomal Location	6p21.3
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Distribution of HLA-DRA expression across immune and molecular subtypes. > Immune subtype > Molecular subtype

> Immune subtype [ TOP ]

> Molecular subtype [ TOP ]

Summary
Symbol	HLA-DRA
Name	major histocompatibility complex, class II, DR alpha
Aliases	HLA-DRA1; MLRW; MHC cell surface glycoprotein; MHC class II antigen DRA; histocompatibility antigen HLA-DR a ......
Chromosomal Location	6p21.3
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Associations between HLA-DRA and clinical features. > Overall survival analysis > Cancer stage > Tumor grade

> Overall survival [ TOP ]

> Stage [ TOP ]

> Grade [ TOP ]

Summary
Symbol	HLA-DRA
Name	major histocompatibility complex, class II, DR alpha
Aliases	HLA-DRA1; MLRW; MHC cell surface glycoprotein; MHC class II antigen DRA; histocompatibility antigen HLA-DR a ......
Chromosomal Location	6p21.3
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Drugs targeting HLA-DRA collected from DrugBank database.

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

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