TISIDB

Summary
Symbol	CCL4
Name	chemokine (C-C motif) ligand 4
Aliases	Act-2; AT744.1; SCYA4; small inducible cytokine A4 (homologous to mouse Mip-1b); ACT2; G-26; HC21; MIP1B; MI ......
Chromosomal Location	17q12
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	PF00048 Small cytokines (intecrine/chemokine)
Function	Monokine with inflammatory and chemokinetic properties. Binds to CCR5. One of the major HIV-suppressive factors produced by CD8+ T-cells. Recombinant MIP-1-beta induces a dose-dependent inhibition of different strains of HIV-1, HIV-2, and simian immunodeficiency virus (SIV). The processed form MIP-1-beta(3-69) retains the abilities to induce down-modulation of surface expression of the chemokine receptor CCR5 and to inhibit the CCR5-mediated entry of HIV-1 in T-cells. MIP-1-beta(3-69) is also a ligand for CCR1 and CCR2 isoform B.

> Gene Ontology [ TOP ]
Biological Process	GO:0002548 monocyte chemotaxis GO:0002685 regulation of leukocyte migration GO:0002687 positive regulation of leukocyte migration GO:0002688 regulation of leukocyte chemotaxis GO:0002690 positive regulation of leukocyte chemotaxis GO:0006816 calcium ion transport GO:0007163 establishment or maintenance of cell polarity GO:0009615 response to virus GO:0009636 response to toxic substance GO:0010959 regulation of metal ion transport GO:0019058 viral life cycle GO:0019080 viral gene expression GO:0019083 viral transcription GO:0019722 calcium-mediated signaling GO:0019932 second-messenger-mediated signaling GO:0030335 positive regulation of cell migration GO:0030593 neutrophil chemotaxis GO:0030595 leukocyte chemotaxis GO:0031349 positive regulation of defense response GO:0032103 positive regulation of response to external stimulus GO:0032897 negative regulation of viral transcription GO:0034341 response to interferon-gamma GO:0034612 response to tumor necrosis factor GO:0035690 cellular response to drug GO:0035747 natural killer cell chemotaxis GO:0035821 modification of morphology or physiology of other organism GO:0040017 positive regulation of locomotion GO:0042493 response to drug GO:0043270 positive regulation of ion transport GO:0043410 positive regulation of MAPK cascade GO:0043900 regulation of multi-organism process GO:0043901 negative regulation of multi-organism process GO:0043903 regulation of symbiosis, encompassing mutualism through parasitism GO:0043921 modulation by host of viral transcription GO:0043922 negative regulation by host of viral transcription GO:0044033 multi-organism metabolic process GO:0046782 regulation of viral transcription GO:0048247 lymphocyte chemotaxis GO:0048525 negative regulation of viral process GO:0050727 regulation of inflammatory response GO:0050729 positive regulation of inflammatory response GO:0050792 regulation of viral process GO:0050848 regulation of calcium-mediated signaling GO:0050850 positive regulation of calcium-mediated signaling GO:0050900 leukocyte migration GO:0050920 regulation of chemotaxis GO:0050921 positive regulation of chemotaxis GO:0051272 positive regulation of cellular component movement GO:0051702 interaction with symbiont GO:0051817 modification of morphology or physiology of other organism involved in symbiotic interaction GO:0051851 modification by host of symbiont morphology or physiology GO:0051924 regulation of calcium ion transport GO:0051928 positive regulation of calcium ion transport GO:0052312 modulation of transcription in other organism involved in symbiotic interaction GO:0052472 modulation by host of symbiont transcription GO:0060326 cell chemotaxis GO:0070098 chemokine-mediated signaling pathway GO:0070371 ERK1 and ERK2 cascade GO:0070372 regulation of ERK1 and ERK2 cascade GO:0070374 positive regulation of ERK1 and ERK2 cascade GO:0070555 response to interleukin-1 GO:0070838 divalent metal ion transport GO:0071346 cellular response to interferon-gamma GO:0071347 cellular response to interleukin-1 GO:0071356 cellular response to tumor necrosis factor GO:0071621 granulocyte chemotaxis GO:0071674 mononuclear cell migration GO:0072511 divalent inorganic cation transport GO:0072676 lymphocyte migration GO:0097529 myeloid leukocyte migration GO:0097530 granulocyte migration GO:1901623 regulation of lymphocyte chemotaxis GO:1903900 regulation of viral life cycle GO:1903901 negative regulation of viral life cycle GO:1990266 neutrophil migration GO:2000147 positive regulation of cell motility GO:2000401 regulation of lymphocyte migration GO:2000403 positive regulation of lymphocyte migration GO:2000501 regulation of natural killer cell chemotaxis GO:2000503 positive regulation of natural killer cell chemotaxis
Molecular Function	GO:0001664 G-protein coupled receptor binding GO:0005125 cytokine activity GO:0005126 cytokine receptor binding GO:0008009 chemokine activity GO:0031726 CCR1 chemokine receptor binding GO:0031730 CCR5 chemokine receptor binding GO:0042379 chemokine receptor binding GO:0048020 CCR chemokine receptor binding
Cellular Component	-

> KEGG and Reactome Pathway [ TOP ]
KEGG	hsa04060 Cytokine-cytokine receptor interaction hsa04062 Chemokine signaling pathway hsa04064 NF-kappa B signaling pathway hsa04620 Toll-like receptor signaling pathway hsa04623 Cytosolic DNA-sensing pathway
Reactome	R-HSA-1280215: Cytokine Signaling in Immune system R-HSA-168256: Immune System R-HSA-6783783: Interleukin-10 signaling R-HSA-449147: Signaling by Interleukins

Summary
Symbol	CCL4
Name	chemokine (C-C motif) ligand 4
Aliases	Act-2; AT744.1; SCYA4; small inducible cytokine A4 (homologous to mouse Mip-1b); ACT2; G-26; HC21; MIP1B; MI ......
Chromosomal Location	17q12
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Literatures that report relations between CCL4 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 CCL4 and anti-tumor immunity in human cancer.

PMID	Cancer type	Relation to immunity	Evidence sentences
26729864	Melanoma	Promote immunity	Vaccination with combination therapy uniquely restricted Th2-cytokine production by CD4 cells, relative to combination therapy alone, and enhanced IFNγ production by CD8 and CD4 cells. We observed an increase in MIP-1α (macrophage inflammatory protein-1α)/CCL3 [chemokine (C-C motif) ligand 3], MIP-1β/CCL4, RANTES (regulated on activation, normal T-cell expressed and excreted)/CCL5, and GM-CSF production by CD8 and CD4 T cells following treatment.
27407095	Cervical carcinoma	Promote immunity	Intravaginal treatment of IL7-Fc, but not native IL7, induces upregulation of chemokines (CXCL10, CCL3, CCL4, and CCL5), cytokines (IFNγ, TNFα, IL6, and IL1β), and an adhesion molecule (VCAM-1) in the genital tract, leading to the recruitment of several leukocytes, including CD4, CD8, γδ T cells, and dendritic cells.
27879269	Melanoma	Promote immunity (infiltration)	Intratumoral basophils enhanced CD8+ T-cell infiltration via production of chemokines CCL3 and CCL4; antibody-based blocking of these chemokines inhibited CD8+ T-cell infiltration.
21480223	Bladder Carcinoma	Inhibit immunity	Both myeloid cell subsets from cancer patients were highly activated and produced substantial amounts of proinflammatory chemokines/cytokines including CCL2, CCL3, CCL4, G-CSF, IL-8 and IL-6. We demonstrate that these highly activated inflammatory myeloid cells represent a source of multiple chemokines/cytokines and may contribute to inflammation and immune dysfunction in bladder cancer.

Summary
Symbol	CCL4
Name	chemokine (C-C motif) ligand 4
Aliases	Act-2; AT744.1; SCYA4; small inducible cytokine A4 (homologous to mouse Mip-1b); ACT2; G-26; HC21; MIP1B; MI ......
Chromosomal Location	17q12
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 CCL4 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	CCL4
Name	chemokine (C-C motif) ligand 4
Aliases	Act-2; AT744.1; SCYA4; small inducible cytokine A4 (homologous to mouse Mip-1b); ACT2; G-26; HC21; MIP1B; MI ......
Chromosomal Location	17q12
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 CCL4 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	-0.356	0.538
2	26997480	Melanoma	MAPKi	Anti-PD-1 (pembrolizumab and nivolumab)	6	5	0.128	0.951
3	26997480	Melanoma	non-MAPKi	Anti-PD-1 (pembrolizumab and nivolumab)	8	7	-0.708	0.646
4	28552987	Urothelial cancer	all	Anti-PD-L1 (atezolizumab)	9	16	-0.073	0.933
5	28552987	Urothelial cancer	smoking	Anti-PD-L1 (atezolizumab)	5	9	-0.652	0.584
6	28552987	Urothelial cancer	non-smoking	Anti-PD-L1 (atezolizumab)	4	7	0.684	0.665
7	29033130	Melanoma	all	Anti-PD-1 (nivolumab)	26	23	0.258	0.629
8	29033130	Melanoma	NIV3-PROG	Anti-PD-1 (nivolumab)	15	11	0.443	0.684
9	29033130	Melanoma	NIV3-NAIVE	Anti-PD-1 (nivolumab)	11	12	0.076	0.948
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	0.371	0.103

> Mutation difference between responders and non-responders

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Points in the above scatter plot represent the mutation difference of CCL4 in various data sets.

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

Summary
Symbol	CCL4
Name	chemokine (C-C motif) ligand 4
Aliases	Act-2; AT744.1; SCYA4; small inducible cytokine A4 (homologous to mouse Mip-1b); ACT2; G-26; HC21; MIP1B; MI ......
Chromosomal Location	17q12
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Relations between abundance of tumor-infiltrating lymphocytes (TILs) and expression, copy number, methylation, or mutation of CCL4. 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	CCL4
Name	chemokine (C-C motif) ligand 4
Aliases	Act-2; AT744.1; SCYA4; small inducible cytokine A4 (homologous to mouse Mip-1b); ACT2; G-26; HC21; MIP1B; MI ......
Chromosomal Location	17q12
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Relations between three kinds of immunomodulators and expression, copy number, methylation, or mutation of CCL4. These immunomo-dulators were collected from Charoentong's study. In this tab, users can examine which immunomodulators might be regulated by CCL4. > Immunoinhibitor > Immunostimulator > MHC molecule

> Immunoinhibitor [ TOP ]

> Immunostimulator [ TOP ]

> MHC molecule [ TOP ]

Summary
Symbol	CCL4
Name	chemokine (C-C motif) ligand 4
Aliases	Act-2; AT744.1; SCYA4; small inducible cytokine A4 (homologous to mouse Mip-1b); ACT2; G-26; HC21; MIP1B; MI ......
Chromosomal Location	17q12
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Relations between chemokines (or receptors) and expression, copy number, methylation, or mutation of CCL4. 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	CCL4
Name	chemokine (C-C motif) ligand 4
Aliases	Act-2; AT744.1; SCYA4; small inducible cytokine A4 (homologous to mouse Mip-1b); ACT2; G-26; HC21; MIP1B; MI ......
Chromosomal Location	17q12
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Distribution of CCL4 expression across immune and molecular subtypes. > Immune subtype > Molecular subtype

> Immune subtype [ TOP ]

> Molecular subtype [ TOP ]

Summary
Symbol	CCL4
Name	chemokine (C-C motif) ligand 4
Aliases	Act-2; AT744.1; SCYA4; small inducible cytokine A4 (homologous to mouse Mip-1b); ACT2; G-26; HC21; MIP1B; MI ......
Chromosomal Location	17q12
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Associations between CCL4 and clinical features. > Overall survival analysis > Cancer stage > Tumor grade

> Overall survival [ TOP ]

> Stage [ TOP ]

> Grade [ TOP ]

Summary
Symbol	CCL4
Name	chemokine (C-C motif) ligand 4
Aliases	Act-2; AT744.1; SCYA4; small inducible cytokine A4 (homologous to mouse Mip-1b); ACT2; G-26; HC21; MIP1B; MI ......
Chromosomal Location	17q12
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Drugs targeting CCL4 collected from DrugBank database.

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

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