TISIDB

Summary
Symbol	GZMB
Name	granzyme B (granzyme 2, cytotoxic T-lymphocyte-associated serine esterase 1)
Aliases	CCPI; CGL-1; CSP-B; CGL1; CTSGL1; SECT; fragmentin 2; cytotoxic serine protease B; cathepsin G-like 1; T-cel ......
Chromosomal Location	14q11.2
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	Cytoplasmic granule Note=Cytoplasmic granules of cytolytic T-lymphocytes and natural killer cells.
Domain	PF00089 Trypsin
Function	This enzyme is necessary for target cell lysis in cell-mediated immune responses. It cleaves after Asp. Seems to be linked to an activation cascade of caspases (aspartate-specific cysteine proteases) responsible for apoptosis execution. Cleaves caspase-3, -7, -9 and 10 to give rise to active enzymes mediating apoptosis.

> Gene Ontology [ TOP ]
Biological Process	GO:0001844 protein insertion into mitochondrial membrane involved in apoptotic signaling pathway GO:0001906 cell killing GO:0001909 leukocyte mediated cytotoxicity GO:0002228 natural killer cell mediated immunity GO:0002443 leukocyte mediated immunity GO:0002449 lymphocyte mediated immunity GO:0006839 mitochondrial transport GO:0007006 mitochondrial membrane organization GO:0008637 apoptotic mitochondrial changes GO:0010821 regulation of mitochondrion organization GO:0010822 positive regulation of mitochondrion organization GO:0016485 protein processing GO:0019835 cytolysis GO:0035794 positive regulation of mitochondrial membrane permeability GO:0042267 natural killer cell mediated cytotoxicity GO:0046902 regulation of mitochondrial membrane permeability GO:0051204 protein insertion into mitochondrial membrane GO:0051205 protein insertion into membrane GO:0051604 protein maturation GO:0070585 protein localization to mitochondrion GO:0072655 establishment of protein localization to mitochondrion GO:0072657 protein localization to membrane GO:0090150 establishment of protein localization to membrane GO:0090559 regulation of membrane permeability GO:0097345 mitochondrial outer membrane permeabilization GO:1900739 regulation of protein insertion into mitochondrial membrane involved in apoptotic signaling pathway GO:1900740 positive regulation of protein insertion into mitochondrial membrane involved in apoptotic signaling pathway GO:1901028 regulation of mitochondrial outer membrane permeabilization involved in apoptotic signaling pathway GO:1901030 positive regulation of mitochondrial outer membrane permeabilization involved in apoptotic signaling pathway GO:1902108 regulation of mitochondrial membrane permeability involved in apoptotic process GO:1902110 positive regulation of mitochondrial membrane permeability involved in apoptotic process GO:1902686 mitochondrial outer membrane permeabilization involved in programmed cell death GO:1903747 regulation of establishment of protein localization to mitochondrion GO:1903749 positive regulation of establishment of protein localization to mitochondrion GO:1903829 positive regulation of cellular protein localization GO:1904951 positive regulation of establishment of protein localization GO:2001233 regulation of apoptotic signaling pathway GO:2001235 positive regulation of apoptotic signaling pathway
Molecular Function	GO:0004175 endopeptidase activity GO:0004252 serine-type endopeptidase activity GO:0008236 serine-type peptidase activity GO:0017171 serine hydrolase activity
Cellular Component	GO:0001772 immunological synapse

> KEGG and Reactome Pathway [ TOP ]
KEGG	hsa04210 Apoptosis hsa04650 Natural killer cell mediated cytotoxicity
Reactome	R-HSA-75108: Activation, myristolyation of BID and translocation to mitochondria R-HSA-109581: Apoptosis R-HSA-109606: Intrinsic Pathway for Apoptosis R-HSA-2197563: NOTCH2 intracellular domain regulates transcription R-HSA-5357801: Programmed Cell Death R-HSA-162582: Signal Transduction R-HSA-157118: Signaling by NOTCH R-HSA-1980145: Signaling by NOTCH2

Summary
Symbol	GZMB
Name	granzyme B (granzyme 2, cytotoxic T-lymphocyte-associated serine esterase 1)
Aliases	CCPI; CGL-1; CSP-B; CGL1; CTSGL1; SECT; fragmentin 2; cytotoxic serine protease B; cathepsin G-like 1; T-cel ......
Chromosomal Location	14q11.2
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Literatures that report relations between GZMB 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 GZMB and anti-tumor immunity in human cancer.

PMID	Cancer type	Relation to immunity	Evidence sentences
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.
24523193	Chronic Myelomonocytic Leukemia; Acute Myelomonocytic Leukemia	Promote immunity (T and NK cell function); essential for immunotherapy	The human serine protease granzyme B is a prominent candidate for tumor immunotherapy because it is expressed in cytotoxic T lymphocytes and natural killer cells. We demonstrate that CD64-specific human CFPs kill CMML and AMML cells ex vivo, and that the mutant granzyme B protein R201K is more cytotoxic than the wild-type enzyme in the presence of the granzyme B inhibitor PI9.
23440424	Neuroblastoma	Promote immunity	The final products contained more than 90% CD56(+) cells and could kill neuroblastoma cells effectively that were originally highly resistant to nonprocessed NK cells. Mechanistically, cytolysis of neuroblastoma was mediated through natural cytotoxicity receptor (NCR), DNAX accessory molecule-1 (DNAM-1; CD226), perforin, and granzyme B.
19688743	Melanoma	Promote immunity (T cell function)	Gadd45b, a signaling molecule highly up-regulated during Th1 type responses, is studied for its role in limiting tumor growth. Mouse B16 melanoma cells implanted into Gadd45b(-/-) mice grew faster than those in WT or Gadd45b(+/-) littermate controls. The defect of Gadd45b(-/-) mice in tumor immunosurveillance was attributed to the reduced expression of IFN-gamma, granzyme B, and CCR5 in Gadd45b(-/-) CD8(+) T cells at the tumor site.
27535994	Chronic Lymphocytic Leukemia	Promote immunity (T cell function); increase the efficacy of immunotherapy	We identified the immunoglobulin M Fc receptor (FcμR), also known as the Fas apoptotic inhibitory molecule-3 or TOSO, as a target for a more selective treatment of CLL by CAR T cells. FcμR is highly and consistently expressed by CLL cells; only minor levels are detected on healthy B cells or other hematopoietic cells. T cells with a CAR specific for FcμR efficiently responded toward CLL cells, released a panel of proinflammatory cytokines and lytic factors, like soluble FasL and granzyme B, and eliminated the leukemic cells. In contrast to CD19 CAR T cells, anti-FcμR CAR T cells did not attack healthy B cells.
17919943	Lymphoma; Melanoma; Acute Myeloid Leukemia	Inhibit immunity (T cell; NK function)	Adoptive transfer of WT Treg cells, but not granzyme B- or perforin-deficient Treg cells, into granzyme B-deficient mice partially restored susceptibility to tumor growth; Treg cells derived from the tumor environment could induce NK and CD8(+) T cell death in a granzyme B- and perforin-dependent fashion.
23964122	B16 Malignant Melanoma	Promote immunity	A2A blockade enhanced natural killer (NK) cell maturation and cytotoxic function in vitro, reduced metastasis in a perforin-dependent manner, and enhanced NK cell expression of granzyme B in vivo, strongly suggesting that the antimetastatic effect of A2A blockade was due to enhanced NK cell function.
23851682	Lung Adenocarcinoma; Non-Small Cell Lung Carcinoma	Promote immunity (infiltration)	Because mice bearing early NSCLC treated with anti-CD25 mAb exhibited increased tumor cell death associated with infiltration by CD8(+) T cells expressing elevated levels of granzyme A, granzyme B, perforin, and IFN-γ, we therefore evaluated carboplatin combination therapy resulting in a significantly extended survival beyond that observed with chemotherapy alone, indicating that Treg depletion in combination with cytotoxic therapy may be beneficial as a treatment strategy for advanced NSCLC.
21527558	Melanoma	Promote immunity (T cell function)	In vaccinated mice, silencing STAT3 increased the proliferation and granzyme B levels of intratumoral CD4(+) and CD8(+) T cells. The combined strategy also increased apoptosis in tumors of treated mice, enhancing tumor-specific killing of tumor targets.
20145137	Breast Carcinoma	Promote immunity (T cell function)	In allogeneic MLTR, antiestrogen-treated MCF-7 cells caused downregulation of the effector molecules granzyme B, perforin, and Fas ligand in CD8(+) T cells, and suppressed the generation of cytotoxic effector cells in a TGFbeta-dependent manner.
29336814	Pancreatic Carcinoma	Promote immunity	Coculture supernatants of conditioned medium displayed significant inhibition of interferon γ and granzyme B secretion, both of which are crucial for induction of target cell cytotoxicity.
29104081	Colon Cacinoma	Promote immunity (T cell function)	Our results also showed that enhancement of the cytolytic activity of γδT cells against human colon cancer cells by TWS119 was chiefly associated with upregulation of the expression of perforin and granzyme B in vitro and in vivo.
25125657	melanoma	Promote immunity(T cell function)	Here, we show that CCDC134 is differentially expressed on resting and activated immune cells and that it promotes CD8(+) T-cell activation, proliferation, and cytotoxicity by augmenting expression of the T-cell effector molecules IFNγ, TNFα, granzyme B, and perforin
23365136	Melanoma; Breast Carcinoma; Colon Carcinoma	Promote immunity	Mechanistic investigations suggested that CpG-ODN upregulates low surface levels of 4-1BBL on tBregs to elicit granzyme B-expressing cytolytic CD8(+) T cells, offering some explanative power for the effect. These findings underscore the immunotherapeutic importance of tBreg inactivation as a strategy to enhance cancer therapy by targeting both the regulatory and activating arms of the immune system in vivo.
17015756	colon carcinoma	Promote immunity	Notably, redirected CD4+ T cells mediate cytolysis of CEA+ tumor cells with high efficiencies. Lysis by redirected CD4+ T cells is independent of death receptor signaling via TNF-alpha or Fas, but mediated by perforin and granzyme because cytolysis is inhibited by blocking the release of cytotoxic granules, but not by blocking of Fas ligand or TNF-alpha.
16998881	Hepatocellular Carcinoma	Promote immunity	Cytotoxic T lymphocyte (CTL) activity after WT p53 peptide-specific stimulation was assessed by analysis of granzyme B and interferon-gamma mRNA transcription, using a quantitative real-time polymerase chain reaction assay.
16868249	lymphoma	Promote immunity	Here, we aimed to develop molecular strategies to overcome the resistance of HL cells against CTL-mediated killing via granzyme B (grzB). In HL cells, grzB-induced mitochondrial release of proapoptotic Smac is blocked, which results in complete abrogation of cytotoxicity mediated by CTLs. Cytosolic expression of recombinant mature Smac enhanced caspase activity induced by grzB and restored the apoptotic response of HL cells. Similarly, down-regulation of XIAP by RNA interference markedly enhanced the susceptibility of HL cells for CTL-mediated cytotoxicity.

Summary
Symbol	GZMB
Name	granzyme B (granzyme 2, cytotoxic T-lymphocyte-associated serine esterase 1)
Aliases	CCPI; CGL-1; CSP-B; CGL1; CTSGL1; SECT; fragmentin 2; cytotoxic serine protease B; cathepsin G-like 1; T-cel ......
Chromosomal Location	14q11.2
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 GZMB 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	GZMB
Name	granzyme B (granzyme 2, cytotoxic T-lymphocyte-associated serine esterase 1)
Aliases	CCPI; CGL-1; CSP-B; CGL1; CTSGL1; SECT; fragmentin 2; cytotoxic serine protease B; cathepsin G-like 1; T-cel ......
Chromosomal Location	14q11.2
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 GZMB 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	-0.265	0.654
2	26997480	Melanoma	MAPKi	Anti-PD-1 (pembrolizumab and nivolumab)	6	5	0.333	0.814
3	26997480	Melanoma	non-MAPKi	Anti-PD-1 (pembrolizumab and nivolumab)	8	7	-0.704	0.535
4	28552987	Urothelial cancer	all	Anti-PD-L1 (atezolizumab)	9	16	0.138	0.857
5	28552987	Urothelial cancer	smoking	Anti-PD-L1 (atezolizumab)	5	9	0.034	0.978
6	28552987	Urothelial cancer	non-smoking	Anti-PD-L1 (atezolizumab)	4	7	0.279	0.859
7	29033130	Melanoma	all	Anti-PD-1 (nivolumab)	26	23	0.71	0.292
8	29033130	Melanoma	NIV3-PROG	Anti-PD-1 (nivolumab)	15	11	0.761	0.479
9	29033130	Melanoma	NIV3-NAIVE	Anti-PD-1 (nivolumab)	11	12	0.641	0.582
10	29301960	Clear cell renal cell carcinoma (ccRCC)	all	Anti-PD-1 (nivolumab)	4	8	0.623	0.62
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	0.068	0.972
13	29443960	Urothelial cancer	all	Anti-PD-L1 (atezolizumab)	68	230	0.544	0.0583

> Mutation difference between responders and non-responders

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Points in the above scatter plot represent the mutation difference of GZMB 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	3.7	2.7	1	1
5	26359337	Melanoma	BRAFi	Anti-CTLA-4 (ipilimumab)	0	14	0	7.1	-7.1	1
6	26359337	Melanoma	non-BRAFi	Anti-CTLA-4 (ipilimumab)	27	59	3.7	1.7	2	0.532
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	GZMB
Name	granzyme B (granzyme 2, cytotoxic T-lymphocyte-associated serine esterase 1)
Aliases	CCPI; CGL-1; CSP-B; CGL1; CTSGL1; SECT; fragmentin 2; cytotoxic serine protease B; cathepsin G-like 1; T-cel ......
Chromosomal Location	14q11.2
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Relations between abundance of tumor-infiltrating lymphocytes (TILs) and expression, copy number, methylation, or mutation of GZMB. 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	GZMB
Name	granzyme B (granzyme 2, cytotoxic T-lymphocyte-associated serine esterase 1)
Aliases	CCPI; CGL-1; CSP-B; CGL1; CTSGL1; SECT; fragmentin 2; cytotoxic serine protease B; cathepsin G-like 1; T-cel ......
Chromosomal Location	14q11.2
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Relations between three kinds of immunomodulators and expression, copy number, methylation, or mutation of GZMB. These immunomo-dulators were collected from Charoentong's study. In this tab, users can examine which immunomodulators might be regulated by GZMB. > Immunoinhibitor > Immunostimulator > MHC molecule

> Immunoinhibitor [ TOP ]

> Immunostimulator [ TOP ]

> MHC molecule [ TOP ]

Summary
Symbol	GZMB
Name	granzyme B (granzyme 2, cytotoxic T-lymphocyte-associated serine esterase 1)
Aliases	CCPI; CGL-1; CSP-B; CGL1; CTSGL1; SECT; fragmentin 2; cytotoxic serine protease B; cathepsin G-like 1; T-cel ......
Chromosomal Location	14q11.2
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Relations between chemokines (or receptors) and expression, copy number, methylation, or mutation of GZMB. 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	GZMB
Name	granzyme B (granzyme 2, cytotoxic T-lymphocyte-associated serine esterase 1)
Aliases	CCPI; CGL-1; CSP-B; CGL1; CTSGL1; SECT; fragmentin 2; cytotoxic serine protease B; cathepsin G-like 1; T-cel ......
Chromosomal Location	14q11.2
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Distribution of GZMB expression across immune and molecular subtypes. > Immune subtype > Molecular subtype

> Immune subtype [ TOP ]

> Molecular subtype [ TOP ]

Summary
Symbol	GZMB
Name	granzyme B (granzyme 2, cytotoxic T-lymphocyte-associated serine esterase 1)
Aliases	CCPI; CGL-1; CSP-B; CGL1; CTSGL1; SECT; fragmentin 2; cytotoxic serine protease B; cathepsin G-like 1; T-cel ......
Chromosomal Location	14q11.2
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Associations between GZMB and clinical features. > Overall survival analysis > Cancer stage > Tumor grade

> Overall survival [ TOP ]

> Stage [ TOP ]

> Grade [ TOP ]

Summary
Symbol	GZMB
Name	granzyme B (granzyme 2, cytotoxic T-lymphocyte-associated serine esterase 1)
Aliases	CCPI; CGL-1; CSP-B; CGL1; CTSGL1; SECT; fragmentin 2; cytotoxic serine protease B; cathepsin G-like 1; T-cel ......
Chromosomal Location	14q11.2
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Drugs targeting GZMB collected from DrugBank database.

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

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