Browse CTLA4

Summary
SymbolCTLA4
Namecytotoxic T-lymphocyte-associated protein 4
Aliases CD152; CELIAC3; IDDM12; celiac disease 3; insulin-dependent diabetes mellitus 12; ALPS5; CTLA-4; GRD4; CD152 ......
Chromosomal Location2q33
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
 
Subcellular Location Cell membrane Single-pass type I membrane protein Note=Exists primarily an intracellular antigen whose surface expression is tightly regulated by restricted trafficking to the cell surface and rapid internalisation;.
Domain PF07686 Immunoglobulin V-set domain
Function

Inhibitory receptor acting as a major negative regulator of T-cell responses. The affinity of CTLA4 for its natural B7 family ligands, CD80 and CD86, is considerably stronger than the affinity of their cognate stimulatory coreceptor CD28.

> Gene Ontology
 
Biological Process GO:0002250 adaptive immune response
GO:0002429 immune response-activating cell surface receptor signaling pathway
GO:0002521 leukocyte differentiation
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: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:0007162 negative regulation of cell adhesion
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:0030888 regulation of B cell proliferation
GO:0030889 negative regulation of B cell proliferation
GO:0031294 lymphocyte costimulation
GO:0031295 T cell costimulation
GO:0032943 mononuclear cell proliferation
GO:0032944 regulation of mononuclear cell proliferation
GO:0032945 negative regulation of mononuclear cell proliferation
GO:0042098 T cell proliferation
GO:0042100 B cell proliferation
GO:0042110 T cell activation
GO:0042113 B cell activation
GO:0042129 regulation of T cell proliferation
GO:0042130 negative regulation of T cell proliferation
GO:0045066 regulatory T cell differentiation
GO:0045580 regulation of T cell differentiation
GO:0045581 negative regulation of T cell differentiation
GO:0045589 regulation of regulatory T cell differentiation
GO:0045590 negative regulation of regulatory T cell differentiation
GO:0045619 regulation of lymphocyte differentiation
GO:0045620 negative regulation of lymphocyte differentiation
GO:0045785 positive regulation of cell adhesion
GO:0046651 lymphocyte proliferation
GO:0050670 regulation of lymphocyte proliferation
GO:0050672 negative regulation of lymphocyte proliferation
GO:0050777 negative regulation of immune response
GO:0050851 antigen receptor-mediated signaling pathway
GO:0050853 B cell receptor signaling pathway
GO:0050863 regulation of T cell activation
GO:0050864 regulation of B 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:0050869 negative regulation of B 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: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:0071593 lymphocyte aggregation
GO:1902105 regulation of leukocyte differentiation
GO:1902106 negative 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
Molecular Function -
Cellular Component GO:0009897 external side of plasma membrane
GO:0030135 coated vesicle
GO:0030136 clathrin-coated vesicle
GO:0030139 endocytic vesicle
GO:0045334 clathrin-coated endocytic vesicle
GO:0098552 side of membrane
GO:0098636 protein complex involved in cell adhesion
> KEGG and Reactome Pathway
 
KEGG hsa04514 Cell adhesion molecules (CAMs)
hsa04660 T cell receptor signaling pathway
Reactome R-HSA-1280218: Adaptive Immune System
R-HSA-389513: CTLA4 inhibitory signaling
R-HSA-388841: Costimulation by the CD28 family
R-HSA-168256: Immune System
Summary
SymbolCTLA4
Namecytotoxic T-lymphocyte-associated protein 4
Aliases CD152; CELIAC3; IDDM12; celiac disease 3; insulin-dependent diabetes mellitus 12; ALPS5; CTLA-4; GRD4; CD152 ......
Chromosomal Location2q33
External Links HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content Literatures that report relations between CTLA4 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
 
  Literatures describing the relation between CTLA4 and anti-tumor immunity in human cancer.
PMID Cancer type Relation to immunity Evidence sentences
26324768Hepatocellular CarcinomaInhibit immunity (T cell function)FOXP3/NFAT interaction is required to repress expression of IL-2, upregulate expression of the Treg markers CTLA4 and CD25, and confer suppressor function to Tregs.
22584123MesotheliomaInhibit immunity (T cell function; infiltration)Blockade of CTLA-4 signaling showed effective anticancer effect, correlating with inhibiting cancer cell repopulation between cycles of chemotherapy and upregulating tumor-infiltrating T lymphocytes, cytokines, and cytolytic enzymes in a murine mesothelioma model.
27622997MelanomaInhibit immunity (T cell function); immunotherapy targetCombined nivolumab and ipilimumab versus ipilimumab alone in patients with advanced melanoma: 2-year overall survival outcomes in a multicentre, randomised, controlled, phase 2 trial. Results from phase 2 and 3 trials in patients with advanced melanoma have shown significant improvements in the proportion of patients achieving an objective response and prolonged progression-free survival with the combination of nivolumab (an anti-PD-1 antibody) plus ipilimumab (an anti-CTLA-4 antibody) compared with ipilimumab alone.
29339377Melanoma; Prostate carcinomaInhibit immunity (infiltration); immunotherapy targetIn murine models of melanoma and prostate cancer, the combination of chemotherapy and CTLA-4 blockade induced a shift in the cellular composition of the tumor microenvironment, with infiltrating CD8+ and CD4+ T cells increasing the CD8/Foxp3 T-cell ratio.
29258739Triple-Negative Breast CancerInhibit immunity (T cell function)Combination Immunotherapy of MUC1 mRNA Nano-vaccine and CTLA-4 Blockade Effectively Inhibits Growth of Triple Negative Breast Cancer. In vivo studies demonstrated that the NP-based mRNA vaccine, targeted to mannose receptors on DCs, could successfully express tumor antigen in the DCs of the lymph node; that the NP vaccine could induce a strong, antigen-specific, in vivo cytotoxic T lymphocyte response against TNBC 4T1 cells; and that combination immunotherapy of the vaccine and anti-CTLA-4 monoclonal antibody could significantly enhance anti-tumor immune response compared to the vaccine or monoclonal antibody alone.
24658665Prostate carcinomaImmunotherapy targetPromising immunotherapeutic agents include poxvirus vaccines and CTLA-4 inhibitor (ipilimumab).
24598590MelanomaInhibit immunity (T cell function); immunotherapy targetCombination therapy with localized NDV and systemic CTLA-4 blockade led to rejection of preestablished distant tumors and protection from tumor rechallenge in poorly immunogenic tumor models, irrespective of tumor cell line sensitivity to NDV-mediated lysis. Therapeutic effect was associated with marked distant tumor infiltration with activated CD8(+) and CD4(+) effector but not regulatory T cells, and was dependent on CD8(+) cells, natural killer cells, and type I interferon.
24523507T-Cell Non-Hodgkin LymphomaInhibit immunity (T cell function); immunotherapy targetCoculture of CTCL cells with normal T lymphocytes consisting of both CD4(+) and CD8(+) populations or the CD4(+) subset alone, transfected with CD152 mRNA, inhibits proliferation of normal T cells in a CD152- and CD80-dependent manner. These data identify a new mechanism of immune evasion in CTCL and suggest that the CD80-CD152 axis may become a therapeutic target in this type of lymphoma.
24485523MelanomaImmunotherapy targetThe potential of combination strategies with these agents has recently been highlighted by clinical observations on CTLA-4+PD-1 combined blockade in melanoma patients.
18303116Prostate carcinomaInhibit immunity (T cell function); immunotherapy targetSPAS-1 (stimulator of prostatic adenocarcinoma-specific T cells)/SH3GLB2: A prostate tumor antigen identified by CTLA-4 blockade. Our findings demonstrate that our in vivo CTLA-4 blockade-based T cell expression cloning can identify immunogenic cancer antigens with potential relevance for human immunotherapy.
18287062MelanomaInhibit immunity (T cell function); immunotherapy targetImmunologic and clinical effects of antibody blockade of cytotoxic T lymphocyte-associated antigen 4 in previously vaccinated cancer patients. Here we show that periodic infusions of anti-CTLA-4 antibodies after vaccination with irradiated, autologous tumor cells engineered to secrete GM-CSF (GVAX) generate clinically meaningful antitumor immunity without grade 3 or 4 toxicity in a majority of metastatic melanoma patients. Together, these findings help clarify the immunologic and clinical effects of CTLA-4 antibody blockade in previously vaccinated patients and raise the possibility that selective targeting of antitumor Tregs may constitute a complementary strategy for combination therapy.
28905118LymphomaImmunotherapy targetOverall intratumoral or peri-tDLN administration of the novel combination of anti-CTLA4, anti-CD137, and anti-OX40, all agents in the clinic or clinical trials, demonstrates potent systemic anti-tumor effects. This immunotherapeutic combination is promising for future clinical development via both these safe and highly efficacious routes of administration.
27354469B-Cell lymphomaInhibit immunityThe therapeutic function of anti-CD20 depends on tumor-specific CD8+?T-cell responses initiated by anti-CD20 through macrophages and DCs. CTLA-4 blockade can synergize with anti-CD20 to overcome adaptive immune response-related resistance in advanced B-cell lymphoma.
23188506LeukemiaInhibit immunityBlocking CTLA4 and PD-1 in vivo combined to promote survival of transferred T-cells despite powerful deletional signals that mediate Bim (BCL2L11)-dependent apoptosis. However, this dual blockade was not optimal for stimulating effector function by responding T-cells, which required the additional blockade of LAG3 to induce full expansion and allow the acquisition of robust cytolytic activity.
23152566Prostate carcinomaInhibit immunity (T cell function)hese PAP-specific CD8(+)CTLA-4(+) suppressor T cells expressed IL-35, which was decreased after blockade of CTLA-4, and inhibition of either CTLA-4 or IL-35 reversed PAP-specific suppression of tvDTH response. PAP-specific CD8(+)CTLA-4(+) T cells also suppressed T cell proliferation in an IL-35-dependent, contact-independent fashion.
19318477MelanomaInhibit immunityIpilimumab is a monoclonal antibody that blocks the immune-inhibitory interaction between CTL antigen 4 (CTLA-4) and its ligands on T cells. Clinical trials in cancer patients with ipilimumab have shown promising antitumor activity, particularly in patients with advanced melanoma. Our results show that Melan-A may be a major target for both the autoimmune and antitumor reactions in patients treated with anti-CTLA-4, and describe for the first time the antigen specificity of CD8-positive T cells that mediate tumor rejection in a patient undergoing treatment with an anti-CTLA-4 antibody.
28484017MelanomaInhibit immunity (T cell function); essential for immunotherapyIn particular, the use of function blocking monoclonal antibodies targeting checkpoint inhibitors such as CTLA-4 and PD-1 have proven to be highly effective for the systemic activation of the human immune system to treat a wide range of cancers. Ipilimumab is a fully human antibody targeting CTLA-4 that received FDA approval for the treatment of metastatic melanoma in 2011. This structure reveals that ipilimumab contacts the front β-sheet of CTLA-4 and intersects with the CTLA-4:Β7 recognition surface, indicating that direct steric overlap between ipilimumab and the B7 ligands is a major mechanistic contributor to ipilimumab function.
23580578Lung CarcinomaInhibit immunity (T cell function); essential for immunotherapyImmunomodulatory antibodies directed against cytotoxic T cell-associated antigen 4 (CTLA-4/CD152) and programmed cell death ligand 1 (PDL1/CD274) showed clinical efficacy in patients with lung cancer.
21173239MelanomaInhibit immunity (T cell function); essential for immunotherapyClinical trials of CTLA-4-blocking antibodies to augment T-cell responses to malignant melanoma are at an advanced stage; however, little is known about the effects of CTLA-4 blockade on memory CD8(+) T-cell responses and the formation and maintenance of long-term CD8(+) T-cell memory. This is followed by an accumulation of memory cells that are capable of producing the effector cytokines IFN-γ and TNF-α.
19581407MelanomaInhibit immunity (T cell function); essential for immunotherapyBlockade of CTLA-4 on both effector and regulatory T cell compartments contributes to the antitumor activity of anti-CTLA-4 antibodies. We conclude that the combination of direct enhancement of T(eff) cell function and concomitant inhibition of T reg cell activity through blockade of CTLA-4 on both cell types is essential for mediating the full therapeutic effects of anti-CTLA-4 antibodies during cancer immunotherapy.
16778987MelanomaInhibit immunity (T cell function); essential for immunotherapyCTLA4 blockade and GM-CSF combination immunotherapy alters the intratumor balance of effector and regulatory T cells. We examined the mechanisms of action of anti-CTLA4 and a GM-CSF-transduced tumor cell vaccine (Gvax) and their impact on the balance of effector T cells (Teffs) and Tregs in an in vivo model of B16/BL6 melanoma. Tumor challenge increased the frequency of Tregs in lymph nodes, and untreated tumors became infiltrated by CD4+Foxp3- and CD4+Foxp3+ T cells but few CD8+ T cells. While Gvax primed the tumor-reactive Teff compartment, inducing activation, tumor infiltration, and a delay in tumor growth, the combination with CTLA4 blockade induced greater infiltration and a striking change in the intratumor balance of Tregs and Teffs that directly correlated with tumor rejection.
23752227B16 Malignant MelanomaImmunotherapy targetHere, we examine the inhibitory role of indoleamine 2,3-dioxygenase (IDO) on the antitumor efficacy of CTLA-4 blockade. To highlight the therapeutic relevance of these findings, we show that CTLA-4 blockade strongly synergizes with IDO inhibitors to mediate rejection of both IDO-expressing and nonexpressing poorly immunogenic tumors, emphasizing the importance of the inhibitory role of both tumor- and host-derived IDO. This effect was T cell dependent, leading to enhanced infiltration of tumor-specific effector T cells and a marked increase in the effector-to-regulatory T cell ratios in the tumors. Overall, these data demonstrate the immunosuppressive role of IDO in the context of immunotherapies targeting immune checkpoints and provide a strong incentive to clinically explore combination therapies using IDO inhibitors irrespective of IDO expression by the tumor cells.
23728179Central Nervous System LymphomaInhibit immunity (T cell function); immunotherapy targetIn tumor-bearing mice, we found that Tregs within the tumor preferentially express the cell surface markers CTLA-4 and OX40. We show that intratumoral coinjection of anti-CTLA-4 and anti-OX40 together with CpG depleted tumor-infiltrating Tregs. This in situ immunomodulation, which was performed with low doses of antibodies in a single tumor, generated a systemic antitumor immune response that eradicated disseminated disease in mice. Further, this treatment modality was effective against established CNS lymphoma with leptomeningeal metastases, sites that are usually considered to be tumor cell sanctuaries in the context of conventional systemic therapy.
23649004NeuroblastomaInhibit immunity (T and NK cell function); immunotherapy targetIn the Neuro2a model, treatment of established tumor with anti-4-1BB, anti-CD40, or anti-CTLA-4 mAb results in tumor regression and long-term survival in 40% to 60% of mice. This is dependent on natural killer (NK) and CD8(+) T cells and is associated with tumor CD8(+) lymphocyte infiltrate. These data suggest that the combination of antigen and costimulatory mAb may provide effective immunotherapy against neuroblastoma and may be of particular use in the minimal residual disease setting.
24856586Pancreatic Ductal AdenocarcinomaImmunotherapy targetAlthough myofibroblast-depleted tumors did not respond to gemcitabine, anti-CTLA4 immunotherapy reversed disease acceleration and prolonged animal survival.
19789309MelanomaInhibit immunityAutologous DC were pulsed with MART-1(26-35) peptide and administered with a dose escalation of the CTLA4-blocking antibody tremelimumab. Four patients had an objective tumor response, two partial responses and two complete responses, all melanoma free between 2 and 4 years after study initiation. There was no difference in immune monitoring results between patients with an objective tumor response and those without a response.
19147765Breast CarcinomaInhibit immunityThe response to radiotherapy plus 9H10 was markedly enhanced in the absence of iNKT cells, with 50% of iNKT-/- versus 0% of wild-type mice showing complete tumor regression, long-term survival, and resistance to a challenge with 4T1 cells. Administration of the iNKT cell activator alpha-galactosylceramide did not enhance the response of wild-type mice to radiotherapy plus 9H10. Tumor-infiltrating iNKT cells were markedly reduced in wild-type mice treated with radiotherapy plus 9H10.
19147575Prostate CarcinomaInhibit immunityOf the six patients treated at the highest dose level, three had confirmed PSA declines of >50%, including one patient that had a partial response in visceral metastases. Expansion of activated, circulating CD25(+) CD69(+) CD8(+) T cells occurred more frequently at higher doses of treatment and was greater in magnitude than was seen in patients who received the same doses of either ipilimumab or GM-CSF alone.
19074257MelanomaInhibit immunityFifteen patients were selected on the basis of availability of suitable specimens for immunologic monitoring, and eight of these showed evidence of clinical benefit. Five of the eight patients with evidence of clinical benefit had NY-ESO-1 antibody, whereas none of seven clinical non-responders was seropositive for NY-ESO-1. All five NY-ESO-1 seropositive patients had clearly detectable CD4(+) and CD8(+) T cells against NY-ESO-1 following treatment with ipilimumab. Overall, NY-ESO-1-specific T cell responses increased in frequency and functionality during anti-CTLA-4 treatment, revealing a polyfunctional response pattern of IFN-gamma, MIP-1beta and TNF-alpha.
25038199melanomaInhibit immunity (T cell function)Because α-CTLA-4 Fab fragments had the same effect as the intact antibody, the higher T-cell motility does not seem to be due to CTLA-4 inhibitory signaling but rather to the release of nonproductive stable interactions between tumor-infiltrating T cells and tumor targets or antigen-presenting cells subsequent to CTLA-4 blockade.
24916470adenocarcinomaInhibit immunity (infiltration)We observed substantial therapeutic synergies when combining dolastatins with tumor antigen-specific vaccination or blockade of the PD-1-PD-L1 and CTLA-4 coinhibitory pathways.
24907635Pancreatic CarcinomaInhibit immunity (infiltration)Tremelimumab (CP-675,206) is a fully human monoclonal antibody binding to cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) on T cells that stimulates the immune system by blocking the CTLA4-negative regulatory signal.
24892807T-Cell Non-Hodgkin LymphomaInhibit immunity (infiltration)These data demonstrate that a CTLA4(apt)-based siRNA delivery strategy allows gene silencing in both tumor-associated T cells and tumor cells and inhibits tumor growth and metastasis.
29663369Squamous Cell CarcinomaInhibit immunity (infiltration)Whereas the population of CD4+ CD73hi /CD8+ CD73hi T cells expressed higher CTLA-4 and PD-1 as compared to untreated controls.
29657128lung adenocarcinomaInhibit immunity (infiltration)TMB should be incorporated in future trials examining PD-(L)1 with CTLA-4 blockade in NSCLC.
29656892melanomaInhibit immunity (infiltration)We validate this gene expression signature in an independent anti-CTLA-4-treated cohort and show its specificity to the CTLA-4 pathway with two independent anti-PD-1-treated cohorts.
29632721B16 Malignant MelanomaInhibit immunity (infiltration)Moreover, immunogenicity of this vaccination platform was enhanced not only by combination with additional adjuvants, but also with antibodies blocking PD-1/PD-L1, CTLA-4 and IL-10, immunosuppressive molecules usually present in the tumor environment and also induced by the vaccine.
29596939melanomaInhibit immunity (infiltration)Two inhibitory molecules, cytotoxic T-lymphocyte antigen 4 (CTLA-4) and programmed cell death protein 1 (PD-1), got high attention, as inhibition of CTLA-4 or PD-1 signaling provides the first immune therapy that significantly improves the survival of patients with metastatic solid cancers.
29581255Colon CarcinomaInhibit immunity (infiltration)The VHH H11 lacks an Fc portion, binds monovalently to CTLA-4, and inhibits interactions between CTLA-4 and its ligand by occluding the ligand-binding motif on CTLA-4 as shown crystallographically.
27873300Bladder CarcinomaImmunotherapy targetHere, we investigated the efficacy of a local low-dose anti-CTLA-4 administration for treatment of subcutaneous or orthotopic murine bladder 49 (MB49) bladder carcinoma in C57BL/6 mice. In addition, p.t. anti-CTLA-4 therapy was potentiated by depletion of regulatory T cells. Our results demonstrate that local anti-CTLA-4 antibody therapy is equally effective as systemic administration, but reduces systemic antibody levels and cytokine release, and enhances the response to anti-PD1 therapy.
27668655MelanomaImmunotherapy targetHere we show that somatic mutations in SERPINB3 and SERPINB4 are associated with survival after anti-CTLA4 immunotherapy in two independent cohorts of patients with melanoma.
24055012MelanomaImmunotherapy targetTwo distinct approaches have emerged to try to extend survival in patients with metastatic melanoma: immunomodulation with anti-CTLA4 monoclonal antibodies, and targeted therapy with BRAF inhibitors or MEK inhibitors for BRAF-mutated melanoma.
24004819Breast CarcinomaInhibit immunity (T cell function)Enhanced immune surveillance in COX-2(MEC)KO tumors was coincident with increased intratumoral CXCL9, a T cell chemoattractant, and decreased expression of T lymphocyte co-inhibitory receptors CTLA4 and PD-1, as well as PD-L1, the ligand for PD-1.
23960017Hepatocellular CarcinomaInhibit immunity (T cell function)Human CD14+ CTLA-4+ regulatory dendritic cells suppress T-cell response by cytotoxic T-lymphocyte antigen-4-dependent IL-10 and indoleamine-2,3-dioxygenase production in hepatocellular carcinoma. CD14(+) DCs significantly suppress T-cell response in vitro through interleukin (IL)-10 and indoleamine-2,3-dioxygenase (IDO). Unexpectedly, CD14(+) DCs expressed high levels of cytotoxic T-lymphocyte antigen-4 (CTLA-4) and programmed death-1, and CTLA-4 was found to be essential to IL-10 and IDO production. So, we identified a novel human tumor-induced regulatory DC subset, which suppresses antitumor immune response through CTLA-4-dependent IL-10 and IDO production, thus indicating the important role of nonregulatory T-cell-derived CTLA-4 in tumor-immune escape or immunosuppression.
23913973Uveal melanomaInhibit immunity (T cell function)The anticytotoxic T-lymphocyte-associated protein 4 (anti-CTLA-4) antibody ipilimumab is a standard of care for metastatic melanoma; however, the clinical activity of CTLA-4 inhibition in patients with metastatic uveal melanoma is poorly defined.
23897981MelanomaInhibit immunity (T cell function)Although subject to debate, current models favor a mechanism of activity involving blockade of the inhibitory activity of CTLA-4 on both effector (T eff) and regulatory (T reg) T cells, resulting in enhanced antitumor effector T cell activity capable of inducing tumor regression.
23871358Acute Myeloid LeukemiaInhibit immunityWe envisage future treatment protocols, in which systemic immune activators, such as vaccines, dendritic cell-based therapies, engineered variants of IL-2, or IL-15, are combined with agents that counter immunosuppression mediated by, e.g., the PD/PDL interaction, CTLA-4, CD200, reactive oxygen species, IDO expression, CXCR4, or the KIR/class I interaction, based on characteristics of the prevailing malignant clone.
23870385MelanomaInhibit immunity (T cell function)The first major advance was the development of selective mitogen-activated protein (MAP) kinase inhibitors (BRAF and MEK inhibitors) and immune checkpoint blockade with a CTLA4 antibody (ipilimumab).
21480325Hepatocellular CarcinomaInhibit immunity (T cell function)Blocking cytotoxic T-lymphocyte antigen-4 (CTLA-4) resulted in unmasking of TAA-specific immune responses by changing cytokine and chemokine profiles of peripheral blood mononuclear cells stimulated by TAA-derived peptides. TAA-specific immunotherapy combined with HCC treatments and anti-CTLA-4 antibody has the possibility to produce stronger tumor-specific immune responses.
21467163MelanomaInhibit immunity (T cell function)Regulatory checkpoints, such as cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), serve to attenuate this signal, thereby preventing autoimmunity. Its key role in regulating the immune system has made CTLA-4 an attractive therapeutic target for cancer, with the development of fully human monoclonal antibodies that have successfully targeted CTLA-4 in clinical trials.
20156971MelanomaInhibit immunity (T cell function)Furthermore, blockade of the coinhibitory receptor CTL-associated antigen 4 (CTLA-4) on the transferred CD4(+) T cells resulted in greater expansion of effector T cells, diminished accumulation of tumor-reactive regulatory T cells, and superior antitumor activity capable of inducing regression of spontaneous mouse melanoma. These findings suggest a novel potential therapeutic role for cytotoxic CD4(+) T cells and CTLA-4 blockade in cancer immunotherapy.
29361059Renal Cell CarcinomaInhibit immunityPD-1, PD-L2, CTLA4 and FOXP3, all of which are implicated in the evasion of an anti-tumor immune response, had a significantly higher expression for samples representing co-detection of productive TcR-α and -β recombination reads.
29360722MelanomaInhibit immunity (T cell function)Part of these advances emerged through the identification of the importance of factors that regulate the immune system, including proteins that negatively modulate T cell-mediated responses termed "immune checkpoints." Indeed, blockade of the cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) immune checkpoint served as a proof of principle that the manipulation of these molecules could induce robust anticancer effects, yet limited to a small percentage of patients.
29326088MelanomaImmunotherapy targetWe used a mouse model of transplantable, orthotopic B16 melanoma to test age effects of treatments with anti-CTLA-4, anti-PD-1 and anti-PD-L1 antibodies.
18612161MelanomaInhibit immunity (T cell function)Blockade of CTLA4 prevents inhibitory signals that downregulate T-cell activation.
16094420Chronic Lymphocytic LeukemiaInhibit immunity (T cell function)Patients with chronic lymphocytic leukemia (CLL) have defects in both cellular and humoral immunity. Since CD152 (CTLA-4) plays a critical role in downregulating T-cell responses, we studied the expression of surface and cytoplasmic CD152 (sCD152 and cCD152, respectively) in freshly isolated T cells from treatment-na?ve patients with CLL.
16034082B16 Malignant MelanomaInhibit immunityThe combination of peptide vaccination and treatment with an Ab directed against the inhibitory receptor CTLA-4 enhanced the immune response against TRP-2 peptide, inducing autoimmune depigmentation and further decreasing lung tumor nodules. Furthermore, addition of CTLA-4 blockade increased the frequency of TRP-2-specific, IFN-secreting T cells in spleen and lymph nodes.
29150430MelanomaInhibit immunity; immunotherapy targetCTLA4 is a cell surface receptor on T cells that functions as an immune checkpoint molecule to enforce tolerance to cognate antigens. Anti-CTLA4 immunotherapy is highly effective at reactivating T-cell responses against melanoma, which is postulated to be due to targeting CTLA4 on T cells.
28716895LymphomaInhibit immunityCTLA4 activation resulted in lymphoma cell proliferation and tumor growth, whereas silencing or antibody-blockade of CTLA4 in B-cell lymphoma tumor cells in the absence of T cells inhibits tumor growth.
28716895B-Cell LymphomaInhibit immunityCTLA4-CD86 ligation recruited and activated the JAK family member Tyk2, resulting in STAT3 activation and expression of genes critical for cancer immunosuppression and tumor growth and survival. CTLA4 activation resulted in lymphoma cell proliferation and tumor growth, whereas silencing or antibody-blockade of CTLA4 in B-cell lymphoma tumor cells in the absence of T cells inhibits tumor growth.
28027300Prostate CarcinomaInhibit immunityFurther supporting a role of inflammation-induced immune-suppression in the development of early-onset prostate cancer, we observed significant up-regulation of CTLA4 and IDO1/TDO2 pathways in tumors of the young cohort. Moreover, over-expression of CTLA4 and IDO1 was significantly associated with biochemical recurrence.
24396833MelanomaInhibit immunity (T cell function)Multiple NY-ESO-1 antigen-specific CD4(+) T cell responses with Th1 dominance were induced or enhanced after ipilimumab treatment in peripheral blood in all four patients. NY-ESO-1 antigen-specific CD4(+) T cell lines established from all 4 patients after ipilimumab treatment recognized naturally processed NY-ESO-1 protein in antigen-presenting cells, expressed master transcription factor Eomesodermin (Eomes) and secreted perforin and Granzyme B. Finally, we demonstrated that these NY-ESO-1 antigen-specific CD4(+) T cell lines directly lysed autologous melanoma cell lines expressing NY-ESO-1 in an MHC class II restricted manner.
24089443MelanomaInhibit immunity; Immunotherapy targetImmune checkpoint blockade with monoclonal antibodies directed at the inhibitory immune receptors CTLA-4, PD-1, and PD-L1 has emerged as a successful treatment approach for patients with advanced melanoma.
22028176MelanomaInhibit immunityEnhancement of anti-tumor immunity through local modulation of CTLA-4 and GITR by dendritic cells. Using in vitro assays with human DCs, we demonstrated that DCs transfected with mRNA encoding a humanized anti-CTLA-4 mAb and mRNA encoding a soluble human GITR-L fusion protein enhance the induction of anti-tumor CTLs in response to DCs transfected with mRNAs encoding either melanoma or breast cancer antigens.
20460483Colon Carcinoma; FibrosarcomaInhibit immunity (infiltration); Immunotherapy targetAnti-CTLA-4/anti-GITR mAb combination treatment exhibited far stronger antitumor effects compared with either antibody alone. This strong antitumor effect was attributed to (a) increased numbers of CD8+ T cells infiltrating tumor sites in anti-CTLA-4 mAb-treated mice and (b) increased cytokine secretion and Treg resistance of tumor-specific CD8+ T cells with strongly upregulated CD25 expression in anti-GITR mAb-treated mice, indicating distinct quantitative/qualitative changes induced by modulating CTLA-4 and GITR signaling.
19001145MelanomaInhibit immunity (T cell function); Immunotherapy targetCD28 provides positive modulatory signals in the early stages of an immune response, while CTLA-4 signaling inhibits T-cell activation, particularly during strong T-cell responses. CTLA-4 blockade using anti-CTLA-4 monoclonal antibody therapy has great appeal because suppression of inhibitory signals results in the generation of an antitumor T-cell response. Both clinical and preclinical data indicate that CTLA-4 blockade results in direct activation of CD4+ and CD8+ effector cells, and anti-CTLA-4 monoclonal antibody therapy has shown promise in a number of cancers, particularly melanoma.
16204013MelanomaImmunotherapy targetCytotoxic T lymphocyte-associated antigen 4 (CTLA4) blockade with CP-675,206, a fully human anti-CTLA4 monoclonal antibody, may break peripheral immunologic tolerance leading to effective immune responses to cancer in humans.
16953240MelanomaInhibit immunityFinally, we show that in situ tumour ablation can be efficiently combined with immune modulation by anti-CTLA-4 antibodies or regulatory T-cell depletion. These combination treatments protected mice from the outgrowth of tumour challenges, and led to in vivo enhancement of tumour-specific T-cell numbers, which produced more IFN-gamma upon activation.
16882704MelanomaInhibit immunityWe found that genetic removal of CTLA-4 induced activation and acquisition of effector functions in pmel-1 CD8 T cells, resulting in the rapid development of severe autoimmune vitiligo. These effects were abrogated by the removal of the CD4 T-cell population. Therefore, we propose that the lack of CTLA-4 on self/tumor antigen–specific CD8 T cells results in autoimmunity and tumor immunity only in the presence of nonspecific, dysregulated CD4 CTLA-4 / T cells.
16849577MelanomaInhibit immunityThis notion is supported by a recent clinical trial involving an anti-CTL antigen-4 (CTLA-4) antibody that showed significant clinical responses but severe autoimmune diseases in melanoma patients
Summary
SymbolCTLA4
Namecytotoxic T-lymphocyte-associated protein 4
Aliases CD152; CELIAC3; IDDM12; celiac disease 3; insulin-dependent diabetes mellitus 12; ALPS5; CTLA-4; GRD4; CD152 ......
Chromosomal Location2q33
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
  Statistical results of CTLA4 in screening data sets for detecting immune reponses.
PMID Screening System Cancer Type Cell Line Data Set Statistical Results Relation to immunity
29301958CRISPR-Cas9 melanomaB16F10Pmel-1 T cell NA/NSNA/NS
29301958CRISPR-Cas9 melanomaB16F10OT-1 T cell NA/NSNA/NS
28783722CRISPR-Cas9 melanomaMel6242CT-CRISPR NA/NSNA/NS
28723893CRISPR-Cas9 melanomaB16GVAX+Anti-PD1 NA/NSNA/NS
28723893CRISPR-Cas9 melanomaB16GVAX NA/NSNA/NS
25691366RNAiBreast cancerMCF7Luc-CTL assay NA/NSNA/NS
24476824shRNAmelanomaB16Primary screen NA/NSNA/NS
24476824shRNAmelanomaB16Secondary screen NA/NSNA/NS
Summary
SymbolCTLA4
Namecytotoxic T-lymphocyte-associated protein 4
Aliases CD152; CELIAC3; IDDM12; celiac disease 3; insulin-dependent diabetes mellitus 12; ALPS5; CTLA-4; GRD4; CD152 ......
Chromosomal Location2q33
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
 
Points in the above scatter plot represent the expression difference of CTLA4 in various data sets.
No PMID Cancer type Group Drug # Res # NRes Log2 (Fold Change) P value Anno
126997480MelanomaallAnti-PD-1 (pembrolizumab and nivolumab)1412-0.4830.384
226997480MelanomaMAPKiAnti-PD-1 (pembrolizumab and nivolumab)65-0.3830.747
326997480Melanomanon-MAPKiAnti-PD-1 (pembrolizumab and nivolumab)87-0.5670.598
428552987Urothelial cancerallAnti-PD-L1 (atezolizumab) 916-0.2710.681
528552987Urothelial cancersmokingAnti-PD-L1 (atezolizumab) 59-0.790.494
628552987Urothelial cancernon-smokingAnti-PD-L1 (atezolizumab) 470.3890.783
729033130MelanomaallAnti-PD-1 (nivolumab) 26231.1490.132
829033130MelanomaNIV3-PROGAnti-PD-1 (nivolumab) 15111.1840.306
929033130MelanomaNIV3-NAIVEAnti-PD-1 (nivolumab) 11121.2540.288
1029301960Clear cell renal cell carcinoma (ccRCC)allAnti-PD-1 (nivolumab) 480.9480.252
1129301960Clear cell renal cell carcinoma (ccRCC)VEGFRiAnti-PD-1 (nivolumab) 2001
1229301960Clear cell renal cell carcinoma (ccRCC)non-VEGFRiAnti-PD-1 (nivolumab) 280.0190.986
1329443960Urothelial cancerallAnti-PD-L1 (atezolizumab) 682300.0590.822
> Mutation difference between responders and non-responders
 
Points in the above scatter plot represent the mutation difference of CTLA4 in various data sets.
No PMID Cancer type Group Drug # Res # NRes % Mut/Res % Mut/NRes % Diff (R vs NR) Pval Anno
125765070Non-small cell lung cancer (NSCLC)allAnti-PD-1 (pembrolizumab) 14170001
225765070Non-small cell lung cancer (NSCLC)smokingAnti-PD-1 (pembrolizumab) 1030001
325765070Non-small cell lung cancer (NSCLC)non-smokingAnti-PD-1 (pembrolizumab) 4140001
426359337MelanomaallAnti-CTLA-4 (ipilimumab) 27733.72.711
526359337MelanomaBRAFiAnti-CTLA-4 (ipilimumab) 0140001
626359337Melanomanon-BRAFiAnti-CTLA-4 (ipilimumab) 27593.73.40.31
726997480MelanomaallAnti-PD-1 (pembrolizumab and nivolumab)21170001
826997480MelanomaMAPKiAnti-PD-1 (pembrolizumab and nivolumab)860001
926997480Melanomanon-MAPKiAnti-PD-1 (pembrolizumab and nivolumab)13110001
1028552987Urothelial cancerallAnti-PD-L1 (atezolizumab) 9160001
1128552987Urothelial cancersmokingAnti-PD-L1 (atezolizumab) 590001
1228552987Urothelial cancernon-smokingAnti-PD-L1 (atezolizumab) 470001
1329033130MelanomaallAnti-PD-1 (nivolumab) 38272.63.7-1.11
1429033130MelanomaNIV3-PROGAnti-PD-1 (nivolumab) 22134.57.7-3.21
1529033130MelanomaNIV3-NAIVEAnti-PD-1 (nivolumab) 16140001
1629301960Clear cell renal cell carcinoma (ccRCC)allAnti-PD-1 (nivolumab) 11130001
1729301960Clear cell renal cell carcinoma (ccRCC)VEGFRiAnti-PD-1 (nivolumab) 610001
1829301960Clear cell renal cell carcinoma (ccRCC)non-VEGFRiAnti-PD-1 (nivolumab) 5120001
Summary
SymbolCTLA4
Namecytotoxic T-lymphocyte-associated protein 4
Aliases CD152; CELIAC3; IDDM12; celiac disease 3; insulin-dependent diabetes mellitus 12; ALPS5; CTLA-4; GRD4; CD152 ......
Chromosomal Location2q33
External Links HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content Relations between abundance of tumor-infiltrating lymphocytes (TILs) and expression, copy number, methylation, or mutation of CTLA4. 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
 
Summary
SymbolCTLA4
Namecytotoxic T-lymphocyte-associated protein 4
Aliases CD152; CELIAC3; IDDM12; celiac disease 3; insulin-dependent diabetes mellitus 12; ALPS5; CTLA-4; GRD4; CD152 ......
Chromosomal Location2q33
External Links HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content Relations between three kinds of immunomodulators and expression, copy number, methylation, or mutation of CTLA4. These immunomo-dulators were collected from Charoentong's study. In this tab, users can examine which immunomodulators might be regulated by CTLA4.
> Immunoinhibitor
> Immunostimulator
> MHC molecule
> Immunoinhibitor
 
> Immunostimulator
 
> MHC molecule
 
Summary
SymbolCTLA4
Namecytotoxic T-lymphocyte-associated protein 4
Aliases CD152; CELIAC3; IDDM12; celiac disease 3; insulin-dependent diabetes mellitus 12; ALPS5; CTLA-4; GRD4; CD152 ......
Chromosomal Location2q33
External Links HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content Relations between chemokines (or receptors) and expression, copy number, methylation, or mutation of CTLA4. In this tab, users can examine which chemokines (or receptors) might be regulated by the current gene.
> Chemokine
> Receptor
> Chemokine
 
> Receptor
 
Summary
SymbolCTLA4
Namecytotoxic T-lymphocyte-associated protein 4
Aliases CD152; CELIAC3; IDDM12; celiac disease 3; insulin-dependent diabetes mellitus 12; ALPS5; CTLA-4; GRD4; CD152 ......
Chromosomal Location2q33
External Links HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content Distribution of CTLA4 expression across immune and molecular subtypes.
> Immune subtype
> Molecular subtype
> Immune subtype
 
> Molecular subtype
 
Summary
SymbolCTLA4
Namecytotoxic T-lymphocyte-associated protein 4
Aliases CD152; CELIAC3; IDDM12; celiac disease 3; insulin-dependent diabetes mellitus 12; ALPS5; CTLA-4; GRD4; CD152 ......
Chromosomal Location2q33
External Links HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content Associations between CTLA4 and clinical features.
> Overall survival analysis
> Cancer stage
> Tumor grade
> Overall survival
 
> Stage
 
> Grade
 
Summary
SymbolCTLA4
Namecytotoxic T-lymphocyte-associated protein 4
Aliases CD152; CELIAC3; IDDM12; celiac disease 3; insulin-dependent diabetes mellitus 12; ALPS5; CTLA-4; GRD4; CD152 ......
Chromosomal Location2q33
External Links HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content Drugs targeting CTLA4 collected from DrugBank database.
> Drugs from DrugBank database
 

  Details on drugs targeting CTLA4.
ID Name Drug Type Targets #Targets
DB06186IpilimumabBiotechCTLA41