CTLA4

Official Full Name

cytotoxic T-lymphocyte associated protein 4

Organism

Homo sapiens

GeneID

1493

Background

This gene is a member of the immunoglobulin superfamily and encodes a protein which transmits an inhibitory signal to T cells. The protein contains a V domain, a transmembrane domain, and a cytoplasmic tail. Alternate transcriptional splice variants, encoding different isoforms, have been characterized. The membrane-bound isoform functions as a homodimer interconnected by a disulfide bond, while the soluble isoform functions as a monomer. Mutations in this gene have been associated with insulin-dependent diabetes mellitus, Graves disease, Hashimoto thyroiditis, celiac disease, systemic lupus erythematosus, thyroid-associated orbitopathy, and other autoimmune diseases. [provided by RefSeq, Jul 2008]

Synonyms

CD; GSE; GRD4; ALPS5; CD152; CTLA-4; IDDM12; CELIAC3;

Bio Chemical Class

Immunoglobulin

Protein Sequence

MACLGFQRHKAQLNLATRTWPCTLLFFLLFIPVFCKAMHVAQPAVVLASSRGIASFVCEYASPGKATEVRVTVLRQADSQVTEVCAATYMMGNELTFLDDSICTGTSSGNQVNLTIQGLRAMDTGLYICKVELMYPPPYYLGIGNGTQIYVIDPEPCPDSDFLLWILAAVSSGLFFYSFLLTAVSLSKMLKKRSPLTTGVYVKMPPTEPECEKQFQPYFIPIN

Open

Disease

Breast cancer, Cervical cancer, Diabetes mellitus, Epidermal dysplasias, Liver cancer, Lung cancer, Melanoma, Non-small-cell lung cancer, Pleural mesothelioma, Prostate cancer, Rheumatoid arthritis, Solid tumour/cancer

Approved Drug

2 +

Clinical Trial Drug

22 +

Discontinued Drug

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Detailed Information

Cytotoxic T-lymphocyte antigen-4 (CTLA-4, also known as CD152) is a member of a growing family of molecules that modify T cell activation. Among these, CTLA-4, PD-1, CD28 and inducible co-stimulator (ICOS) and their ligands B7 (i.e. B7-1 or B7-2), PD-L1 and ICOSL are members of the B7 family (within the immunoglobulin superfamily), however e.g. OX40 is a member of the TNF receptor (TNFR) superfamily. These molecules have in common that they modulate, as the so-called second signal (co-inhibition or co-stimulation), the intensity of the first signal delivered to T cells from the interaction of the T-cell receptor (TCR) with the (tumor-) antigen presented in the major histocompatibility complex (MHC).

Overview of the CTLA-4 Pathway

CD28 interacts with the CD80 dimer with relatively high affinity and the CD86 monomer with lower affinity, mediating T-cell costimulation in conjunction with TCR signals. Instead, interactions of the ligands with CTLA-4 serve to inhibit T-cell responses, although the precise mechanisms are not fully understood. CTLA-4 interacts with both ligands with higher affinity and avidity than CD28 with CTLA-4-CD80 forming the highest avidity interaction and CD28-CD86 forming the weakest interaction. Among multiple possibilities, this raises the concept that CTLA-4 can compete with CD28 for ligand binding and thereby act as an antagonist of CD28-mediated costimulation. These interactions are thought to occur at the immune synapse between T cells and APCs where CTLA-4 has been shown to recruit CD80, thus limiting its interactions with CD28.

Figure 1. The diagram of CTLA-4 cell biology. (Rowshanravan B, et al., 2018)

CTLA-4 in Cancer

Cancer immunotherapy was announced as the "breakthrough of the year" in oncology in 2013. The euphoria is mainly based on the clinical success of the antibodies targeting CTLA-4 and PD-1 to regulate immune checkpoints. Immune checkpoints are inhibitory pathways that modulate the strength and duration of co-stimulatory signaling between T cells and antigen-presenting cells (APCs).

It was first shown that transfecting CD80, a CD28/CTLA-4 ligand, on a poorly immunogenic cancer cell line stimulated the mouse immune system for rejection upon tumor transplantation. The data suggested that recognition of antigens on a tumor can be augmented by additional signals mediated by CD28 and/or CTLA-4, resulting in efficient T-cell activation and attack. Allison et al. proved that a systemic administration with blocking anti-CTLA-4 mAb in mice enhanced the anti-tumor response, leading to the rejection of transplanted tumors. These reports established a milestone that the blockade of negative costimulatory molecules to their physiological ligand promotes tumor immunity. Later, the CTLA-4 blockade was shown to be effective in combination with tumor vaccination in mice. Shrikant et al. used an antigen-specific tumor elimination mouse model to elucidate the mechanism of augmented tumor immunity by CTLA-4 blockade. They found that tumor-specific CD8+ cells are usually anergic, but exhibit tumor attack upon administration of anti-CTLA-4 antibody in vivo. This re-activation of CD8+ T cells was dependent on CD4+ helper T cells and IL-2 produced by this population, suggesting that re-activation of the helper response indirectly boosts the killer-mediated anticancer responses. The result also supported the notion that CTLA-4 blockade not only directly boosts effector CD8+ T cells, but also indirectly augments immune responses by acting on helper T cells.

Clinical Development of Targeting the CTLA-4 Pathway

Based on the efficacy of CTLA-4 blockade in animal models, anti–CTLA-4 antibodies were developed for clinical use. Reports from human trials in melanoma, non–small cell lung cancer, prostate, ovarian, mesothelioma, breast, and urothelial cancer treatment have shown efficacy. Alongside the benefits in tumor control, these trials nonetheless demonstrate a broad range of immune-related adverse events (irAEs) occurring in 60% to 65% of patients. irAEs most commonly affect the skin, gastrointestinal (GI) tract, and endocrine organs. Currently, patients with immune-related adverse events higher than grade 3 are primarily treated by steroids. In the future, adequate management if these side effects are likely and it is expected that there will be an abrogation of adverse events without avoiding anticancer response.

References:

Chikuma S. CTLA-4, an essential immune-checkpoint for T-cell activation. Emerging Concepts Targeting Immune Checkpoints in Cancer and Autoimmunity. Springer, Cham, 2017: 99-126.
Seidel J A, et al. Anti-PD-1 and anti-CTLA-4 therapies in cancer: mechanisms of action, efficacy, and limitations. Frontiers in oncology, 2018, 8: 86.
Rowshanravan B, et al. CTLA-4: a moving target in immunotherapy. Blood, The Journal of the American Society of Hematology, 2018, 131(1): 58-67.
Blank C U, Enk A. Therapeutic use of anti-CTLA-4 antibodies. International immunology, 2015, 27(1): 3-10.

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