This site is intended for
U.S.
Healthcare Professionals only.
CTLA-4
Cytotoxic T-lymphocyte antigen 4 (CTLA-4) is an immune checkpoint receptor that negatively regulates the immune response. Blocking CTLA-4 may directly restore -
driven T-cell suppression, and lead to
- CTLA-4 is an immune checkpoint receptor expressed on the surface of activated
T cells1,2 - Binding of CTLA-4 on cytotoxic T cells
to CD80/86 on
antigen-presenting cells (APCs)inhibits T-cell activation3
- Activation is initiated when an antigen is presented to the T-cell receptor (TCR) by the major histocompatibility complex (MHC) on APCs3
- Completion of the activation process requires a second signal.4-6 This occurs when CD28, the primary costimulatory receptor on T cells, binds to CD80 and CD86 on APCs to maintain immune response2,3
- When CTLA-4 is upregulated, it competes with CD28 for binding to CD80/86. CTLA-4 binding inhibits T-cell activation and preserves balance when the immune system is overactive6-8
- CTLA-4 signaling on Tregs leads to suppression of the immune response9
- Tregs play a key role in counterbalancing excessive immune activation by inhibiting the activation and function of other immune cells10,11
- Continuous expression of
CTLA-4 on Tregs is critical for their suppressive activity9,12
- In cancer, tumor cells leverage the CTLA-4 pathway to decrease T-cell activation, proliferation, and effector function8,13
- CTLA-4 signaling in cancer also diminishes the ability of memory T cells
to sustain a response, damaging a key element of durable immunity8,13
- Memory T cells, which have an almost indefinite lifespan, provide long-term immunity.14 When exposed to a tumor antigen, memory T cells can recognize and immediately mount an immune response against the tumor.15 In cancer, these cells are associated with long-term survival and low risk of tumor recurrence16,17
- CTLA-4 signaling in cancer reduces proliferation of memory T cells8,13
- According to preclinical data,
CTLA-4–specific antibodies can restore an immune response by increasing the activation, accumulation, function, and survival of T cells and memory T cells, and by depleting Tregsin the tumor microenvironment8,18,19
- However, CTLA-4 inhibition may also lead to immune attack of healthy cells.20 CTLA-4 inhibition, either alone or in combination with other checkpoint pathways, is currently being researched to optimize the antitumor response21
- One approach aims to regulate the degree of immune activity using
non-fucosylated antibodies to deplete Tregs - Poor prognosis in various cancers is associated with the presence of Tregs22,23
- Unlike fucosylated antibodies,
non-fucosylated antibodies have a modified Fc region, which enhances binding to Fc receptors on immune cells that mediateantibody-dependent cellular cytotoxicity (ADCC).24 The enhanced binding leads to increased antibody activity that depletes Tregs and results in greater T-cell activation19,24 - Mouse models have shown that increased Treg depletion can improve
cytotoxic T-cellactivation and antitumor activity25
- Another approach uses
pro-antibodies that can improveCTLA-4–blockade specificity by reducing antibody binding outside of the tumor microenvironment, sparing healthy tissues26,27 - These antibodies are primarily active at the tumor site because they have been masked with a peptide that is removed by enzymes that are either highly expressed by or only present on tumor cells26
- Preclinical data indicate that limiting antibody binding in the tumor microenvironment may prevent the immune system from attacking healthy cells, yet still enable an antitumor response27,28
- Novel approaches for optimizing CTLA-4 blockade’s ability to restore the immune response are currently under investigation
How can CTLA-4 play a role in long-term immunity?
Learn more about CTLA-4 and memory
Get I-O Resources
Order or download
educational tools for your
patients and practice
REFERENCES–CTLA-4
1. Perkins D, Wang Z, Donovan C, et al. Regulation of CTLA-4 expression during T cell activation. J Immunol. 1996;156(11):4154-4159. 2. Le Mercier I, Lines JL, Noelle RJ. Beyond CTLA-4 and PD-1, the generation Z of negative checkpoint regulators. Front Immunol. 2015. doi:10.3389/fimmu.2015.00418. 3. Chen L, Flies DB. Molecular mechanisms of T cell