Page 138 - Read Online

Page 6 Spiliopoulou et al. Cancer Drug Resist 2024;7:2 https://dx.doi.org/10.20517/cdr.2023.46

Figure 3. General Concept of Developing Drugs Blocking Activity of T cells: In general, there are three main compartments enriched in
reg
T cells, which are currently being targeted with drugs: (1) Extracellularly by blocking Ligands (white background), such as IL-2.
reg
Alternatively, blocking specific receptors on T cells, e.g., CTLA-4, CCR4, with monoclonal antibodies, such as ipilimumab or
reg
mogamulizumab, can arrest the activity of T cells; (2) Intracellularly (red background), signaling pathways can be blocked with small
reg
molecule inhibitors, e.g., targeting PI3K-δ; (3) Transcription, gene modification is targeted with different pharmacological agents, such
as antisense oligonucleotides, molecular glue, and small molecules. These pharmacological interventions are mainly in non-clinical or
early clinical investigations. They target a variety of factors, of which HELIOS and FOXP3 are perhaps the most unique to T cells.
reg
T cells: T regulatory cells; IL: interleukin; CTLA-4: cytotoxic T lymphocyte antigen-4; CCR4: C-C chemokine receptor; PI3K-δ:
reg
phosphoinositide-3-kinase delta; FOXP3: forkhead box protein P3.
In addition to intracellular transcription factors and the interaction with TCR, chemokines such as C-C
motif chemokine ligand (CCL22) can induce the formation of T cells . CCL22, secreted by dendritic cells
[46]
reg
(DC) and macrophages, engages with its receptor C-C chemokine receptor (CCR4), which is predominantly
expressed on T cells . Blocking this CCL22/CCR4 axis and consequently removing T cells leads to anti-
[47]
reg
reg
tumor immune responses . Recent studies further show that FOXP3 is required to increase the expression
[48]
of CCR4 on T cells . This co-regulation underscores that soluble and molecular events determine the fate
[49]
reg
of T cells.
reg
Epiregulation
The function or the generation of T cells can also be influenced by mechanisms of epiregulation . In
[50]
reg
murine models, complement factors determined the methylation of the FOXP3 in T cells. Since
reg
complement is part of the innate immune system, epigenetic regulation of T cells appears to occur early
reg
during an immune response. Hence, interventions of blocking complement activation may have an impact
on the generation of T cells.
reg
Immunosuppressive function of T cells
reg
The classifications of T cells can be based on functional studies for all T cells or their subsets. Generally,
reg
reg
T cells exert their suppressive function in three ways: (1) soluble factors; (2) inhibitory receptors; (3)
reg
[51]
competition for activation or growth factors . In recent years, the list of such mechanisms has expanded,
and the following examples for each mechanism are presented to illustrate the basis for novel anti-cancer