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Gurska et al. Cancer Drug Resist 2023;6:674-87 https://dx.doi.org/10.20517/cdr.2023.39 Page 676

T CELLS FRONT THE ADAPTIVE IMMUNE RESPONSE
The adaptive immune system plays an essential role in eliminating a variety of threats to our bodies,
including cancer and infection. Key players in the adaptive immune response are B lymphocytes (B-cells)
and T lymphocytes (T cells). They are distinguishable from cell types that primarily function in the innate
immune response because they have antigen-specific receptors - B-cell receptor (BCR) and T cell receptor
[16]
(TCR), respectively . T cells can differentiate into three different cell types: effector T cells, cytotoxic T
cells, and regulatory T cells. Effector T cells, also known as “helper T cells”, which express the cell-surface
protein CD4, function through cytokine signaling, such as interferon gamma (IFNγ) and tumor necrosis
factor alpha (TNFα), which stimulate other immune cells . Cytotoxic T cells, which express the cell-
[16]
surface protein CD8, program invading cells to undergo apoptosis via the secretion of granzyme B,
perforin, and IFNγ . Unlike effector and cytotoxic T cells, regulatory T cells function to suppress
[16]
immune cells to mitigate any possible damage from a prolonged immune response, and to prevent
auto-immunity . They can be identified through flow cytometry by the expression of CD4, CD25, and
[16]
FoxP3 .
[16]
In order to activate a T cell-mediated immune response, two different signals are required. The first signal
occurs when the disease-causing cell presents an antigen, or host-derived protein molecule, to a T cell
[Figure 1]. Specifically, short peptide fragments of an antigen are presented on the surface of host cells,
termed antigen-presenting cells (APCs), by major histocompatibility complex (MHC) molecules. There are
two classes of MHC molecules, MHC class I and MHC class II. Notably, CD8+ T cells selectively recognize
MHC class I molecules, while CD4+ T cells selectively recognize MHC class II molecules. MHC class II
molecules are often expressed on dendritic cells and macrophages, which engulf the antigen and process it
for presentation. MHC class II molecules can also be present on the surface of foreign APCs. The Class II
[17]
transactivator (CIITA) is a master regulator of MHC gene expression . CIITA responds to IFNγ activation,
where it then acts as a transcriptional activator to turn on MHC gene expression .
[17]
The second signal required for T cell activation is termed the co-stimulatory signal, and co-stimulation is
thought to occur through the interaction between the CD28 molecule on T-lymphocytes and either CD80
(B7.1) or CD86 (B7.2) molecules on the APC [Figure 1]. The discovery of CD28 and its essential role in T
[18]
cell activation has led to further discovery of other cell-surface molecules that regulate T cell activity.
Interestingly, the discovery of cytotoxic T lymphocyte antigen 4 (CTLA4) on T cells identified another
binding partner of B7-1. However, CTLA4 expression is induced following T cell activation, where it can
out-compete CD28 binding to B7.1 to dampen the T cell response .
[18]
This has led to the discovery and categorization of other cell-surface molecules that positively (referred to as
co-stimulatory receptors) and negatively (co-inhibitory receptors) modulate T cell activity. Other
co-inhibitory receptors on T cells include programmed cell death protein 1 (PD1), which binds to its ligands
programmed death-ligand 1 (PD-L1, also known as B7-H1) or programmed death-ligand 2 (PD-L2, also
known as B7-H2) on APCs; T cell immunoglobulin and mucin domain-containing protein 3 (TIM3), and
lymphocyte activation gene-3 (LAG3) [19,20] . TIM3 binds to various ligands (including Galectin-9, Ceacam-1,
and HMGB-1), while LAG3 binds to MHC class II molecules with higher affinity than the CD4+ TCR [19,20] .
Other co-inhibitory ligands on APCs include B7-H3, B7-H4, and B7-H5 .
[21]

MECHANISMS OF IMMUNE EVASION IN AML
There are currently several different immunotherapy strategies being investigated in hematologic
malignancies, including in AML [11,21] . Immune checkpoint inhibitors, such as antibodies targeting CTLA4
and PD1, have been approved for the treatment of some types of lymphoma and some solid tumors,
including melanoma, lung cancer, kidney cancer, head and neck cancer, bladder cancer, and colorectal