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4.1 Cancer immunotherapy 71

by recombination of ligands or receptors. The different immune checkpoints can be
referred to as CTLA4, PD-1, PD-L1, LAG 3, B7-H3, B7-H4, CD27, and CD70. Cyto-
toxic T lymphocyte antigen 4 (CTLA-4), and programmed cell death1/programmed
cell death ligand (PD-1/PD-L1) are the two most studied immune check points.

4.1.1.1 CTLA4
The first FDA approved strategy in the immunotherapeutics category was CTLA-4
antibodies [4]. CTLA-4 (also named CD152) is expressed on regulatory T cells (T )
reg
and modulated on activated CD8+ effector T cells. It works by binding to its ligands,
CD80 (B7-1) or CD86 (B7-2) on the surface of antigen presenting cells (APC).
The route of T cell activation includes multiple activating signals. CD28, which is
expressed on T cells, binds to the same ligands of CTLA-4, providing a principal
co-stimulatory signal for subsequent T cell activation after the T cell receptor (TCR)
signaling. Moreover, CTLA-4 also participates in the immune regulation of CD4+ T
cells. CTLA-4 is expressed on activated CD8+ effector T cells, and seems to operate
through two main subtypes of CD4+ T cells: downregulating the activity of helper
T cells, and boosting immunosuppression of T . Recent research has also demon-
reg
strated that the T -specific CTLA4 blockade could noticeably reduce the regulation
reg
of both auto-immunity and antitumor immunity. Hence, the mechanism of CTLA4
blockade, both the increase of CTLA-4/B7 binding and inhibition of T -dependent
reg
immunosuppression can be a cancer treatment strategy.
4.1.1.2 PD-1
PD-1, also known as CD279, is one of the main immune checkpoints that restrains
an excessive immune response and thus inhibits autoimmunity. The difference of
PD-1 with other members of CD28/CTLA-4 family is the absence of an extracellular
cysteine residue preventing the creation of covalent dimers [5].
Unlike the CTLA4, the main role of PD-1 is to restrict the activity of T cells in
peripheral tissues at the time of an inflammatory response to an infection and to
restrict autoimmunity. PD-1 expression is stimulated when T cells become activated.
When actuated by one of its ligands, PD-1 impedes kinases that are required in T
cell activation through the phosphatase SHP 250, although extra signaling pathways
are also most likely stimulated. Also, because PD-1 engagement impedes the TCR
‘stop signal,’ this pathway could improve the duration of T cell—APC or T cell—
target cell contact. PD-1, like CTLA4, is greatly expressed on T cells, where their
reg
proliferation may be increased in the presence of the ligand. Since many tumors
are extremely infiltrated with T cells, probably suppress more effector immune
reg
responses, blockade of the PD-1 pathway may also increase antitumor immune
responses by reducing the number and/or the suppressive activity of intratumoral
T cells.
reg
The ligands of PD-1 consist of PD-L1 (also known as B7-H1, CD274) and PD-L2
(also known as B7-DC, CD273). However, separate from PD-1, PD-L1 can also
connect to B7-1 (CD80) and PD-L2 can connect to repulsive guidance molecule B
(RGMb). The expression of PD-L1 on T cells, B cells, endothelial and epithelial cells