**2. Mechanisms of immune checkpoint therapy (ICT)**

T cells enable to distinguish tumor cells from normal cells and launch attack accordingly, which plays a critical role in maintaining appropriate immune responses. However, such immunologic effects may be prevented in the TME. The prevention of T cells activation in the presence of antigen is related with the T cells dysfunction and inhibiting the receptors expression, such as those of CTLA-4 and PD-1 [9] ICP aim to block such inhibition and reverse the immunosuppressive TME, thus achieving functions mainly by activating normal immune system to eradicate cancer cells. Despite a few overlaps in inhibitory roles, each checkpoint inhibitor also performs some unique functions.

#### **2.1 CTLA-4**

The normal T cell activation requires the binding of CD28 on T cells with co-stimulatory B7 molecules (CD80 and CD86) on DC surface, also known as *Immune Checkpoint and Tumor Therapy DOI: http://dx.doi.org/10.5772/intechopen.107203*

**Figure 2.**

*Scheme illustration showing the mechanism of (A) CTLA-4 blockade; and (B) PD-1 Blockade.*

signal 2 of T-cell receptors (TCR) activation [10]. However, CTLA-4 which is expressed on the surface of late-stage T cells can competitively bind with CD80/ CD86 to prevent T-cell activation [5]. Regarding this, blockade with monoclonal antibody against CTLA-4 enables to proceed CD28/B7 pathway and restore T-cells activity. CTLA-4 is also constitutively overexpressed on regulatory T cells (Tregs), which can mediate dendritic cell (DC) function inhibition and suppress the T cell response against tumors [11]. Additionally, CTLA-4 was reported to be expressed in some other cells such as activated B cells, placental fibroblasts and monocytes, and may playing roles in immune regulation of other cells. For instance, it is associated with decreased circulating B cell amounts and antibody expression levels [12]. Of note, the exact cellular mechanisms underlying CTLA-4 blockade remains to be investigated and different anti-CTLA-4 antibody has distinct properties (**Figure 2**) [13].

#### **2.2 PD-1/PD-L1**

In normal physiological conditions, ICIs can modulate T cell activity and protect healthy tissues from immune attack. T cell activity can be suspended by the binding of PD-1 on T-cells with its ligands programmed death ligand 1 (PD-L1) and programmed death ligand 2 (PD-L2) which are largely distributed on tumor cells and DCs. Regarding this, PD1 PD-L1/2 blockade by using monoclonal antibody can lead to restoration of T cell activity. PD-L2 shows higher affinity to PD-1 but with more limited expression profile and is mainly expressed on activated DCs, macrophages, and some B cells [14]. PD-L1 is more widely expressed on DCs, macrophages, T and B cells, as well as some cell types in non-hematologic tissues, such as epithelia, endothelial cells, astrocytes and neurons.

#### **2.3 Other immune checkpoints**

Some other ICI molecules under investigation include positive regulators such as tumor necrosis factor receptor superfamily membrane 9 (4-1BB) and tumor necrosis factor receptor superfamily member 4 (OX-40), and negative regulators such as T-cell immunoglobulin and mucin domain (TIM-3) and lymphocyte activation gene-3 (LAG-3) [5]. These immune checkpoints also have been recognized for their roles in regulating tumor immunity and elicits antitumor response.
