**6. Other immune checkpoints under investigation**

Apart from the above two immune checkpoints, a variety of other immune stimulatory and suppressive checkpoints are currently under investigation as immunotherapy targets that include; TIM-3, LAG-3, TIGIT, VISTA and BTLA-4, these reduce the anti-tumor immune response by regulating T cell activity like CTLA-4 and PD-1. Among them TIM 3, BTLA-4 and LAG-3 are implicated as T cell exhaustion markers in tumors same as that of PD-1. TIM 3 negatively regulates the cytotoxic CD8 T cells and Th1 CD4 T cells, thereby shifting the immune responses. TIGIT is expressed by a number of cells such as: T cells, Treg cells and NK cells


#### **Table 2.**

*Immune checkpoints in immunotherapy.*

#### *Integrating Immunotherapy with Chemotherapy: A New Approach to Drug Repurposing DOI: http://dx.doi.org/10.5772/intechopen.100183*

and is known to bind to poliovirus receptor on APCs or tumor cells. It is supposed to perform both direct and indirect immunosuppressive effects by competitively binding to NK and T cell receptors in place of CD226; it also leads to downstream inhibition of AKT signaling in T cells [14, 44]. In addition, TIGIT increases the suppressive activity and releases inhibitory cytokines by receptor binding of TIGIT on the APCs and Tregs [45]. Moreover, VISTA is expressed by both APCs and T cells play a role in both Treg function and myeloid cell activation [14].

On the contrary, other checkpoints like OX40, ICOS and CD40L are immunostimulatory checkpoints that function in the maintenance and activation of effector T cells. The expression of OX40 is induced at the time of T-cell activation leading to the expression of anti-apoptotic factors such as BCL-2 and BCL-XL that leads to the sustenance of T cells proliferation. It also acts as a co-stimulatory signal in tumor induction and is constitutively expressed on Tregs and OX40 also decreases the Treg function by binding to its receptor on Treg [46–48]. Furthermore, ICOS leads to the activation of second signal in immune activation by binding to B7H/B7RP-1 [49]. Another immunostimulatory checkpoint CD40L interacts with CD40 on APCs induces via NF-ƙB signaling a proinflammatory immune response **Table 2** [14].

The immunostimulatory checkpoints can be inhibited by therapeutic agents targeting recombinant ligand peptides, ligands expressing viral particles or agonistic monoclonal antibody that is in contrast, to the inhibitory checkpoints where monoclonal antibodies inhibit the interaction between the respective ligand and receptors. Therefore, there is an emerging need to fully explore these biomarkers for better prognosis of patients using immunotherapy strategy [14].
