*1.1.1 Programmed cell death 1*

PD-1 is mainly expressed on mature effector T cells within the peripheral and tumor microenvironment [4], responsible for immune tolerance. Besides T cells, PD-1 expression is also found on B cells, natural killer (NK) cells, dendritic cells (DCs), macrophages, and monocytes [5]. Therefore, it is an inhibitor of both innate and adaptive immunity. In cancers, numerous pathways are responsible for the upregulation of PD-1/PD-L1 signaling; and these major pathways include phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) pathway, mitogen-activated protein kinase (MAPK) pathway, Jak-Stat pathway, Wnt pathway, NF-κB pathway, and Hedgehog (Hh) pathway [6]. Upon interaction with its ligands, programmed **cell death-ligand 1** or 2 (PD-L1 or PD-L2) expressed on cancer cells or antigen-presenting cells (APCs) of the tumor microenvironments [7–9], PD-1 signaling leads to T cell dysfunction, reduced cytokine production and anergy, thus protecting cancer cells from immune attack [10].

However, the detailed underlying mechanism of PD-1 signaling requires further elucidation. The inhibitory signal transduction of PD-1 needs both the interaction of PD-1/PD-L1 and peptide/MHC class I complex (MHC-I) from the same cells [11]. Src homology region 2 domain-containing phosphatase-2 (SHP-2) is a major downstream mediator of PD-1 and is capable of inhibiting key molecules and pathways such as ZAP70, PI3K/Akt pathway, and Ras pathway. Ultimately, PD-1 signaling counters the T-cell receptor (TCR) cascade and co-stimulatory receptor CD28 signaling in T cells, leading to reduced T cell activation and proliferation [11, 12]. Moreover, PD-1 can

#### **Figure 1.**

*Major immune checkpoints on T cells. PD-1 and CTLA-4 are the major co-inhibitory receptors expressed on activated T cells. Through ZAP70, PD-1 signaling is able to inhibit ZAP70, PI3K/Akt pathway, and Ras pathway, resulting in reduced T-cell activation. PD-1 can also directly induce T cell exhaustion by upregulating BATF. Furthermore, PD-L1 protects cancer cells in a PD-1-independent manner. CTLA-4 is a competitive inhibitor of co-stimulatory receptor CD28. It also inhibits T cell function via inhibition of ZAP70, PI3K/Akt pathway, cell-cycle progression, and trans-endocytosis of CD80/CD86.*

#### *Immune Checkpoint Inhibitors in Hodgkin Lymphoma and Non-Hodgkin Lymphoma DOI: http://dx.doi.org/10.5772/intechopen.107435*

directly exhaust T cells by upregulating the basic leucine transcription factor, ATF-like (BATF) [13]. Interestingly, PD-L1 may protect cancer cells in a PD-1 independent manner, leading to inhibition of autophagy and activation of mammalian target of rapamycin (mTOR; **Figure 1**) [14]. In addition, PD-1 is also highly expressed on regulatory T cells (Treg), enhancing its proliferation and immunosuppressive effects [12].

#### *1.1.2 Cytotoxic T-lymphocyte-associated protein 4*

In contrast to PD-1, CTLA-4 is mainly expressed in the endocytic vesicles of naïve T cells, and it translocates to the cell surface upon TCR activation. CTLA-4 shares the same ligands (CD80 and CD86) with co-stimulatory receptor CD28 (as competitive binding with higher affinity). Therefore, it can suppress T-cell activation [15, 16]. In addition, like PD-1, CTLA-4 is also able to directly inhibit ZAP70 to suppress TCR signaling and reverse T cell activation [17, 18]. Moreover, CTLA-4 exerts its immunosuppressive function via inhibition of PI3K/Akt pathway, cell-cycle progression, and removal of CD80/CD86 from the APCs via trans-endocytosis (**Figure 1**) [19–22]. Similar to PD-1, CTLA-4 is constitutively expressed in Tregs for immunosuppression and ligand (CD80/CD86) masking [4].

#### *1.1.3 Blockade of immune checkpoints for cancer therapy*

In cancers, the suppressive immune checkpoints introduced above are likely dysregulated, allowing them to escape from immune surveillance [23]. Therefore, blocking such immune checkpoints by antibodies is able to reverse the immune suppression for the treatment of cancers [24]. Preclinical studies have indicated that inhibition of immune checkpoints is able to enhance anti-tumor immunity. In the 1990s, initial research already indicated that the blockade of CTLA-4 by antibodies is able to reduce tumor burden in murine models [25, 26]. Since then, enormous advancements have been achieved in the use of immune checkpoint inhibition in cancer treatment, and the monoclonal antibodies targeting CTLA-4 and PD-1 have been approved by US Food and Drug Administration (FDA) for different cancers [27, 28]. In the following part of the chapter, we will summarize the current applications of immune checkpoint inhibitors (ICIs) for Hodgkin lymphomas (HLs) and non-Hodgkin lymphomas (NHLs).
