pharmaceuticals Review TIGIT/CD226 Axis Regulates Anti-Tumor Immunity Jinah Yeo 1,†, Minkyung Ko 1,† , Dong-Hee Lee 2, Yoon Park 1,* and Hyung-seung Jin 2,* 1 Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology (KIST), Seoul 02792, Korea; [email protected] (J.Y.); [email protected] (M.K.) 2 Department of Convergence Medicine, Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul 44610, Korea; [email protected] * Correspondence: [email protected] (Y.P.); [email protected] (H.-s.J.); Tel.: +82-2-958-5945 (Y.P.); +82-2-3010-0207 (H.-s.J.) † Both authors contributed equally to this work. Abstract: Tumors escape immune surveillance by inducing various immunosuppressive pathways, including the activation of inhibitory receptors on tumor-infiltrating T cells. While monoclonal anti- bodies (mAbs) blocking programmed cell death 1 (PD-1), programmed death-ligand 1 (PD-L1), and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) have been approved for multiple cancer indica- tions, only a subset of patients benefit from immune checkpoint blockade therapies, highlighting the need for additional approaches. Therefore, the identification of new target molecules acting in distinct or complementary pathways in monotherapy or combination therapy with PD-1/PD-L1 blockade is gaining immense interest. T cell immunoreceptor with Ig and immunoreceptor tyrosine-based in- hibitory motif (ITIM) domains (TIGIT) has received considerable attention in cancer immunotherapy. Recently, anti-TIGIT mAb (tiragolumab) has demonstrated promising clinical efficacy in non-small cell lung cancer treatment when combined with an anti-PD-L1 drug (Tecentriq), leading to phase III trial initiation. TIGIT is expressed mainly on T and natural killer cells; it functions as an inhibitory checkpoint receptor, thereby limiting adaptive and innate immunity. CD226 competes for binding Citation: Yeo, J.; Ko, M.; Lee, D.-H.; with the same ligands with TIGIT but delivers a positive stimulatory signal to the immune cells. Park, Y.; Jin, H.-s. TIGIT/CD226 Axis This review discusses the recent discoveries regarding the roles of TIGIT and CD226 in immune cell Regulates Anti-Tumor Immunity. function and their potential application in cancer immunotherapy. Pharmaceuticals 2021, 14, 200. https://doi.org/10.3390/ph14030200 Keywords: cancer immunotherapy; immune checkpoint blockade; CD226; TIGIT; PVR Academic Editor: Eduardo Castañón Álvarez Received: 31 January 2021 1. Introduction Accepted: 24 February 2021 Cancers harbor genetic alterations. The adaptive immune system discriminates be- Published: 28 February 2021 tween normal and cancer cells according to the protein products of these genetic alterations. T cells express T cell receptors (TCRs) that can recognize antigenic peptides presented Publisher’s Note: MDPI stays neutral by major histocompatibility complex (MHC) molecules [1,2]. Tumor antigens may trig- with regard to jurisdictional claims in ger anti-tumor T cell responses; however, tumor-infiltrating lymphocytes (TILs) fail to published maps and institutional affil- efficiently eradicate the cancer cells. This is largely because TILs become dysfunctional iations. or exhausted in the tumor environment, presumably due to persistent tumor antigen stimulation and the presence of immunosuppressive molecules. It is increasingly clear that exhausted T cells (Tex) are the major target population for immune checkpoint block- ade (ICB) therapy [3,4]. Tex cells exhibit distinct functional and phenotypic properties, Copyright: © 2021 by the authors. such as impaired proliferation, decreased cytokine production, and high expression of Licensee MDPI, Basel, Switzerland. co-inhibitory receptors including cytotoxic T lymphocyte-associated antigen-4 (CTLA-4, This article is an open access article CD152), programmed death-1 (PD-1, CD279), T cell immunoglobulin and mucin-domain distributed under the terms and containing protein-3 (TIM-3, CD366), lymphocyte activation gene-3 (LAG-3, CD223), and T conditions of the Creative Commons cell immunoreceptor with Ig and immunoreceptor tyrosine-based inhibitory motif (ITIM) Attribution (CC BY) license (https:// domains (TIGIT) [5]. Tumor-derived ligands that interact with the co-inhibitory receptors, creativecommons.org/licenses/by/ such as programmed death-ligand 1 (PD-L1), directly inhibit anti-tumor T cell responses, 4.0/). Pharmaceuticals 2021, 14, 200. https://doi.org/10.3390/ph14030200 https://www.mdpi.com/journal/pharmaceuticals Pharmaceuticals 2021, 14, 200 2 of 20 Pharmaceuticals 2021, 14, 200 2 of 20 thereby promoting tumor immune escape [6]. Blockade of the PD-1/PD-L1 pathway using either anti-PD-1 or anti-PD-L1 monoclonal antibodies (mAbs) has only been successful in therebya subset promoting of patients tumor with immune particular escape [6]. cancer Blockade types of the [7,8]. PD-1/PD-L1 Presently, pathway numerous using studies have eitherbeen anti-PD-1 conducted or anti-PD-L1 to improve monoclonal the antibodiestherapeutic (mAbs) efficacy has only of been PD-1/PD-L1 successful in blockades a [9–12]. subsetTIGIT of family patients withreceptors particular are cancer a cluster types of [7 ,immunoglobulin8]. Presently, numerous superfamily studies have beenreceptors, which in- conductedteract with to improve nectin theand therapeutic nectin-like efficacy molecules of PD-1/PD-L1 (Necls) blockades [13]. This [9–12 group]. TIGIT includes TIGIT, family receptors are a cluster of immunoglobulin superfamily receptors, which interact withCD226 nectin (also and nectin-likeknown as molecules DNAX accessory (Necls) [13]. molecule This group [DNAM]-1), includes TIGIT, CD96 CD226 (also (also known as T cell knownactivation, as DNAX increased accessory late molecule expression [DNAM]-1), [TAC CD96TILE]), (also and known CD112R as T cell (also activation, known as poliovirus increasedreceptor-related late expression immunoglobulin [TACTILE]), and domain-conta CD112R (also knownining as[PVRIG]) poliovirus [14]. receptor- Competitive or co- relatedoperative immunoglobulin interactions domain-containing between these [PVRIG]) receptors [14 ].and Competitive their cognate or cooperative ligands modulate im- interactions between these receptors and their cognate ligands modulate immune cell activationmune cell(Figure activation1)[15,16 (Figure] . Among 1) these, [15,16]. in the Among present these, study, in we the focus present on the rolesstudy, of we focus on the TIGITroles and of CD226TIGIT inand regulating CD226 T in and regulating natural killer T (NK)and cellnatural function killer and (NK) the potential cell function and the therapeuticpotential applicationtherapeutic of theseapplication receptors of in cancerthese receptors immunotherapies. in cancer immunotherapies. FigureFigure 1. 1.Interactions Interactions of T of cell T immunoreceptor cell immunoreceptor with Ig andwith immunoreceptor Ig and immunoreceptor tyrosine-based tyrosine-based in- inhib- hibitoryitory motif motif (ITIM) domains domains (TIGIT) (TIGIT) and and CD226 CD226 with nectinwith nectin and nectin-like and nectin-lik molecules.e molecules. TIGIT TIGIT and andCD226 CD226 are are mainly mainly expressed on on T andT an naturald natural killer killer (NK) (NK) cells. TIGITcells. hasTIGI multipleT has multiple ligands, ligands, includ- includinging poliovirus poliovirus receptor receptor (PVR), (PVR), nectin-2,nectin-2, nectin-3, nectin-3, and an nectin-4.d nectin-4. TIGIT TIGIT binds to binds nectin-2 to andnectin-2 and nectin-3 nectin-3with lower with lower affinity affinity than than PVR. PVR. Upon engagement, engagement, TIGIT TIGIT transmits transmits inhibitory inhibitory signals through signals through ITIM ITIMand and immunoglobulin immunoglobulin tyrosinetyrosine tail tail (ITT)-like (ITT)-like motifs mo intifs its cytoplasmic in its cytoplasmic domain. CD226 domain. interacts CD226 interacts withwith PVR PVR and and nectin-2 nectin-2 to deliver to deliver a positive a positive signal. TIGIT signal binds. TIGIT to PVR binds with to higher PVR affinitywith higher than affinity than CD226. The integrated signals formed by their complex interactions regulate immune-cell functions, CD226. The integrated signals formed by their complex interactions regulate immune-cell func- which is important for immunity and inflammatory responses. Interactions between receptors and tions, which is important for immunity and inflammatory responses. Interactions between recep- ligands are depicted by two-sided arrows. The arrows are proportional to the reported affinities of thetors interactions and ligands except are nectin-4. depicted by two-sided arrows. The arrows are proportional to the reported affinities of the interactions except nectin-4. 2. TIGIT 2.1. TIGIT Structure and Its Ligands TIGIT is a transmembrane glycoprotein comprising one immunoglobulin variable (IgV) domain, a type I transmembrane domain, and a cytoplasmic tail with an immuno- receptor tyrosine-based inhibitory motif (ITIM) and immunoglobulin tyrosine tail (ITT)- Pharmaceuticals 2021, 14, 200 3 of 20 2. TIGIT 2.1. TIGIT Structure and Its Ligands TIGIT is a transmembrane glycoprotein comprising one immunoglobulin variable (IgV) domain, a type I transmembrane domain, and a cytoplasmic tail with an immunore- ceptor tyrosine-based inhibitory motif (ITIM) and immunoglobulin tyrosine tail (ITT)-like motif [17–19]. The cytoplasmic tail of TIGIT initiates an inhibitory signaling cascade. Previ- ous studies have reported that ITT-like