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http://dx.doi.org/10.5483/BMBRep.2021.54.1.229

Hitting the complexity of the TIGIT-CD96-CD112R-CD226 axis for next-generation cancer immunotherapy  

Jin, Hyung-seung (Department of Convergence Medicine, Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine)
Park, Yoon (Theragnosis Research Center, Biomedical Research Division, Korea Institute of Science and Technology (KIST))
Publication Information
BMB Reports / v.54, no.1, 2021 , pp. 2-11 More about this Journal
Abstract
Antibody-based therapeutics targeting the inhibitory receptors PD-1, PD-L1, or CTLA-4 have shown remarkable clinical progress on several cancers. However, most patients do not benefit from these therapies. Thus, many efforts are being made to identify new immune checkpoint receptor-ligand pathways that are alternative targets for cancer immunotherapies. Nectin and nectin-like molecules are widely expressed on several types of tumor cells and play regulatory roles in T- and NK-cell functions. TIGIT, CD226, CD96 and CD112R on lymphoid cells are a group of immunoglobulin superfamily receptors that interact with Nectin and nectin-like molecules with different affinities. These receptors transmit activating or inhibitory signals upon binding their cognate ligands to the immune cells. The integrated signals formed by their complex interactions contribute to regulating immune-cell functions. Several clinical trials are currently evaluating the efficacy of anti-TIGIT and anti-CD112R blockades for treating patients with solid tumors. However, many questions still need to be answered in order to fully understand the dynamics and functions of these receptor networks. This review addresses the rationale behind targeting TIGIT, CD226, CD96, and CD112R to regulate T- and NK-cell functions and discusses their potential application in cancer immunotherapy.
Keywords
Cancer immunotherapy; CD112R; CD226; CD96; TIGIT;
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1 O'Brien SM, Klampatsa A, Thompson JC et al (2019) Function of human tumor-infiltrating lymphocytes in earlystage non-small cell lung cancer. Cancer Immunol Res 7, 896-909   DOI
2 Ostroumov D, Duong S, Wingerath J et al (2020) Transcriptome profiling identifies TIGIT as a marker of T cell exhaustion in liver cancer. Hepatology [Online ahead of print]
3 Stalhammar G, Seregard S, Grossniklaus HE (2019) Expression of immune checkpoint receptors Indoleamine 2,3-dioxygenase and T cell Ig and ITIM domain in metastatic versus nonmetastatic choroidal melanoma. Cancer Med 8, 2784-2792   DOI
4 Xu D, Zhao E, Zhu C et al (2020) TIGIT and PD-1 may serve as potential prognostic biomarkers for gastric cancer. Immunobiology 225, 151915   DOI
5 Wu L, Mao L, Liu JF et al (2019) Blockade of TIGIT/CD155 signaling reverses T-cell exhaustion and enhances antitumor capability in head and neck squamous cell carcinoma. Cancer Immunol Res 7, 1700-1713   DOI
6 Lucca LE, Lerner BA, Park C et al (2020) Differential expression of the T-cell inhibitor TIGIT in glioblastoma and MS. Neurol Neuroimmunol Neuroinflamm 7, e712   DOI
7 Jin HS, Ko M, Choi DS et al (2020) CD226(hi)CD8(+) T cells are a prerequisite for anti-TIGIT immunotherapy. Cancer Immunol Res 8, 912-925   DOI
8 McLane LM, Abdel-Hakeem MS, Wherry EJ (2019) CD8 T cell exhaustion during chronic viral infection and cancer. Annu Rev Immunol 37, 457-495   DOI
9 Hashimoto M, Kamphorst AO, Im SJ et al (2018) CD8 T cell exhaustion in chronic infection and cancer: opportunities for interventions. Annu Rev Med 69, 301-318   DOI
10 Tang W, Pan X, Han D et al (2019) Clinical significance of CD8(+) T cell immunoreceptor with Ig and ITIM domains(+) in locally advanced gastric cancer treated with SOX regimen after D2 gastrectomy. Oncoimmunology 8, e1593807   DOI
11 Gibney GT, Weiner LM, Atkins MB (2016) Predictive biomarkers for checkpoint inhibitor-based immunotherapy. Lancet Oncol 17, e542-e551   DOI
12 Thommen DS, Schumacher TN (2018) T cell dysfunction in cancer. Cancer Cell 33, 547-562   DOI
13 Chen DS, Mellman I (2013) Oncology meets immunology: the cancer-immunity cycle. Immunity 39, 1-10   DOI
14 Ribas A, Wolchok JD (2018) Cancer immunotherapy using checkpoint blockade. Science 359, 1350-1355   DOI
15 Zaretsky JM, Garcia-Diaz A, Shin DS et al (2016) Mutations associated with acquired resistance to PD-1 blockade in melanoma. N Engl J Med 375, 819-829   DOI
16 Kong X (2018) Discovery of new immune checkpoints: family grows up. Adv Exp Med Biol 1248, 61-82   DOI
17 Chiu DK, Yuen VW, Wing-Sum Cheu J et al (2020) Hepatocellular carcinoma cells up-regulate PVRL1, stabilizing poliovirus receptor and inhibiting the cytotoxic T-cell response via TIGIT to mediate tumor resistance to PD1 inhibitors in mice. Gastroenterology 159, 609-623   DOI
18 Duan X, Liu J, Cui J et al (2019) Expression of TIGIT/CD155 and correlations with clinical pathological features in human hepatocellular carcinoma. Mol Med Rep 20, 3773-3781
19 Fourcade J, Sun Z, Chauvin JM et al (2018) CD226 opposes TIGIT to disrupt Tregs in melanoma. JCI Insight 3, e121157   DOI
20 Dixon KO, Schorer M, Nevin J et al (2018) Functional anti-TIGIT antibodies regulate development of autoimmunity and antitumor immunity. J Immunol 200, 3000-3007   DOI
21 Lee BR, Chae S, Moon J et al (2020) Combination of PD-L1 and PVR determines sensitivity to PD-1 blockade. JCI Insight 5, e128633   DOI
22 Jin HS, Choi DS, Ko M et al (2019) Extracellular pH modulating injectable gel for enhancing immune checkpoint inhibitor therapy. J Control Release 315, 65-75   DOI
23 Whelan S, Ophir E, Kotturi MF et al (2019) PVRIG and PVRL2 are induced in cancer and inhibit CD8(+) T-cell function. Cancer Immunol Res 7, 257-268   DOI
24 Rotte A, Jin JY, Lemaire V (2018) Mechanistic overview of immune checkpoints to support the rational design of their combinations in cancer immunotherapy. Ann Oncol 29, 71-83   DOI
25 Chan CJ, Andrews DM, Smyth MJ (2012) Receptors that interact with nectin and nectin-like proteins in the immunosurveillance and immunotherapy of cancer. Curr Opin Immunol 24, 246-251   DOI
26 Sanchez-Correa B, Valhondo I, Hassouneh F et al (2019) DNAM-1 and the TIGIT/PVRIG/TACTILE axis: novel immune checkpoints for natural killer cell-based cancer immunotherapy. Cancers (Basel) 11, 877   DOI
27 Wang B, Zhang W, Jankovic V et al (2018) Combination cancer immunotherapy targeting PD-1 and GITR can rescue CD8(+) T cell dysfunction and maintain memory phenotype. Sci Immunol 3, eaat7061   DOI
28 Hung AL, Maxwell R, Theodros D et al (2018) TIGIT and PD-1 dual checkpoint blockade enhances antitumor immunity and survival in GBM. Oncoimmunology 7, e1466769   DOI
29 Fuhrman CA, Yeh WI, Seay HR et al (2015) Divergent phenotypes of human regulatory T cells expressing the receptors TIGIT and CD226. J Immunol 195, 145-155   DOI
30 Grapin M, Richard C, Limagne E et al (2019) Optimized fractionated radiotherapy with anti-PD-L1 and anti-TIGIT: a promising new combination. J Immunother Cancer 7, 160   DOI
31 Nakanishi H, Takai Y (2004) Roles of nectins in cell adhesion, migration and polarization. Biol Chem 385, 885-892   DOI
32 Marin-Acevedo JA, Soyano AE, Dholaria B, Knutson KL, Lou Y (2006) Cancer immunotherapy beyond immune checkpoint inhibitors. J Hematol Oncol 11, 8   DOI
33 Gorvel L, Olive D (2020) Targeting the "PVR-TIGIT axis" with immune checkpoint therapies. F1000Res 9, F1000 Faculty Rev-354
34 Fuchs A, Colonna M (2006) The role of NK cell recognition of nectin and nectin-like proteins in tumor immunosurveillance. Semin Cancer Biol 16, 359-366   DOI
35 Zhang Q, Bi J, Zheng X et al (2018) Blockade of the checkpoint receptor TIGIT prevents NK cell exhaustion and elicits potent anti-tumor immunity. Nat Immunol 19, 723-732   DOI
36 Iguchi-Manaka A, Kai H, Yamashita Y et al (2008) Accelerated tumor growth in mice deficient in DNAM-1 receptor. J Exp Med 205, 2959-2964   DOI
37 Shibuya K, Lanier LL, Phillips JH (1999) Physical and functional association of LFA-1 with DNAM-1 adhesion molecule. Immunity 11, 615-623   DOI
38 Enqvist M, Ask EH, Forslund E et al (2015) Coordinated expression of DNAM-1 and LFA-1 in educated NK cells. J Immunol 194, 4518-4527   DOI
39 Shibuya A, Campbell D, Hannum C et al (1996) DNAM-1, a novel adhesion molecule involved in the cytolytic function of T lymphocytes. Immunity 4, 573-581   DOI
40 Sanchez-Correa B, Gayoso I, Bergua JM et al (2012) Decreased expression of DNAM-1 on NK cells from acute myeloid leukemia patients. Immunol Cell Biol 90, 109-115   DOI
41 Carlsten M, Norell H, Bryceson YT (2009) Primary human tumor cells expressing CD155 impair tumor targeting by down-regulating DNAM-1 on NK cells. J Immunol 183, 4921-4930   DOI
42 Kucan Brlic P, Lenac Rovis T, Cinamon G, Tsukerman P, Mandelboim O, Jonjic S (2019) Targeting PVR (CD155) and its receptors in anti-tumor therapy. Cell Mol Immunol 16, 40-52   DOI
43 Nishiwada S, Sho M, Yasuda S et al (2015) Clinical significance of CD155 expression in human pancreatic cancer. Anticancer Res 35, 2287-2297
44 Triki H, Charfi S, Bouzidi L et al (2019) CD155 expression in human breast cancer: clinical significance and relevance to natural killer cell infiltration. Life Sci 231, 116543   DOI
45 Joller N, Hafler JP, Brynedal B et al (2011) Cutting edge: TIGIT has T cell-intrinsic inhibitory functions. J Immunol 186, 1338-1342   DOI
46 Fuchs A, Cella M, Giurisato E, Shaw AS, Colonna M (2004) Cutting edge: CD96 (tactile) promotes NK cell-target cell adhesion by interacting with the poliovirus receptor (CD155). J Immunol 172, 3994-3998   DOI
47 Gilfillan S, Chan CJ, Cella M et al (2008) DNAM-1 promotes activation of cytotoxic lymphocytes by nonprofessional antigen-presenting cells and tumors. J Exp Med 205, 2965-2973   DOI
48 Minnie SA, Kuns RD, Gartlan KH et al (2018) Myeloma escape after stem cell transplantation is a consequence of T-cell exhaustion and is prevented by TIGIT blockade. Blood 132, 1675-1688
49 Jin Z, Lan T, Zhao Y et al (2020) Higher TIGIT(+)CD226(-) gammadelta T cells in patients with acute myeloid leukemia. Immunol Invest 1-11 [Online ahead of print]
50 Liu S, Zhang H, Li M et al (2013) Recruitment of Grb2 and SHIP1 by the ITT-like motif of TIGIT suppresses granule polarization and cytotoxicity of NK cells. Cell Death Differ 20, 456-464   DOI
51 Chan CJ, Martinet L, Gilfillan S et al (2014) The receptors CD96 and CD226 oppose each other in the regulation of natural killer cell functions. Nat Immunol 15, 431-438   DOI
52 Lakshmikanth T, Burke S, Ali TH et al (2009) NCRs and DNAM-1 mediate NK cell recognition and lysis of human and mouse melanoma cell lines in vitro and in vivo. J Clin Invest 119, 1251-1263   DOI
53 Zhu Y, Paniccia A, Schulick AC et al (2016) Identification of CD112R as a novel checkpoint for human T cells. J Exp Med 213, 167-176   DOI
54 Yu X, Harden K, Gonzalez LC et al (2009) The surface protein TIGIT suppresses T cell activation by promoting the generation of mature immunoregulatory dendritic cells. Nat Immunol 10, 48-57   DOI
55 Stanietsky N, Rovis TL, Glasner A et al (2013) Mouse TIGIT inhibits NK-cell cytotoxicity upon interaction with PVR. Eur J Immunol 43, 2138-2150   DOI
56 Deuss FA, Watson GM, Fu Z, Rossjohn J, Berry R (2019) Structural basis for CD96 immune receptor recognition of nectin-like protein-5, CD155. Structure 27, 219-228   DOI
57 Okumura G, Iguchi-Manaka A, Murata R, Yamashita-Kanemaru Y, Shibuya A, Shibuya K (2020) Tumor-derived soluble CD155 inhibits DNAM-1-mediated antitumor activity of natural killer cells. J Exp Med 217, 1
58 Weulersse M, Asrir A, Pichler AC et al (2020) Eomesdependent loss of the co-activating receptor CD226 restrains CD8(+) T cell anti-tumor functions and limits the efficacy of cancer immunotherapy. Immunity 53, 824-839   DOI
59 Pende D, Castriconi R, Romagnani P et al (2006) Expression of the DNAM-1 ligands, nectin-2 (CD112) and poliovirus receptor (CD155), on dendritic cells: relevance for natural killer-dendritic cell interaction. Blood 107, 2030-2036   DOI
60 Seth S, Maier MK, Qiu Q et al (2007) The murine pan T cell marker CD96 is an adhesion receptor for CD155 and nectin-1. Biochem Biophys Res Commun 364, 959-965   DOI
61 Satoh-Horikawa K, Nakanishi H, Takahashi K (2000) Nectin-3, a new member of immunoglobulin-like cell adhesion molecules that shows homophilic and heterophilic cell-cell adhesion activities. J Biol Chem 275, 10291-10299   DOI
62 Reches A, Ophir Y, Stein N et al (2020) Nectin4 is a novel TIGIT ligand which combines checkpoint inhibition and tumor specificity. J Immunother Cancer 8, e000266   DOI
63 Mittal D, Lepletier A, Madore J et al (2019) CD96 is an immune checkpoint that regulates CD8(+) T-cell antitumor function. Cancer Immunol Res 7, 559-571   DOI
64 Braun M, Aguilera AR, Sundarrajan A et al (2020) CD155 on tumor cells drives resistance to immunotherapy by inducing the degradation of the activating receptor CD226 in CD8(+) T cells. Immunity 53, 805-823   DOI
65 Georgiev H, Ravens I, Papadogianni G, Bernhardt G (2018) Coming of age: CD96 emerges as modulator of immune responses. Front Immunol 9, 1072   DOI
66 Lepletier A, Lutzky VP, Mittal D et al (2019) The immune checkpoint CD96 defines a distinct lymphocyte phenotype and is highly expressed on tumor-infiltrating T cells. Immunol Cell Biol 97, 152-164   DOI
67 Sun H, Huang Q, Huang M et al (2019) Human CD96 correlates to natural killer cell exhaustion and predicts the prognosis of human hepatocellular carcinoma. Hepatology 70, 168-183   DOI
68 Peng YP, Xi CH, Zhu Y et al (2016) Altered expression of CD226 and CD96 on natural killer cells in patients with pancreatic cancer. Oncotarget 7, 66586-66594   DOI
69 Zhang Z, Wu N, Lu Y, Davidson D, Colonna M, Veillette A (2015) DNAM-1 controls NK cell activation via an ITT-like motif. J Exp Med 212, 2165-2182   DOI
70 Blake SJ, Stannard K, Liu J et al (2016) Suppression of metastases using a new lymphocyte checkpoint target for cancer immunotherapy. Cancer Discov 6, 446-459   DOI
71 Chiang EY, de Almeida PE, de Almeida Nagata DE et al (2020) CD96 functions as a co-stimulatory receptor to enhance CD8(+) T cell activation and effector responses. Eur J Immunol 50, 891-902   DOI
72 Meyer D, Seth S, Albrecht J et al (2009) CD96 interaction with CD155 via its first Ig-like domain is modulated by alternative splicing or mutations in distal Ig-like domains. J Biol Chem 284, 2235-2244   DOI
73 Joller N, Lozano E, Burkett PR et al (2014) Treg cells expressing the coinhibitory molecule TIGIT selectively inhibit proinflammatory Th1 and Th17 cell responses. Immunity 40, 569-581   DOI
74 Harjunpaa H, Guillerey C (2020) TIGIT as an emerging immune checkpoint. Clin Exp Immunol 200, 108-119   DOI
75 Chambers CA (2001) The expanding world of co-stimulation: the two-signal model revisited. Trends Immunol 22, 217-223   DOI
76 Roman Aguilera A, Lutzky VP, Mittal D et al (2018) CD96 targeted antibodies need not block CD96-CD155 interactions to promote NK cell anti-metastatic activity. Oncoimmunology 7, e1424677   DOI
77 Murter B, Pan X, Ophir E et al (2019) Mouse PVRIG has CD8(+) T cell-specific coinhibitory functions and dampens antitumor immunity. Cancer Immunol Res 7, 244-256   DOI
78 Xu F, Sunderland A, Zhou Y, Schulick RD, Edil BH, Zhu Y (2017) Blockade of CD112R and TIGIT signaling sensitizes human natural killer cell functions. Cancer Immunol Immunother 66, 1367-1375   DOI
79 Lozano E, Dominguez-Villar M, Kuchroo V, Hafler DA (2012) The TIGIT/CD226 axis regulates human T cell function. J Immunol 188, 3869-3875   DOI
80 Johnston RJ, Comps-Agrar L, Hackney J et al (2014) The immunoreceptor TIGIT regulates antitumor and antiviral CD8(+) T cell effector function. Cancer Cell 26, 923-937   DOI
81 Kurtulus S, Sakuishi K, Ngiow SF et al (2015) TIGIT predominantly regulates the immune response via regulatory T cells. J Clin Invest 125, 4053-4062   DOI
82 Yang ZZ, Kim HJ, Wu H et al (2020) TIGIT expression is associated with T-cell suppression and exhaustion and predicts clinical outcome and anti-PD-1 response in follicular lymphoma. Clin Cancer Res 26, 5217-5231   DOI
83 Kong Y, Zhu L, Schell TD et al (2016) T-cell immunoglobulin and ITIM domain (TIGIT) associates with CD8+ T-cell exhaustion and poor clinical outcome in AML patients. Clin Cancer Res 22, 3057-3066   DOI
84 Chauvin JM, Pagliano O, Fourcade J et al (2015) TIGIT and PD-1 impair tumor antigen-specific CD8(+) T cells in melanoma patients. J Clin Invest 125, 2046-2058   DOI
85 Guillerey C, Harjunpaa H, Carrie N et al (2018) TIGIT immune checkpoint blockade restores CD8(+) T-cell immunity against multiple myeloma. Blood 132, 1689-1694   DOI
86 He W, Zhang H, Han F et al (2017) CD155T/TIGIT signaling regulates CD8(+) T-cell metabolism and promotes tumor progression in human gastric cancer. Cancer Res 77, 6375-6388   DOI