Nowadays, ample evidence has shown the roles of immune checkpoints in cancer immunotherapy. Intriguingly, CD226, a well-known active receptor, it is increasingly being recognized and researched through the two articles published on Oct. 13 in Immunity. One suggests that CD226 is absence in CD8+T cells as tumor infiltrates, and the loss of CD226 limits the checkpoint blockaded efficacy and CD137 agonists . The other introduces that the degradation of CD226 induced by CD155 can enhance immune therapy resistance, whereas CD226 stimulation may represent a useful strategy to increase the efficacy immunotherapy .
The recent two researches have demonstrated that CD226 expression represents the important role for immune responses in cancer. CD226, as a focal point in cancer immunotherapy is making waves. In case you missed it, here are some highlights from CD226 studies to date.
 Braun M, Aguilera AR, et al., CD155 on Tumor Cells Drives Resistance to Immunotherapy by Inducing the Degradation of the Activating Receptor CD226 in CD8+T Cells[J]. Immunity, 2020, 53(4): 805-823.e15.
 Weulersse M, Asrir A, et al., Eomes-Dependent Loss of the Co-activating Receptor CD226 Restrains CD8+ T Cell Anti-tumor Functions and Limits the Efficacy of Cancer Immunotherapy [J]. Immunity, 2020, 53(4): 824-839.e10.
 Nicolas Reymond, Anne-Marie Imbert, et al., DNAM-1 and PVR Regulate Monocyte Migration through Endothelial Junctions [J]. Journal of Experimental Medicine, 2004; 199(10): 1331–1341.
 Mattana T C C, Santos A S, Fukui R T, et al., CD226 rs763361 Is Associated with the Susceptibility to Type 1 Diabetes and Greater Frequency of GAD65 Autoantibody in a Brazilian Cohort[J]. Mediators of Inflammation, 2014.
 Han, Wang, Jianxun, et al., Binding mode of the side-by-side two-IgV molecule CD226/DNAM-1 to its ligand CD155/Necl-5[J]. Proceedings of the National Academy of Sciences of the United States of America, 2018.
 Huang Z, Qi G, Miller J S, et al., CD226: An Emerging Role in Immunologic Diseases [J]. Frontiers in Cell and Developmental Biology, 2020, 8.
 Kojima H, Kanada H, Shimizu S, et al., CD226 Mediates Platelet and Megakaryocytic Cell Adhesion to Vascular Endothelial Cells [J]. Journal of Biological Chemistry, 2003, 278(38): 36748-36753.
 Kim J S, Shin B R, Lee H K, et al., Cd226−/− natural killer cells fail to establish stable contacts with cancer cells and show impaired control of tumor metastasis in vivo[J]. OncoImmunology, 2017.
 Bottino C, Castriconi R, Pende D, et al., Identification of PVR (CD155) and Nectin-2 (CD112) as cell surface ligands for the human DNAM-1 (CD226) activating molecule [J]. Journal of Experimental Medicin, 2003, 198(4): 557-567.
 Tahara-Hanaoka S, Miyamoto A, Hara A, et al., Identification and characterization of murine DNAM-1 (CD226) and its poliovirus receptor family ligands [J]. Biochemical and Biophysical Research Communications, 2005, 329(3): 996-1000.
 Pende D, Castriconi R, Romagnani P, et al., Expression of the DNAM-1 ligands, Nectin-2 (CD112) and poliovirus receptor (CD155), on dendritic cells: relevance for natural killer-dendritic cell interaction [J]. Blood, 2006, 107(5): 2030-2036.
 Lozano E, Joller N, Cao Y, et al., The CD226/CD155 interaction regulates the proinflammatory (Th1/Th17)/anti-inflammatory (Th2) balance in humans [J]. Journal of Immunology, 2013, 191(7): 3673-3680.
 Iguchi-Manaka A, Okumura G, Ichioka E, et al., High expression of soluble CD155 in estrogen receptor-negative breast cancer [J]. Breast Cancer, 2020, 27(1): 92-99.
 Wagner A K, Kadri N, Sn?Ll J, et al., Expression of CD226 is associated to but not required for NK cell education[J]. Nature Communications, 2017, 8: 15627.
 Fourcade J, Sun Z, Chauvin JM, et al., CD226 opposes TIGIT to disrupt Tregs in melanoma [J]. JCI Insight, 2018, 26, 3(14): e121157.
 Chauvin JM, Zarour HM. TIGIT in cancer immunotherapy [J]. Immunother Cancer, 2020, 8(2): e000957.
 Lozano E, Dominguez-Villar M, Kuchroo V, et al., The TIGIT/CD226 axis regulates human T cell function[J]. Journal of Immunology, 2012, 188(8): 3869-3875.
 Kraus A K, Chen J, Edenhofer I, et al., The Role of T Cell Costimulation via DNAM-1 in Kidney Transplantation [J]. PLOS ONE, 2016.
 Du X, De Almeida P, Manieri N, et al., CD226 regulates natural killer cell antitumor responses via phosphorylation-mediated inactivation of transcription factor FOXO1[J]. Proceedings of the National Academy of Sciences, 2018.
 Brunner Weinzierl M C, Rudd C E. CTLA-4 and PD-1 Control of T-Cell Motility and Migration: Implications for Tumor Immunotherapy [J]. Frontiers in Immunology, 2018, 9.
 Waite JC, Wang B, Haber L, et al., Tumor-targeted CD28 bispecific antibodies enhance the antitumor efficacy of PD-1 immunotherapy [J]. Science Translational Medicine, 2020, 24, 12(549): eaba2325.
 Glorieux C, Huang P. CD137 expression in cancer cells: regulation and significance [J]. Cancer Communications, 2019, 39(1): 70.
 Gong J, Fang L, Liu R, et al., UPR decreases CD226 ligand CD155 expression and sensitivity to NK cell‐mediated cytotoxicity in hepatoma cells [J]. European Journal of Immunology, 2014, 44(12): 3758-67.
 Jin HS, Ko M, Choi DS, et al., CD226hiCD8+T Cells Are a Prerequisite for Anti-TIGIT Immunotherapy [J]. Cancer Immunol Res, 2020, 8(7): 912-925.