Inhibitory receptors expressed on the immune cell surface have emerged as checkpoint molecules that could be therapeutically targeted for tumor immunotherapy. However, antitumor immunity mediated by checkpoint blockade depends on optimal recognition of tumor cells through the activation of receptors on antitumor effector immune cells, such as CD8+ T cells and NK cells. Therefore, sufficient and maintained expression levels of activating receptors on these effector immune cells are essential for antitumor immunity and checkpoint blockade immunotherapy. One such activating receptor, CD226, however, was recently reported to be transcriptionally downregulated in an Eomes-dependent manner1 and posttranslationally downregulated by tumor-derived CD1552 (Fig. 1).
CD226 (DNAX Accessory Molecule-1, DNAM-1, PTA-1, TLiSA1) is a transmembrane protein that is expressed on T cells, natural killer (NK) cells, B cells, monocytes, and platelets. CD226, together with the inhibitory receptors TIGIT and CD96, belongs to a cell-surface receptor family3 that binds nectin and nectin-like proteins. The interesting feature of this family is that these receptors compete for common ligands. For example, CD226 competes with TIGIT and CD96 for binding to CD155 (Nectin-like molecule 5, Necl-5, PVR) and CD112 (Nectin-2), and the expression of these ligands is usually abundant in tumors.
CD226 has been shown to be required for optimal immunosurveillance in various tumor models. Recently, Weulersse et al.1 and Braun et al.2 further revealed the essential role of CD226 in facilitating the antitumor immune response. These groups showed that the absence of CD226 limits LFA-1 activation and indicates hyporesponsive CD8+ T cells. During tumor development, CD226−CD8+ T cells accumulate in tumors and correlate with poor survival in tumor patients. Increased CD226 expression on tumor-infiltrating CD8+ T cells correlates with increased effector functions by these cells in mouse tumor models and in head and neck squamous cell carcinoma patients. The researchers also showed that the absence of CD226 limits the efficacy of anti-PD1 checkpoint blockade both in the B16K1 melanoma model and the MC38 colon cancer model. Importantly, CD226 levels in melanoma tumor samples from patients were assessed before PD1-based immune checkpoint blockade therapy and positively correlated with patient survival in both the discovery and validation cohorts, independent of the levels of CD8+ T cell infiltration in tumors. These data demonstrate that CD226 is a potent driver of antitumor immunity.
Despite its importance in antitumor immunity, the expression levels of CD226 on lymphocytes are reduced in tumors. Weulersse et al. showed that Eomes mediates the downregulation of CD226 on CD8+ T cells, as evidenced by the resistance to CD226 downregulation on tumor-infiltrating CD8+ T cells in the absence of Eomes, as well as decreased CD226 expression on Eomes-overexpressing CD8+ T cells. Moreover, an anti-CD137 agonist antibody, which induces Eomes expression, downregulated CD226 on CD8+ T cells in a CD155-independent manner. This downregulation was also abolished in Eomes−/− CD8+ T cells. In addition, Braun et al. showed that CD155 mediates the downregulation of CD226 via posttranslational mechanisms. In their study, CD226 expression was higher on tumor-infiltrating CD8+ T cells in CD155−/− tumors than in wild-type tumors. Mice with a Y319F mutation in CD226, which abrogates both Y319 phosphorylation in CD226 and recruitment of the E3 ubiquitin ligase CBL-B for ubiquitinylation and proteasomal degradation, exhibit increased expression levels of CD226 on the surface of CD8+ T cells and suppressed tumor growth. These results indicate that CD226 expression on CD8+ T cells is suppressed in tumors through multiple mechanisms. Given that the inhibitory receptor TIGIT is usually upregulated on both CD8+ T cells4 and NK cells5 in tumors, the upregulation of TIGIT, together with the downregulation of CD226, might result in increased inhibitory signals upon recognition of their common ligands (CD155 and CD112) and exacerbate the dysfunctional status of these antitumor effector cells. Furthermore, downregulated expression of CD226 might also diminish checkpoint blockade efficacy after blocking the inhibitory receptors CD96 or TIGIT, since the optimal therapeutic efficacy of blocking these two checkpoint molecules at least partially relies on the activating signaling of CD226.4,6 Further studies are required to assess the effects of CD226 downregulation on the efficacy of CD96/TIGIT checkpoint blockade.
On the other hand, downregulated expression of the activating receptor CD226 and upregulated expression of the inhibitory receptor TIGIT might result in increased inhibitory signaling input of this protein family through the recognition of the common ligand(s) CD155 and/or CD112, which supports the blockade of common ligand(s) such as CD155 to promote antitumor immunity. In addition, suppressing the tumor cell-intrinsic functions of CD155,7,8 such as promoting tumor progression, invasion, and metastasis, might be additional benefits from targeting CD155 in cancer therapy. Indeed, CD155 deficiency in host cells or in tumor cells reduces tumor growth, and CD155 deficiency in both host cells and tumor cells further exhibits tumor-suppressive effects.9 Importantly, a monoclonal antibody against CD155 suppresses tumor cell metastasis to the lung.10
In summary, Weulersse et al. and Braun et al. revealed novel and nonredundant mechanisms underlying the downregulation of the activating receptor CD226 on CD8+ T cells in tumors, adding to the growing list of tumor escape mechanisms. These studies are important for developing strategies to maintain (or even increase) the expression of activating receptors on antitumor effector lymphocytes to improve tumor immunotherapy. These studies also highlight the potent roles of this protein family (activating CD226 and inhibitory CD96 and TIGIT) in regulating tumor immunity and PD1/CTLA4-based checkpoint therapy, further supporting targeting inhibitory receptors (such as CD96 and TIGIT)/ligands (such as CD155) while maintaining the activating receptor CD226 in this family.
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Li, X. Y. et al. CD155 loss enhances tumor suppression via combined host and tumor-intrinsic mechanisms. J. Clin. Investig. 128, 2613–2625 (2018).
Morimoto, K. et al. Interaction of cancer cells with platelets mediated by Necl-5/poliovirus receptor enhances cancer cell metastasis to the lungs. Oncogene 27, 264–273 (2008).
This work was supported by the National Key R&D Program of China (2020YFA0710802) and the Natural Science Foundation of China (reference number 82071768).
The author declares no competing interests.
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Bi, J. CD226: a potent driver of antitumor immunity that needs to be maintained. Cell Mol Immunol (2021). https://doi.org/10.1038/s41423-020-00633-0