Revisiting T-cell adhesion molecules as potential targets for cancer immunotherapy: CD226 and CD2

Abstract

Cancer immunotherapy aims to initiate or amplify immune responses that eliminate cancer cells and create immune memory to prevent relapse. Immune checkpoint inhibitors (ICIs), which target coinhibitory receptors on immune effector cells, such as CTLA-4 and PD-(L)1, have made significant strides in cancer treatment. However, they still face challenges in achieving widespread and durable responses. The effectiveness of anticancer immunity, which is determined by the interplay of coinhibitory and costimulatory signals in tumor-infiltrating immune cells, highlights the potential of costimulatory receptors as key targets for immunotherapy. This review explores our current understanding of the functions of CD2 and CD226, placing a special emphasis on their potential as novel agonist targets for cancer immunotherapy. CD2 and CD226, which are present mainly on T and NK cells, serve important functions in cell adhesion and recognition. These molecules are now recognized for their costimulatory benefits, particularly in the context of overcoming T-cell exhaustion and boosting antitumor responses. The importance of CD226, especially in anti-TIGIT therapy, along with the CD2‒CD58 axis in overcoming resistance to ICI or chimeric antigen receptor (CAR) T-cell therapies provides valuable insights into advancing beyond the current barriers of cancer immunotherapy, underscoring their promise as targets for novel agonist therapy.

Fig. 1. The TIGIT/CD226/CD96/CD112R axis.

TIGIT, CD226, CD96, and CD112R are expressed mainly on T cells and NK cells. The ligands PVR, Nectin-1, Nectin-2, Nectin-3 and Nectin-4 are expressed on tumor cells and antigen-presenting cells (APCs). TIGIT binds PVR, Nectin-2, Nectin-3, and Nectin-4, while CD226 binds PVR and Nectin-2, and CD96 binds PVR and Nectin-1. CD226 competes with TIGIT and CD96 for PVR binding and with CD112R for Nectin-2 binding. The cytoplasmic tails of TIGIT, CD96, CD112R, and PVR contain ITIM motifs that initiate inhibitory signals, while TIGIT also features an ITT-like motif. CD226 binds PVR to transmit positive signals and associates with LFA-1. The signaling outcome of CD96 binding to CD155 in human T cells is still unclear. CD112R binds CD112 to deliver an inhibitory signal via its ITIM. Two-sided arrows indicate receptor‒ligand interactions, and their size is proportional to the reported affinities. Keywords: APCs (antigen-presenting cells), ITIM (immunoreceptor tyrosine-based inhibitory motif), ITT (Ig tail-tyrosine), NK cells (natural killer cells), TIGIT (T-cell immunoreceptor with immunoglobulin and ITIM domains).

Fig. 2. Regulation of CD226 activity: extracellular and intracellular mechanisms.

CD226 activity is regulated through two main mechanisms: competitive ligand binding at the extracellular level and SHP-2-mediated tyrosine dephosphorylation at the intracellular level. With respect to the extracellular regulation of CD226, there are two main hypotheses: a. TIGIT binds to PVR with a higher affinity than does CD226 and inhibits the homodimerization of CD226. This inhibition leads to a decreased accumulation of CD226 at the sites of cell-to-cell contact. b. In addition to ligand engagement, CD226 and TIGIT can colocalize at the IS, and the presence of CD226 does not affect TIGIT clustering. In terms of intracellular regulation, there are two proposed mechanisms for regulating the tyrosine phosphorylation of CD226: a. The binding of TIGIT to PVR, which induces the phosphorylation of the ITT-like motif of TIGIT, recruits SHP-2. This results in the dephosphorylation of tyrosine 322 on CD226. b. TIGIT prevents the interaction between CD226 and PVR through its ECD, but its ICD does not influence the phosphorylation of CD226. Instead, PD-1 recruits SHP-2, which leads to the dephosphorylation of CD226.

Fig. 3. Regulation of tumor immunity and immune evasion via the CD2‒CD58 axis.

CD58 downregulation on tumor cells is associated with resistance to cancer treatments such as ICI and CAR T-cell therapies. At the molecular level, this occurs when PD-L1 competes with CD58 for binding to extracellular loops within the MARVEL domain of CMTM6, leading to the downregulation of CD58 by promoting its lysosomal degradation instead of endosomal recycling. This increase in PD-L1, resulting from the loss of CD58, contributes to tumor immune evasion. In addition, impaired CD58 binding to CD2 on T cells hampers antitumor immune responses through various mechanisms, including reduced T-cell activation, directional migration, infiltration into tumors and cytotoxicity.