THE CD226 AXIS

Tumors are recognized by the immune system and their progression can be controlled or stopped through a natural process known as immunosurveillance. ^1,2

The CD226 Axis includes the T- and natural killer (NK)-cell inhibitory receptors TIGIT, CD96, and PVRIG (CD112R); the T/NK-cell activating receptor CD226 (DNAM-1) ; and cognate ligands CD155 (PVR) and CD112. This multifaceted group of immune receptors plays a critical role in the regulation of antitumor responses. ^3,4

THE ROLE OF CD226

CD226 is expressed on the surface of T and NK cells and is involved in the recognition and lysis of a wide range of solid tumors. ^2,5,6

CD226 binds to CD155 and CD112, expressed in high levels on tumor cells and on myeloid cells/antigen presenting cells, to stimulate an immune response. ^3,5-7

REGULATION OF CD226

The immune checkpoints TIGIT, CD96, and PVRIG (CD112R) may prevent CD226 from interacting with CD155 and CD112, directly impairing NK- and T-cell function; this results in a reduced antitumor immune response. ⁵

TIGIT

TIGIT is a multifunctional immunoregulatory receptor. ^4,5

In addition to intrinsic inhibitory signaling, TIGIT sequesters CD155 and, to a lesser extent, CD112 from CD226, effectively attenuating T- and NK-cell antitumor immune responses. ^4,8

TIGIT is highly expressed by immunosuppressive T cells (Tregs) and promotes tumor immune evasion by enhancing Treg function. ^4,5,9

CD96

CD96 is an immune receptor that modulates T- and NK-cell activity to promote tumor immune evasion. ¹⁰

CD96 sequesters a shared ligand, CD155, from CD226, effectively inhibiting T- and NK-cell antitumor immune responses. ¹¹

PVRIG

PVRIG is an immune receptor that suppresses T- and NK-cell function to promote tumor immune evasion. ^3,4

PVRIG sequesters CD112 from the costimulatory receptor CD226, effectively attenuating antitumor immune responses. ^4,5

In addition to ligand competition, PVRIG has also been shown to directly impair immune activation following CD112 engagement. ¹²

IMMUNE EVASION

Tumors often co-opt normal pathways to their advantage and escape immune surveillance by inducing regulatory pathways, including inhibitory immune receptors. ^1,13

The inhibitory effects of TIGIT, CD96, and PVRIG checkpoints, as well as the expression of CD112 and CD155 across tumor types, suggest a broad role in promoting tumor progression and metastasis. ^3,5,8,11,14

IMMUNE ENHANCERS

Blocking the TIGIT, CD96, and PVRIG receptors in combination with other checkpoint therapies may enable T and NK cells to better target tumor cells. ³

Preclinical and clinical evidence support targeting TIGIT, CD96, and PVRIG in cancer, especially in combination with other therapies such as those involving PD-1/PD-L1 checkpoint blockade. ^3,4,9,15,16

TARGETING THE CD226 AXIS

Current oncology immunotherapies, such as those involving the inhibition of the PD-1/PD-L1 and CTLA-4 pathways, have shown tremendous potential to change cancer treatment. ¹⁷

While PD-1/PD-L1 and CTLA-4 blockade can result in dramatic therapeutic responses, these therapies are often effective only in a subset of patients, and those who benefit can develop therapeutic resistance. ^17,18

Enhancing natural antitumor responses by blocking inhibitory signaling in the CD226 Axis has the potential to expand the number of patients who respond to immunotherapy treatment and increase the duration of their response, which could bring the promise of effective immunotherapies to more patients with cancer. ^3,4