CD155-Binding Peptide Enhances Antitumor T Cell Activity in Colon Tumors

CD155 is an immunoglobulin-like protein overexpressed in most tumor cells and promotes the proliferation, adhesion, and migration/invasion of tumor cells. CD155 has multiple immune checkpoint receptors, including CD226, TIGIT, CD96, CD112R (PVRIG) and KIR2DL5. These ligands bind with different affinities to PVR-like protein receptors, thus exerting immune-activating or immunosuppressive functions.CD155 binds to TIGIT with far higher affinity than binds to CD96 or CD226. Moreover, the CD155 immunosuppressive target TIGIT, CD96 competes with the immune activation target CD226 to inhibit immune system activation. As a result, TIGIT exerts an immunosuppressive impact on immune cells by preventing CD226-mediated co-stimulation. Upregulation of CD155 in colon tumor is associated with poor patient outcomes, which highlights its potential as therapeutic target. Using a phage-displayed peptide library, we identified a peptide that binds CD155 with a high affinity (CD155pep). Treatment of CT26 colon tumor cells with CD155pep during co-cultures with CD8+ T cells down-regulated CD155 expression of the tumor cells and enhanced antitumor activity of T cells, including the release of granzyme B, interferon-γ, and tumor necrosis factor-α, and the increase of tumor cells lysis. In addition, treatment of tumor-associated macrophages with CD155pep during co-cultures with CD8+ T cells decreased anti-inflammatory IL-10 production while increasing pro-inflammatory IL-12 secretion of macrophages. Furthermore, CD155pep-linked lytic peptide showed a selective toxicity in tumor cells over normal cells and inhibited tumor growth in mice. These results highlight the therapeutic potential of CD155pep and CD155pep-linked lytic peptide for targeted therapy of CD155-high tumors. Citation Format: Gunassekaran Gowri Rangaswamy, Poongkavithai Vadevoo Sri Murugan, Byungheon Lee, . CD155- binding peptide enhances antitumor activity of T cells and cytotoxic activity of a lytic peptide in colon tumor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 4979.