Abstract 6172: PI3K/Akt signaling pathway regulates CD155 expression involved in resistance to cancer immunotherapy

Abstract Although anti-programmed death 1 (PD-1)/PD-1 ligand 1 monoclonal antibodies are effective against various cancers, resistance remains a significant issue in many patients. The immunosuppressive T cell immunoreceptor with Ig and ITIM domains (TIGIT)/CD155 axis has emerged as one of the crucial mechanisms contributing to this resistance. However, the complexities of CD155 expression remain incompletely understood. In this study, we conducted clustered regularly interspaced palindromic repeats (CRISPR) screening to identify key molecules involved in the regulation of CD155 expression and to investigate their roles in modulating CD155 within the tumor microenvironment (TME). CRISPR screening revealed that dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1A (DYRK1A) as one of the key regulators of CD155 expression via the PI3K/Akt signaling pathway. In mouse models, inhibition of Dyrk1a using CRISPR/CRISPR-associated protein 9 (Cas9) technology or treatment with harmine, a DYRK1A inhibitor reduced CD155 expression, resulting in overcoming the resistance to PD-1 blockade. Moreover, in human head and neck squamous cell carcinoma (HNSCC) cell lines, inhibition of the PI3K/Akt signaling pathway reduced CD155 expression, similar to mouse models. In addition, cetuximab-mediated epidermal growth factor receptor blockade reduced CD155 expression by targeting downstream PI3K/Akt signaling in certain HNSCC cell lines. Clinically, patients with HNSCC harboring high CD155 expression exhibited elevated levels of Akt phosphorylation, consistently indicating that the PI3K/Akt signaling pathway is involved in CD155 expression. Furthermore, high CD155 expression contributed to PD-1 blockade resistance especially in patients who had high CD8+ T cell infiltration. These results emphasized the role of the PI3K/Akt signaling pathway in regulating CD155 expression, which may influence resistance to PD-1 blockade therapies in various cancers, particularly those characterized by an inflamed TME. This study suggests that the reduction of CD155 expression by inhibiting the PI3K/Akt signaling pathway could overcome resistance to PD-1 blockade therapies. Citation Format: Katsushige Kawase, Shusuke Kawashima, Tatsuya Nishi, Takashi Inozume, Takao Morinaga, Masahito Kawazu, Toyoyuki Hanazawa, Yosuke Togashi. PI3K/Akt signaling pathway regulates CD155 expression involved in resistance to cancer immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6172.