PI3K/Akt Signaling Pathway Regulates CD155 Expression Involved in Resistance to Cancer Immunotherapy

Abstract Despite the effectiveness of anti–PD-1/PD-L1 mAbs against various cancers, resistance remains a significant issue among patients. The immunosuppressive T-cell immunoreceptor with Ig and ITIM domains/CD155 axis has emerged as a key mechanism contributing to this resistance. However, the intricacies of CD155 expression are not fully elucidated. In this study, we aimed to identify the key molecules involved in the regulation of CD155 expression and explore their role in modulating CD155 within the tumor microenvironment (TME). By using clustered regularly interspaced palindromic repeats (CRISPR) screening, we identified dual-specificity tyrosine-(Y)-phosphorylation–regulated kinase 1A (DYRK1A) as one of the key regulators of CD155 expression. Subsequent inhibition of Dyrk1a through CRISPR/CRISPR-associated protein 9 technology or treatment with DYRK1A inhibitors mitigated PD-1 blockade resistance. Moreover, in certain head and neck squamous cell carcinoma cell lines, cetuximab-mediated EGF receptor blockade reduced CD155 expression by targeting downstream PI3K/Akt signaling. In patients with head and neck squamous cell carcinoma (n = 96), CD155 expression correlated with Akt phosphorylation, particularly affecting PD-1 blockade resistance in those with high CD8+ T-cell infiltration. These findings underscore the role of the PI3K/Akt signaling pathway in regulating CD155 expression, which may influence resistance to PD-1 blockade therapies in a variety of cancers, particularly those characterized by an inflamed TME. This study suggests that targeting the PI3K/Akt pathway could overcome resistance, particularly in cancers with an inflamed TME and high CD155 expression.