Kawase Katsushige, Kawashima Shusuke, Nishi Tatsuya, Inozume Takashi, Morinaga Takao, Kawazu Masahito, Hanazawa Toyoyuki, Togashi Yosuke
Chiba Cancer Center, Chiba-shi, Chiba, Japan.
Chiba University, Chiba, Chiba, Japan.
Cancer Immunol Res. 2025 Jul 31. doi: 10.1158/2326-6066.CIR-24-0853.
Despite the effectiveness of anti-programmed death 1 (PD-1)/PD-1 ligand 1 monoclonal antibodies against various cancers, resistance remains a significant issue among patients. The immunosuppressive T cell immunoreceptor with Ig and ITIM domains (TIGIT)/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 employing 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 (Cas9) technology or treatment with DYRK1A inhibitors effectively mitigated PD-1 blockade resistance. Moreover, in certain head and neck squamous cell carcinoma (HNSCC) cell lines, cetuximab-mediated epidermal growth factor receptor blockade reduced CD155 expression by targeting downstream PI3K/Akt signaling. In patients with HNSCC (n = 96), CD155 expression correlated with Akt phosphorylation, particularly impacting 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.
尽管抗程序性死亡蛋白1（PD-1）/PD-1配体1单克隆抗体对各种癌症有效，但耐药性仍是患者面临的一个重大问题。具有Ig和ITIM结构域的免疫抑制性T细胞免疫受体（TIGIT）/CD155轴已成为导致这种耐药性的关键机制。然而，CD155表达的复杂性尚未完全阐明。在本研究中，我们旨在确定参与调节CD155表达的关键分子，并探索它们在肿瘤微环境（TME）中调节CD155的作用。通过使用成簇规律间隔短回文重复序列（CRISPR）筛选，我们确定双特异性酪氨酸（Y）磷酸化调节激酶1A（DYRK1A）是CD155表达的关键调节因子之一。随后通过CRISPR/CRISPR相关蛋白9（Cas9）技术抑制Dyrk1a或用DYRK1A抑制剂治疗可有效减轻PD-1阻断耐药性。此外，在某些头颈部鳞状细胞癌（HNSCC）细胞系中，西妥昔单抗介导的表皮生长因子受体阻断通过靶向下游PI3K/Akt信号传导降低了CD155表达。在HNSCC患者（n = 96）中，CD155表达与Akt磷酸化相关，尤其影响CD8 + T细胞浸润高的患者对PD-1阻断的耐药性。这些发现强调了PI3K/Akt信号通路在调节CD155表达中的作用，这可能影响多种癌症对PD-1阻断疗法的耐药性，尤其是那些具有炎症性TME特征的癌症。本研究表明，靶向PI3K/Akt通路可以克服耐药性，特别是在具有炎症性TME和高CD155表达的癌症中。
