PI3K/Akt信号通路调控CD155表达参与肿瘤免疫治疗耐药。

IF 8.2 1区 医学 Q1 IMMUNOLOGY
Katsushige Kawase, Shusuke Kawashima, Tatsuya Nishi, Takashi Inozume, Takao Morinaga, Masahito Kawazu, Toyoyuki Hanazawa, Yosuke Togashi
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引用次数: 0

摘要

尽管抗程序性死亡1 (PD-1)/PD-1配体1单克隆抗体对各种癌症有效,但耐药性仍然是患者的一个重要问题。具有Ig和ITIM结构域的免疫抑制T细胞免疫受体(TIGIT)/CD155轴已成为促成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。在这项研究中,我们旨在确定参与CD155表达调控的关键分子,并探讨它们在肿瘤微环境(TME)中调节CD155的作用。通过聚集规律间隔回文重复序列(CRISPR)筛选,我们确定了双特异性酪氨酸-(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或使用Dyrk1a抑制剂治疗可有效减轻PD-1阻断剂耐药性。此外,在某些头颈部鳞状细胞癌(HNSCC)细胞系中,西图昔单抗介导的表皮生长因子受体阻断通过靶向下游PI3K/Akt信号通路降低CD155的表达。在HNSCC患者(n = 96)中,CD155表达与Akt磷酸化相关,特别是在CD8+ T细胞浸润高的患者中,影响PD-1阻断剂耐药性。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,特别是那些以炎症性TME为特征的癌症。这项研究表明,靶向PI3K/Akt通路可以克服耐药,特别是在TME炎症和CD155高表达的癌症中。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
PI3K/Akt signaling pathway regulates CD155 expression involved in resistance to cancer immunotherapy.

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.

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来源期刊
Cancer immunology research
Cancer immunology research ONCOLOGY-IMMUNOLOGY
CiteScore
15.60
自引率
1.00%
发文量
260
期刊介绍: Cancer Immunology Research publishes exceptional original articles showcasing significant breakthroughs across the spectrum of cancer immunology. From fundamental inquiries into host-tumor interactions to developmental therapeutics, early translational studies, and comprehensive analyses of late-stage clinical trials, the journal provides a comprehensive view of the discipline. In addition to original research, the journal features reviews and opinion pieces of broad significance, fostering cross-disciplinary collaboration within the cancer research community. Serving as a premier resource for immunology knowledge in cancer research, the journal drives deeper insights into the host-tumor relationship, potent cancer treatments, and enhanced clinical outcomes. Key areas of interest include endogenous antitumor immunity, tumor-promoting inflammation, cancer antigens, vaccines, antibodies, cellular therapy, cytokines, immune regulation, immune suppression, immunomodulatory effects of cancer treatment, emerging technologies, and insightful clinical investigations with immunological implications.
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