m1A inhibition fuels oncolytic virus-elicited antitumor immunity via downregulating MYC/PD-L1 signaling

IF 10.8 1区 医学 Q1 DENTISTRY, ORAL SURGERY & MEDICINE International Journal of Oral Science Pub Date : 2024-05-10 DOI:10.1038/s41368-024-00304-0
Shujin Li, Tian Feng, Yuantong Liu, Qichao Yang, An Song, Shuo Wang, Jun Xie, Junjie Zhang, Bifeng Yuan, Zhijun Sun
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Abstract

N1-methyladenosine (m1A) RNA methylation is critical for regulating mRNA translation; however, its role in the development, progression, and immunotherapy response of head and neck squamous cell carcinoma (HNSCC) remains largely unknown. Using Tgfbr1 and Pten conditional knockout (2cKO) mice, we found the neoplastic transformation of oral mucosa was accompanied by increased m1A modification levels. Analysis of m1A-associated genes identified TRMT61A as a key m1A writer linked to cancer progression and poor prognosis. Mechanistically, TRMT61A-mediated tRNA-m1A modification promotes MYC protein synthesis, upregulating programmed death-ligand 1 (PD-L1) expression. Moreover, m1A modification levels were also elevated in tumors treated with oncolytic herpes simplex virus (oHSV), contributing to reactive PD-L1 upregulation. Therapeutic m1A inhibition sustained oHSV-induced antitumor immunity and reduced tumor growth, representing a promising strategy to alleviate resistance. These findings indicate that m1A inhibition can prevent immune escape after oHSV therapy by reducing PD-L1 expression, providing a mutually reinforcing combination immunotherapy approach.

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抑制 m1A 可通过下调 MYC/PD-L1 信号促进溶瘤病毒诱导的抗肿瘤免疫力
N1-甲基腺苷(m1A)RNA甲基化是调节mRNA翻译的关键;然而,它在头颈部鳞状细胞癌(HNSCC)的发生、发展和免疫疗法反应中的作用在很大程度上仍然未知。我们利用 Tgfbr1 和 Pten 条件性基因敲除(2cKO)小鼠发现,口腔黏膜的肿瘤性转化伴随着 m1A 修饰水平的增加。对m1A相关基因的分析发现,TRMT61A是与癌症进展和不良预后相关的关键m1A基因。从机理上讲,TRMT61A介导的tRNA-m1A修饰促进了MYC蛋白的合成,上调了程序性死亡配体1(PD-L1)的表达。此外,用溶瘤性单纯疱疹病毒(oHSV)治疗的肿瘤中,m1A修饰水平也会升高,从而导致PD-L1的反应性上调。治疗性 m1A 抑制可维持 oHSV 诱导的抗肿瘤免疫力并减少肿瘤生长,是一种很有前景的缓解抗药性策略。这些研究结果表明,m1A抑制剂可以通过减少PD-L1的表达来防止oHSV治疗后的免疫逃逸,提供了一种相互促进的联合免疫疗法方法。
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来源期刊
International Journal of Oral Science
International Journal of Oral Science DENTISTRY, ORAL SURGERY & MEDICINE-
CiteScore
31.80
自引率
1.30%
发文量
53
审稿时长
>12 weeks
期刊介绍: The International Journal of Oral Science covers various aspects of oral science and interdisciplinary fields, encompassing basic, applied, and clinical research. Topics include, but are not limited to: Oral microbiology Oral and maxillofacial oncology Cariology Oral inflammation and infection Dental stem cells and regenerative medicine Craniofacial surgery Dental material Oral biomechanics Oral, dental, and maxillofacial genetic and developmental diseases Craniofacial bone research Craniofacial-related biomaterials Temporomandibular joint disorder and osteoarthritis The journal publishes peer-reviewed Articles presenting new research results and Review Articles offering concise summaries of specific areas in oral science.
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