t细胞启动转录组标记:免疫组异质性对精确免疫治疗的影响。

IF 4.7 2区 医学 Q1 GENETICS & HEREDITY NPJ Genomic Medicine Pub Date : 2023-08-08 DOI:10.1038/s41525-023-00359-8
Hirotaka Miyashita, Razelle Kurzrock, Nicholas J Bevins, Kartheeswaran Thangathurai, Suzanna Lee, Sarabjot Pabla, Mary Nesline, Sean T Glenn, Jeffrey M Conroy, Paul DePietro, Eitan Rubin, Jason K Sicklick, Shumei Kato
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引用次数: 0

摘要

免疫检查点阻断仅对一部分癌症有效。靶向t细胞启动标记物(TPMs)可能会增强活性,但由于免疫的复杂性和异质性,这些药物在临床中的正确应用具有挑战性。我们在一个泛癌症队列(N = 514例患者,30种癌症)中研究了15种TPMs (CD137、CD27、CD28、CD80、CD86、CD40、CD40LG、GITR、ICOS、ICOSLG、OX40、OX40LG、GZMB、IFNG和TBX21)的转录组学。分析TPM表达与组织学类型、微卫星不稳定性高(MSI-H)、肿瘤突变负荷(TMB)和程序性死亡配体1 (PD-L1)表达的相关性。在514例患者中,最常见的组织学类型是结直肠癌(27%)、胰腺癌(11%)和乳腺癌(10%)。组织学类型与TPM表达无统计学意义。相比之下,在MSI-H、TMB≥10个突变/mb和PD-L1≥1%的肿瘤中,GZMB(颗粒酶B,一种储存在活化T细胞和NK细胞中诱导癌细胞凋亡的丝氨酸蛋白酶)和IFNG(活化细胞毒性T细胞)的表达显著升高。PD-L1≥1%也与CD137、GITR和ICOS表达显著升高相关。基于TPM表达,采用分层聚类方法将患者肿瘤分为“热”、“混合”或“冷”聚类。冷簇中PD-L1≥1%的肿瘤比例明显降低。总的来说,502例患者(98%)有个体不同的TPM表达模式。观察到不同的TPMs表达模式独立于组织学类型,但与其他免疫治疗生物标志物(PD-L1≥1%,MSI-H和TMB≥10突变/mb)相关。基于TPM免疫谱的患者个性化选择可能有助于优化免疫治疗。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

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T-cell priming transcriptomic markers: implications of immunome heterogeneity for precision immunotherapy.

Immune checkpoint blockade is effective for only a subset of cancers. Targeting T-cell priming markers (TPMs) may enhance activity, but proper application of these agents in the clinic is challenging due to immune complexity and heterogeneity. We interrogated transcriptomics of 15 TPMs (CD137, CD27, CD28, CD80, CD86, CD40, CD40LG, GITR, ICOS, ICOSLG, OX40, OX40LG, GZMB, IFNG, and TBX21) in a pan-cancer cohort (N = 514 patients, 30 types of cancer). TPM expression was analyzed for correlation with histological type, microsatellite instability high (MSI-H), tumor mutational burden (TMB), and programmed death-ligand 1 (PD-L1) expression. Among 514 patients, the most common histological types were colorectal (27%), pancreatic (11%), and breast cancer (10%). No statistically significant association between histological type and TPM expression was seen. In contrast, expression of GZMB (granzyme B, a serine protease stored in activated T and NK cells that induces cancer cell apoptosis) and IFNG (activates cytotoxic T cells) were significantly higher in tumors with MSI-H, TMB ≥ 10 mutations/mb and PD-L1 ≥ 1%. PD-L1 ≥ 1% was also associated with significantly higher CD137, GITR, and ICOS expression. Patients' tumors were classified into "Hot", "Mixed", or "Cold" clusters based on TPM expression using hierarchical clustering. The cold cluster showed a significantly lower proportion of tumors with PD-L1 ≥ 1%. Overall, 502 patients (98%) had individually distinct patterns of TPM expression. Diverse expression patterns of TPMs independent of histological type but correlating with other immunotherapy biomarkers (PD-L1 ≥ 1%, MSI-H and TMB ≥ 10 mutations/mb) were observed. Individualized selection of patients based on TPM immunomic profiles may potentially help with immunotherapy optimization.

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来源期刊
NPJ Genomic Medicine
NPJ Genomic Medicine Biochemistry, Genetics and Molecular Biology-Molecular Biology
CiteScore
9.40
自引率
1.90%
发文量
67
审稿时长
17 weeks
期刊介绍: npj Genomic Medicine is an international, peer-reviewed journal dedicated to publishing the most important scientific advances in all aspects of genomics and its application in the practice of medicine. The journal defines genomic medicine as "diagnosis, prognosis, prevention and/or treatment of disease and disorders of the mind and body, using approaches informed or enabled by knowledge of the genome and the molecules it encodes." Relevant and high-impact papers that encompass studies of individuals, families, or populations are considered for publication. An emphasis will include coupling detailed phenotype and genome sequencing information, both enabled by new technologies and informatics, to delineate the underlying aetiology of disease. Clinical recommendations and/or guidelines of how that data should be used in the clinical management of those patients in the study, and others, are also encouraged.
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