免疫检查点阻断只对一部分癌症有效。靶向T细胞启动标志物 (TPMs) 可能增强其活性，但在临床中正确应用这些药物是具有挑战性的，原因是免疫复杂性和异质性。我们调查了一个包含15种TPMs（CD137、CD27、CD28、CD80、CD86、CD40、CD40LG、GITR、ICOS、ICOSLG、OX40、OX40LG、GZMB、IFNG和TBX21）的转录组学在全癌症队列中的表达情况（N = 514例患者，30种癌症类型）。分析了TPM表达与组织学类型、高度微卫星不稳定性（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%）。没有观察到组织学类型与TPM表达之间的显著相关性。相反，MSI-H、TMB≥10个突变/Mb和PD-L1≥1%的肿瘤中GZMB (一种储存在活化的T细胞和NK细胞中的丝氨酸蛋白酶，可诱导癌细胞凋亡) 和IFNG (激活细胞毒性T细胞) 的表达显著增高。PD-L1≥1%还与CD137、GITR和ICOS的表达显著相关。基于TPM表达使用分层聚类将患者的肿瘤分类为“热”、“混合”或“冷”聚类。冷聚类中PD-L1≥1%的肿瘤比例显著较低。总体而言，502例患者（98%）具有独特的TPM表达模式。观察到与组织学类型无关但与其他免疫治疗生物标志物（PD-L1≥1%、MSI-H和TMB≥10个突变/Mb）相关的TPM多样的表达模式。基于TPM免疫基因组学特征选择患者可能有助于免疫治疗优化。© 2023 Springer Nature Limited 和卡大基因组医学研究卓越中心.

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.© 2023. Springer Nature Limited and Centre of Excellence in Genomic Medicine Research, King Abdulaziz University.