大小很重要:综合肿瘤体积和免疫激活特征预测免疫疗法反应

IF 27.7 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Molecular Cancer Pub Date : 2024-10-11 DOI:10.1186/s12943-024-02146-0
Su Yin Lim, Ines Pires da Silva, Nurudeen A. Adegoke, Serigne N. Lo, Alexander M. Menzies, Matteo S. Carlino, Richard A. Scolyer, Georgina V. Long, Jenny H. Lee, Helen Rizos
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引用次数: 0

摘要

免疫检查点抑制剂(ICIs)改变了癌症治疗,为包括黑色素瘤在内的各种肿瘤类型的患者带来了重大益处。然而,约有40%的黑色素瘤患者无法从ICI治疗中获益,准确预测ICI反应仍是一项挑战。我们现在介绍一种新颖而简单的方法,该方法综合了免疫相关转录组特征和肿瘤体积负担,能更好地预测黑色素瘤患者的 ICI 反应。我们对 32 例接受 PD1 和 CTLA4 联合抑制剂治疗的晚期黑色素瘤患者的治疗前(PRE)肿瘤标本进行了 RNA 测序。在这32名患者中,有11名患者还获得了治疗早期(EDT,治疗开始后5-15天)的肿瘤样本。所有32名患者的肿瘤体积均在PRE时进行评估,11名有EDT样本的患者的肿瘤体积则在首次计算机断层扫描(CT)成像时进行评估。对 Hallmark IFNγ 基因集的分析表明,在 PRE 阶段,IFNγ 基因与 ICI 反应无关(AUC ROC 曲线 = 0.6404,p = 0.24,灵敏度为 63%,特异性为 71%)。当使用逻辑回归法评估 IFNg 活性与肿瘤体积(基因组表达量与肿瘤体积之比)以预测 ICI 反应时,我们观察到在区分 ICI 反应者与非反应者方面具有很高的鉴别力(AUC = 0.7760,p = 0.02,灵敏度为 88%,特异度为 67%);其他免疫相关转录组基因组也采用了这种方法。这些研究结果在接受 PD1 抑制剂治疗的 23 例黑色素瘤患者的独立队列中得到了进一步证实。因此,将肿瘤体积与免疫相关转录组特征相结合可改善对 ICI 反应的预测,并表明相对于肿瘤负荷而言,更高水平的免疫激活是持久 ICI 反应的必要条件。
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Size matters: integrating tumour volume and immune activation signatures predicts immunotherapy response
Immune checkpoint inhibitors (ICIs) have transformed cancer treatment, providing significant benefit to patients across various tumour types, including melanoma. However, around 40% of melanoma patients do not benefit from ICI treatment, and accurately predicting ICI response remains challenging. We now describe a novel and simple approach that integrates immune-associated transcriptome signatures and tumour volume burden to better predict ICI response in melanoma patients. RNA sequencing was performed on pre-treatment (PRE) tumour specimens derived from 32 patients with advanced melanoma treated with combination PD1 and CTLA4 inhibitors. Of these 32 patients, 11 also had early during treatment (EDT, 5–15 days after treatment start) tumour samples. Tumour volume was assessed at PRE for all 32 patients, and at first computed tomography (CT) imaging for the 11 patients with EDT samples. Analysis of the Hallmark IFNγ gene set revealed no association with ICI response at PRE (AUC ROC curve = 0.6404, p = 0.24, 63% sensitivity, 71% specificity). When IFNg activity was evaluated with tumour volume (ratio of gene set expression to tumour volume) using logistic regression to predict ICI response, we observed high discriminative power in separating ICI responders from non-responders (AUC = 0.7760, p = 0.02, 88% sensitivity, 67% specificity); this approach was reproduced with other immune-associated transcriptomic gene sets. These findings were further replicated in an independent cohort of 23 melanoma patients treated with PD1 inhibitor. Hence, integrating tumour volume with immune-associated transcriptomic signatures improves the prediction of ICI response, and suggest that higher levels of immune activation relative to tumour burden are required for durable ICI response.
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来源期刊
Molecular Cancer
Molecular Cancer 医学-生化与分子生物学
CiteScore
54.90
自引率
2.70%
发文量
224
审稿时长
2 months
期刊介绍: Molecular Cancer is a platform that encourages the exchange of ideas and discoveries in the field of cancer research, particularly focusing on the molecular aspects. Our goal is to facilitate discussions and provide insights into various areas of cancer and related biomedical science. We welcome articles from basic, translational, and clinical research that contribute to the advancement of understanding, prevention, diagnosis, and treatment of cancer. The scope of topics covered in Molecular Cancer is diverse and inclusive. These include, but are not limited to, cell and tumor biology, angiogenesis, utilizing animal models, understanding metastasis, exploring cancer antigens and the immune response, investigating cellular signaling and molecular biology, examining epidemiology, genetic and molecular profiling of cancer, identifying molecular targets, studying cancer stem cells, exploring DNA damage and repair mechanisms, analyzing cell cycle regulation, investigating apoptosis, exploring molecular virology, and evaluating vaccine and antibody-based cancer therapies. Molecular Cancer serves as an important platform for sharing exciting discoveries in cancer-related research. It offers an unparalleled opportunity to communicate information to both specialists and the general public. The online presence of Molecular Cancer enables immediate publication of accepted articles and facilitates the presentation of large datasets and supplementary information. This ensures that new research is efficiently and rapidly disseminated to the scientific community.
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