免疫检查点抑制剂（ICIs）已经改变了癌症治疗，为包括黑色素瘤在内的各种肿瘤类型的患者带来了显着的益处。然而，大约 40% 的黑色素瘤患者没有从 ICI 治疗中受益，准确预测 ICI 反应仍然具有挑战性。我们现在描述了一种新颖且简单的方法，该方法整合了免疫相关转录组特征和肿瘤体积负荷，以更好地预测黑色素瘤患者的 ICI 反应。对 32 名接受 PD1 和 CTLA4 抑制剂联合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，11 名还采集了治疗早期（EDT，治疗开始后 5-15 天）的肿瘤样本。在 PRE 时对所有 32 名患者的肿瘤体积进行了评估，并首先对 11 名患者的 EDT 样本进行了计算机断层扫描 (CT) 成像。 Hallmark IFNγ 基因集的分析显示与 PRE 时的 ICI 反应无关（AUC ROC 曲线 = 0.6404，p = 0.24，63% 敏感性，71% 特异性）。当使用逻辑回归以肿瘤体积（基因集表达与肿瘤体积之比）评估 IFNg 活性以预测 ICI 反应时，我们观察到区分 ICI 反应者与无反应者的高辨别力（AUC = 0.7760，p = 0.02，88%敏感性，特异性 67%）；这种方法被其他免疫相关转录组基因组复制。这些发现在一个由 23 名接受 PD1 抑制剂治疗的黑色素瘤患者组成的独立队列中得到了进一步重复。因此，将肿瘤体积与免疫相关转录组特征相结合可以改善 ICI 反应的预测，并表明持久 ICI 反应需要相对于肿瘤负荷更高水平的免疫激活。© 2024。作者。

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.© 2024. The Author(s).