检查点抑制剂（CPI）免疫疗法为一些癌症患者提供了针对一系列实体瘤类型的持久临床反应。尽管如此，不同癌症类型对 CPI 的反应率差异很大。解决 CPI 引起的肿瘤内转录组变化可能会提高我们对敏感性和耐药机制的理解。我们利用来自 5 种癌症类型的转录组测序数据，收集了来自 174 名接受 CPI 治疗的患者的一组纵向治疗前和治疗中样本，涉及六种癌症类型。对已发表的 RNA 标记物的荟萃分析揭示了乳腺癌患者治疗中的免疫重振模式，这种模式在治疗前是不可辨别的，这为了解 CPI 对乳腺癌免疫微环境的影响提供了生物学见解。我们鉴定了 98 个与 CPI 反应相关的乳腺癌特异性相关基因，其中包括 13 个已知的 IO 靶点基因，例如 Toll 样受体 TLR1、TLR4 和 TLR8，这些基因有可能成为接受 CPI 治疗的乳腺癌患者的联合靶点。此外，我们证明在乳腺癌中鉴定的反应基因子集在治疗前在黑色素瘤中已经高表达，此外，我们在 CPI 治疗后建立了乳腺癌和黑色素瘤之间不同的 RNA 动态，这可能表明两种癌症之间存在不同的免疫微环境总体而言，描绘 CPI 治疗后的纵向 RNA 动力学揭示了不同反应轨迹的潜在机制，并确定了联合治疗的假定目标。© 作者（或其雇主）2023。CC 允许重复使用BY-NC。不得商业再利用。请参阅权利和权限。由英国医学杂志出版。

Checkpoint inhibitor (CPI) immunotherapies have provided durable clinical responses across a range of solid tumor types for some patients with cancer. Nonetheless, response rates to CPI vary greatly between cancer types. Resolving intratumor transcriptomic changes induced by CPI may improve our understanding of the mechanisms of sensitivity and resistance.We assembled a cohort of longitudinal pre-therapy and on-therapy samples from 174 patients treated with CPI across six cancer types by leveraging transcriptomic sequencing data from five studies.Meta-analyses of published RNA markers revealed an on-therapy pattern of immune reinvigoration in patients with breast cancer, which was not discernible pre-therapy, providing biological insight into the impact of CPI on the breast cancer immune microenvironment. We identified 98 breast cancer-specific correlates of CPI response, including 13 genes which are known IO targets, such as toll-like receptors TLR1, TLR4, and TLR8, that could hold potential as combination targets for patients with breast cancer receiving CPI treatment. Furthermore, we demonstrate that a subset of response genes identified in breast cancer are already highly expressed pre-therapy in melanoma, and additionally we establish divergent RNA dynamics between breast cancer and melanoma following CPI treatment, which may suggest distinct immune microenvironments between the two cancer types.Overall, delineating longitudinal RNA dynamics following CPI therapy sheds light on the mechanisms underlying diverging response trajectories, and identifies putative targets for combination therapy.© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.