Roelands Jessica, Hendrickx Wouter, Zoppoli Gabriele, Mall Raghvendra, Saad Mohamad, Halliwill Kyle, Curigliano Giuseppe, Rinchai Darawan, Decock Julie, Delogu Lucia G, Turan Tolga, Samayoa Josue, Chouchane Lotfi, Ballestrero Alberto, Wang Ena, Finetti Pascal, Bertucci Francois, Miller Lance D, Galon Jerome, Marincola Francesco M, Kuppen Peter J K, Ceccarelli Michele, Bedognetti Davide
Cancer Research Department, Research Branch, Sidra Medicine, Doha, Qatar.
Department of Surgery, Leiden University Medical Center (LUMC), Leiden, The Netherlands.
J Immunother Cancer. 2020 Apr;8(1). doi: 10.1136/jitc-2020-000617.
An immune active cancer phenotype typified by a T helper 1 (Th-1) immune response has been associated with increased responsiveness to immunotherapy and favorable prognosis in some but not all cancer types. The reason of this differential prognostic connotation remains unknown.
To explore the contextual prognostic value of cancer immune phenotypes, we applied a multimodal pan-cancer analysis among 31 different histologies (9282 patients), encompassing immune and oncogenic transcriptomic analysis, mutational and neoantigen load and copy number variations.
We demonstrated that the favorable prognostic connotation conferred by the presence of a Th-1 immune response was abolished in tumors displaying specific tumor-cell intrinsic attributes such as high transforming growth factor-beta (TGF-β) signaling and low proliferation capacity. This observation was independent of mutation rate. We validated this observation in the context of immune checkpoint inhibition. WNT- catenin, barrier molecules, Notch, hedgehog, mismatch repair, telomerase activity and AMPK signaling were the pathways most coherently associated with an immune silent phenotype together with mutations of driver genes including and .
This is the first systematic study demonstrating that the prognostic and predictive role of a bona fide favorable intratumoral immune response is dependent on the disposition of specific oncogenic pathways. This information could be used to refine stratification algorithms and prioritize hierarchically relevant targets for combination therapies.
以辅助性T细胞1（Th-1）免疫反应为特征的免疫活性癌症表型，在某些但并非所有癌症类型中，与免疫治疗反应性增加及良好预后相关。这种不同的预后内涵的原因尚不清楚。
为了探索癌症免疫表型的背景预后价值，我们对31种不同组织学类型（9282例患者）进行了多模态泛癌分析，包括免疫和致癌转录组分析、突变和新抗原负荷以及拷贝数变异。
我们证明，在显示出特定肿瘤细胞内在属性（如高转化生长因子-β（TGF-β）信号传导和低增殖能力）的肿瘤中，Th-1免疫反应的存在所赋予的良好预后内涵被消除。这一观察结果与突变率无关。我们在免疫检查点抑制的背景下验证了这一观察结果。WNT-连环蛋白、屏障分子、Notch、刺猬、错配修复、端粒酶活性和AMPK信号传导是与免疫沉默表型最密切相关的途径，同时还有包括 和 在内的驱动基因的突变。
这是第一项系统性研究，表明真正良好的肿瘤内免疫反应的预后和预测作用取决于特定致癌途径的状态。这些信息可用于完善分层算法，并为联合治疗按层次确定相关靶点的优先级。
