PO.CL01.15 · 临床研究
影像学评估的胸腺健康作为跨癌种免疫治疗结局的宿主内在决定因素
Radiographic thymic health as host-intrinsic determinant of immunotherapy outcomes across cancer types
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景：免疫检查点抑制剂（ICI）依赖于有效的T细胞启动和更新，然而当前生物标志物主要聚焦于肿瘤内在特征（PD-L1、TMB）。由于胸腺维持初始T细胞的输出和库多样性，我们假设个体的胸腺健康代表ICI获益的宿主内在决定因素。
方法：我们开发了一种自监督深度学习模型，从常规CT扫描中量化胸腺功能（此处称为胸腺健康）。胸腺健康在3,476例接受ICI治疗的多种肿瘤实体患者中进行了独立评估。采用多变量Cox模型评估其与PFS和OS的关联，并校正关键流行病学和临床因素。敏感性分析评估了胸腺健康的增量贡献。生物学验证在来自TRACERx的未经治疗的NSCLC患者（n=464）中进行，采用T细胞受体（TCR）测序和血浆蛋白质组学。
结果：在NSCLC患者（n=1,218）中，高胸腺健康与显著降低的疾病进展风险（HR 0.65；95% CI，0.54-0.77）和死亡风险（HR 0.56；95% CI，0.46-0.68）相关；在对性别、年龄、PD-L1、TMB、ECOG、组织学、治疗线数进行充分多变量校正并按治疗类型分层后仍保持（P<0.001）。加入胸腺健康后，模型拟合优于人口统计学、临床和肿瘤内在变量（似然比P<0.001）。重要的是，纳入胸腺健康并未削弱PD-L1或TMB的效应，表明其提供了互补、非冗余的预后信息。在各PD-L1和TMB分层中，较高的胸腺健康持续与改善的PFS和OS相关（P<0.03）。在TRACERx中，胸腺健康与T细胞受体切除环（即T细胞输出）呈正相关，并与更高的外周和肿瘤内TCR多样性以及适应性免疫激活的蛋白质组学特征相关，从生物学上支持其作为免疫能力影像学替代指标的作用。跨2,258例接受ICI治疗患者（黑色素瘤、肾癌、乳腺癌等）的泛癌种分析显示，胸腺健康与改善的结局之间存在一致的正相关。
结论：胸腺健康在各癌种中持续与改善的免疫治疗结局相关，并在PD-L1、TMB和标准临床变量之外增加了独立信息。这些发现支持胸腺健康作为一种可能的非侵入性、宿主内在生物标志物，具有细化患者分层和推进精准免疫肿瘤学的潜力。
临床试验标识：ClinicalTrials.gov：TRACERx，NCT01888601
查看英文原文 English abstract
Background: Immune checkpoint inhibitors (ICIs) depend on effective T-cell priming and renewal, yet current biomarkers focus primarily on tumor-intrinsic features (PD-L1, TMB). Because the thymus maintains naïve T-cell output and repertoire diversity, we hypothesized that an individual's thymic health represents a host-intrinsic determinant of ICI benefit.
Methods: We developed a self-supervised deep learning model to quantify thymic function, here termed thymic health, from routine CT scans. Thymic health was independently evaluated in 3,476 patients treated with ICI for tumors of various entities. Associations with PFS and OS were assessed using multivariable Cox models adjusting for key epidemiological and clinical factors. Sensitivity analyses evaluated the incremental contribution of thymic health. Biological validation was performed in treatment-naïve NSCLC patients from TRACERx (n=464) using T-cell receptor (TCR) sequencing and plasma proteomics.
Results: In patients with NSCLC (n=1,218), high thymic health was associated with significantly reduced risk of progression (HR 0.65; 95% CI, 0.54-0.77) and death (HR 0.56; 95% CI, 0.46-0.68); preserved after full multivariate adjustments for sex, age, PD-L1, TMB, ECOG, histology, treatment line and stratification by treatment type (P<0.001). Adding thymic health improved model fit beyond demographic, clinical, and tumor-intrinsic variables (likelihood ratio P<0.001). Importantly, including thymic health did not attenuate PD-L1 or TMB effects, indicating complementary, non-redundant prognostic information. Across PD-L1 and TMB strata, higher thymic health was consistently associated with improved PFS and OS (P<0.03). In TRACERx, thymic health was positively associated with T cell receptor excision circles, i.e., T cell output, and correlated with greater peripheral and intratumoral TCR diversity and with proteomic signatures of adaptive immune activation, biologically supporting its role as a radiographic proxy for immune competence. Pan-cancer analyses across 2,258 ICI-treated patients (melanoma, renal, breast, and others) showed consistent positive associations between thymic health and improved outcomes.
Conclusions: Thymic health was consistently associated with improved immunotherapy outcomes across cancer types and added independent information beyond PD-L1, TMB, and standard clinical variables. These findings support thymic health as a possible non-invasive, host-intrinsic biomarker with potential to refine patient stratification and advance precision immuno-oncology.
Clinical trial identification: ClinicalTrials.gov: TRACERx, NCT01888601
利益披露 Disclosure
S. Bernatz,
Ambient Inc. Independent Contractor.
German Research Foundation (DFG) ), Research Grant from the German Research Foundation (DFG, # 502050303)..
V. Prudente, None..
S. Pai, None.
A. D. Federico,
multiple Other, ADF reports fees and advisory fees from Novartis, IQVIA, Hanson-Wade..
A. Rowan, None.
S. Veeriah,
Patent Other, S.V. is a co-inventor to a patent of methods for detecting molecules in a sample (patent no. 10,578,620).
L. Dyrskjøt,
multiple Other, LD has sponsored research agreements with C2i Genomics, Natera, AstraZeneca, Photocure, and Ferring and has an advisory/consulting role at Ferring, MSD, Cystotech and UroGen. LD has received speaker honoraria from AstraZeneca, Pfizer, and Roche and travel support from MSD. LD is a board member at BioXpedia..
L. Nürnberg, None.
A. Hackshaw,
Roche Other, A.H. has received fees for being a member of independent data monitoring committees for Roche-sponsored clinical trials and academic projects coordinated by Roche.
R. H. Mak,
multiple Other, Advisory Board (ViewRay, AstraZeneca,), Consulting (AstraZeneca, Varian Medical Systems, Sio Capital Management, Pfizer), Honorarium (Novartis, Springer Nature), Research Funding (National Institute of Health, ViewRay, AstraZeneca, Siemens Medical Solutions USA, Inc, Varian Medical Systems).
D. S. Bitterman,
MercurialAI Other, DB is a member of the MercurialAI scientific advisory board.
M. M. Awad, None.
C. Swanton,
multiple Other, C.S. reports receiving support from the Francis Crick Institute and the Royal Society; has received grants or contracts from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Invitae (formerly Archer Dx), Ono Pharmaceuticals, Pfizer and Roche-Ventana; has received consulting fees from Bicycle Therapeutics, Genentech, Medicxi, Metabomed, Novartis, and as a member of the GRAIL SAB.
multiple continue Relay Therapeutics SAB, China Innovation Centre of Roche (CICoR), SAGA Diagnostics SAB, and the Sarah Cannon Research Institute; has received honoraria from Amgen, AstraZeneca, Bristol Myers Squibb, Illumina, GlaxoSmithKline, MSD, Roche-Ventana, and Pfizer; holds patents, planned, issued, or pending, including PCT/GB2017/053289, PCT/EP2016/059401, PCT/EP2016/071471, PCT/GB2018/052004.
multiple continue Other, , PCT/GB2020/050221, PCT/GB2018/051912, PCT/US2017/28013, and PCT/GB2018/051892; have leadership or fiduciary roles with Cancer Research UK and AACR; holds stock or stock options in Apogen Biotech, Epic Biosciences, GRAIL, and Achilles Therapeutics; has other financial or non-financial interests with AstraZeneca and GRAIL Bio UK.
M. Jamal-Hanjani,
multiple Other, CRUK, NIH National Cancer Institute, IASLC International Lung Cancer Foundation, Lung Cancer Research Foundation, Rosetrees Trust, UKI NETs and NIHR. M.J-H. has consulted for Astex Pharmaceutical and Achilles Therapeutics, and is a member of, the Achilles Therapeutics Scientific Advisory Board and Steering Committee, has received speaker honoraria from Pfizer, Astex Pharmaceuticals.
multiple Other, Oslo Cancer Cluster, Bristol Myers Squibb and Genentech. MJ-H is listed as a co-inventor on a European patent application relating to methods to detect lung cancer PCT/US2017/028013), this patent has been licensed to commercial entities and, under terms of employment.
multiple Other, M.J.-H. is due a share of any revenue generated from such license(s), and is also listed as a co-inventor on the GB priority patent application (GB2400424.4) with title: Treatment and Prevention of Lung Cancer.
H. J. Aerts,
multiple Other, HJWLA reports consulting fees and/or stock from Onc.AI, Love Health, Sphera, Health-AI, Ambient, and AstraZeneca.