PO.CL01.15 · 临床研究
Radiographic thymic health as host-intrinsic determinant of immunotherapy outcomes across cancer types
作者与单位 Authors & Affiliations
摘要 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.