Thymic health and immunotherapy outcomes in patients with cancer.
Authors
Affiliations (17)
Affiliations (17)
- Artificial Intelligence in Medicine (AIM) Program, Mass General Brigham, Harvard Medical School, Boston, MA, USA.
- Department of Radiation Oncology, Brigham and Women's Hospital and Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
- Radiology and Nuclear Medicine, GROW and CARIM, Maastricht University, Maastricht, The Netherlands.
- Department of Radiology and Nuclear Medicine, Goethe University, Frankfurt, Germany.
- Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark.
- Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.
- Bioinformatics Research Center, Aarhus University, Aarhus, Denmark.
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
- Cancer Evolution and Genome Instability Laboratory, Francis Crick Institute, London, UK.
- Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK.
- Department of Medical Oncology, University College London Hospitals NHS Foundation Trust, London, UK.
- Cancer Research UK and UCL Cancer Trials Centre, London, UK.
- Cancer Genome Evolution Research Group, University College London Cancer Institute, London, UK.
- Cancer Metastasis Laboratory, University College London Cancer Institute, London, UK.
- Artificial Intelligence in Medicine (AIM) Program, Mass General Brigham, Harvard Medical School, Boston, MA, USA. [email protected].
- Department of Radiation Oncology, Brigham and Women's Hospital and Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA. [email protected].
- Radiology and Nuclear Medicine, GROW and CARIM, Maastricht University, Maastricht, The Netherlands. [email protected].
Abstract
Although immunotherapy has revolutionized cancer treatment, many patients still experience limited benefit, highlighting the urgent need for improved biomarkers<sup>1</sup>. Although immunotherapy is founded on unleashing T cells<sup>2</sup>, most existing biomarkers remain tumour-centric and mainly overlook host immune competence. The thymus is a key immune organ that is crucial for T cell maturation, and we hypothesized that thymic functionality is associated with immunotherapy outcomes<sup>3</sup>. Here we show that thymic health, a radiographic measure of thymic functionality, is strongly associated with immunotherapy outcomes across several cancer types. Using a deep-learning framework applied to routine computed tomography images, we quantified thymic health in a pan-cancer cohort of 3,476 patients receiving immune checkpoint inhibitors. In patients with non-small cell lung cancer, higher thymic health was associated with reduced risks of progression and all-cause mortality. These associations remained significant across clinically relevant levels of programmed death ligand 1 (PD-L1) and tumour mutation burden. In the prospective TRACERx lung cancer study, thymic health was positively associated with T cell receptor diversity and T cell receptor excision circles, and correlated with immune-system signalling pathways, supporting radiographic thymic health as a proxy for thymic activity and adaptive immune competence. Analysis across patients with melanoma, breast cancer or renal cancer demonstrated pan-cancer relevance. Together, these findings identify thymic health as a previously unrecognized, tumour-agnostic determinant of immunotherapy efficacy, with potential implications for patient stratification, treatment timing and the development of immune-rejuvenating strategies in precision immuno-oncology.