Disturbed mitochondrial dynamics in CD8+ TILs reinforce T cell exhaustion

Supplementary Website

The metabolic challenges present in tumors attenuate the metabolic fitness and antitumor activity of tumor-infiltrating T lymphocytes (TILs). However, it remains unclear whether persistent metabolic insufficiency can imprint permanent T cell dysfunction. We found that TILs accumulated depolarized mitochondria as a result of decreased mitophagy activity and displayed functional, transcriptomic and epigenetic characteristics of terminally exhausted T cells. Mechanistically, reduced mitochondrial fitness in TILs was induced by the coordination of T cell receptor stimulation, microenvironmental stressors and PD-1 signaling. Enforced accumulation of depolarized mitochondria with pharmacological inhibitors induced epigenetic reprogramming toward terminal exhaustion, indicating that mitochondrial deregulation caused T cell exhaustion. Furthermore, supplementation with nicotinamide riboside enhanced T cell mitochondrial fitness and improved responsiveness to anti-PD-1 treatment. Together, our results reveal insights into how mitochondrial dynamics and quality orchestrate T cell antitumor responses and commitment to the exhaustion program.

Graphical overview

Graphical summary of the impacts of TME factors on mitochondrial fitness and commitment of exhaustion in CD8+ TILs.

Data

This section provides access to raw data and analysis results.

Description Links
UCSC Genome (mm10) browser tracks:
 UCSC Genome Browser Link
Sequencing data
(Uploaded to Gene expression omnibus - GEO) 		Superseries across all data (GEO SuperSeries GSE144584)
ATAC-seq data (GEO Series GSE144582)
WGBS data (GEO Series GSE144583)
RNA data (GEO Series GSE156506)
Results:
 Extended Data Table 1 (XLS)
Extended Data Table 2 (XLS)
Extended Data Table 3 (XLS)
Extended Data Table 4 (XLS)
Extended Data Table 5 (XLS)
Extended Data Table 6 (XLS)
Extended Data Table 7 (XLS)
Code:
 All code relevant for data processing and analysis (ZIP-Archive)

Citation

If you use these data in your research, please cite:

Yi-Ru Yu*, Hana Imrichova*, Haiping Wang, Tung Chao, Zhengtao Xiao, Min Gao, Marcela Rincon-Restrepo, Fabien Franco, Raphael Genolet, Wan-Chen Cheng, Camilla Jandus, George Coukos, Yi-Fan Jiang, Jason W. Locasale, Alfred Zippelius, Pu-Ste Liu, Li Tang, Christoph Bock, Nicola Vannini and Ping-Chih Ho. Disturbed mitochondrial dynamics in CD8+ TILs reinforce T cell exhaustion. Nature Immunology (2020), doi: 10.1038/s41590-020-0793-3
* These authors contributed equally to this work

Correspondence: ping-chih.ho@unil.ch (Ping-Chih Ho)