Disturbed mitochondrial dynamics in CD8+ TILs reinforce T cell exhaustion

Yu YR, Imrichova H, Wang H, et al. Disturbed mitochondrial dynamics in CD8+ TILs reinforce T cell exhaustion. Nat Immunol. 2020 Dec;21(12):1540-1551. doi: 10.1038/s41590-020-0793-3.

The anti-tumor activity of Tumor-Infiltrating T Lymphocytes (TILs) can be attenuated by metabolic challenges present in tumors. The tumour microenvironment (TME) is home to many factors that impose restrictions on the anti-tumor activities of TILs by interfering with their metabolic pathways and transcriptional and translational regulations.1 It is not clearly understood how TILs adapt to these sustained metabolic challenges imposed by the TME and whether any inability to adapt can result in T cell dysfunction or exhaustion.

Mitochondria play a key role in sustaining the metabolic fitness of cells in response to metabolic perturbations by increased mitochondrial fusion and biogenesis. Mitochondria that are damaged during this process are cleared from the cell by mitophagy. Non-clearance of damaged mitochondria results in an increased accumulation of mitochondrial mass with reduced membrane potential (depolarised mitochondria) and the prevention of mitochondrial biogenesis through reprogramming of the epigenome and transcriptome. Mitochondrial dynamics have also been suggested to modulate the generation of memory CD8+ cells. Furthermore, decreased mitochondrial biogenesis and production of reactive oxygen species (ROS) can promote T cell dysfunction in chronic viral infections and tumors.2-4

In this paper published in Nature Immunology, Yu, et.al have investigated how T cell anti-tumor responses may be influenced by mitochondrial dynamics and quality. Using flow cytometry data from MitoTracker Green and MitoTracker Deep Red staining of CD8+ T cells from spleens, draining lymph nodes and tumors from melanoma-engrafted mice, the authors propose that CD8+ T cells in the TME are prone to accumulating mitochondria with compromised mitochondrial membrane potentials. They propose that CD8+ TILs contain two subsets with distinct mitochondrial morphologies – one with normal and the other with impaired mitophagy activity. The authors opine that the disruption of mitophagy activity further enhances the mitochondrial depolarisation phenotype in CD8+ TILs. Furthermore, comparing the two subsets of CD8+ TILs using Gene Set Enrichment Analysis, the authors observe that the CD8+ T cell subset with disrupted mitophagy activity is enriched in gene signatures of exhausted CD8+ T cells.  According to the authors, these cells also undergo less population expansion, express higher amounts of PD-1 and LAG-3, and produce less IFN-γ, suggestive of terminal T cell exhaustion. These results enable the authors to suggest that the accumulation of depolarized mitochondria in CD8+ TILs propels T cells towards terminal exhaustion and locks them in a permanent dysfunctional state.

The experiments have also allowed the authors to establish a link between depolarized mitochondria and exhaustion epigenetic programs. Looking at differential chromatin accessibility of the two CD8+ TIL subsets, the authors could propose that the subset with depolarized mitochondria is more exhausted and less memory-like compared to the subset with normal mitochondria. Finally, the authors also observe that TCR and PD-1 signals drive the accumulation of depolarized mitochondria. They observe that TCR stimulation coordinates with metabolic stress to suppress mitophagy and thereby maximise the formation of the CD8+ TIL subset with depolarized mitochondria.

All the results put together have enabled the authors to derive more information into how mitochondrial dynamics and quality orchestrate CD8+ T cell anti-tumor responses and reinforce T cell exhaustion.

To learn more about the actual experiments, read the article online.

Li, X. et al. Navigating metabolic pathways to enhance antitumor immunity and immunotherapy. Nat. Rev. Clin. Oncol. 16, 425–441 (2019).
2Bengsch, B. et al. Bioenergetic insufficiencies due to metabolic alterations regulated by the inhibitory receptor PD-1 are an early driver of CD8+ T cell exhaustion. Immunity 45, 358–373 (2016).
3 Scharping, N. E. et al. The tumor microenvironment represses T cell mitochondrial biogenesis to drive intratumoral T cell metabolic insufficiency and dysfunction. Immunity 45, 374–388 (2016).
4 Siska, P. J. et al. Mitochondrial dysregulation and glycolytic insufficiency functionally impair CD8 T cells infiltrating human renal cell carcinoma. JCI Insight 2, e93411 (2017).
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