T cells in a stress response state may be associated with more aggressive cancers and poor response to immunotherapy.Credit: Thom Leach/ Science Photo Library/ Getty Images
T cells, the hunter-killers of the immune system, exist in many different states. The race is on to better understand how these states might contribute to cancer progression and influence immunotherapy efficacy.
For researchers looking for new insights, a team at The University of Texas MD Anderson Cancer Center has developed a potent tool: a pan-cancer single-cell T cell atlas, integrating 27 single-cell RNA sequencing datasets, including 10 unique datasets, covering 16 cancer types. The study, published in Nature Medicine, provides the most detailed overview to date of the diversity of T cell states in the tumour microenvironment (Chu, Y. et al. Nat Med 29, 1550-1562; 2023).
The data revealed a distinct and previously overlooked T cell stress response state (TSTR). It is likely that these TSTR cells are less effective at their job of fighting cancer — just as a person suffering with stress may struggle to perform at work.
“In this study, we noticed the presence of stressed T cells seemed to be associated with some aggressive phenotypes of the disease in multiple cancer types,” says Linghua Wang, associate professor of genomic medicine at MD Anderson and corresponding author of the study. “Following immunotherapy, we observed a significant increase in stressed T cells, particularly among those who did not respond to treatment.”
From stress to resistance?
Previous single-cell studies have predominantly focused on exhausted T cells, while stressed T cells were largely overlooked. Both states are likely dysfunctional, but the new research showed that TSTR cells follow a distinct differentiation path and are a separate group, unique from other CD4+ or CD8+ T cell subsets. The study also revealed that TSTR cells are characterized by high levels of heat shock gene expression, specifically those encoding the heat shock protein 70 family. Notably, the expression of these genes significantly increased in both CD4+ and CD8+ T cells following immunotherapy. This increase was particularly evident in patients who did not respond to treatment, suggesting that TSTR cells may contribute to immunotherapy resistance.
“Across various types of cancer, most patients either do not respond to immunotherapy or develop resistance to treatment,” says Wang. “A greater understanding of stressed T cells could provide new insights into immunotherapy resistance. But there are still many questions left to answer.”
Two such questions — what are the mechanisms causing stress response in T cells, and can these be prevented or reversed to improve immunotherapy efficacy? Answers are needed as to the specific T cell populations from which the TSTR cells originate, what triggers their state, whether they are specific to tumour cells, and how they communicate with other cells.
The study also highlights the value of big data analytics in oncology. “Few studies have looked at T cells in such granularity,” says Wang. “Being able to analyse large, integrative datasets offers us the power to look at T cells in high resolution and better define the various T cell states.”
The team has made its T cell atlas available through the Single-Cell Research Portal, enabling researchers to align their own T cell datasets with the maps using the tool TCellMap.
Wang says: “We hope these high-resolution maps will help the wider oncology community to better understand T cell states, facilitate biomarker discovery and, ultimately, enhance strategies for T-cell therapy.”