T-cells are known to get “exhausted” when fighting cancer. Early exhaustion can sometimes be reversed with immunotherapy drugs, but until now it was believed that this had limits. Genengnews.com reports that recent studies by University of Pittsburgh and University of Pittsburgh Medical Centre (UPMC) indicated the possibility of reviving “the most fatigued T-cells”.  

The researchers “profiled molecular features” of the cells as they moved from “early to terminal exhaustion”. The team noted that “differentiation to exhaustion is progressive”. It is represented by “at least two transcriptionally and functionally distinct states: one progenitor or stem-like and another terminally differentiated”.  To their surprise, the results suggested that terminally exhausted T-cells could “be functional again”.   

Dr Amanda Poholek of Pitt’s School of Medicine and the UPMC Children’s Hospital of Pittsburgh stated that these findings “have incredible potential for immunotherapy”. Providing T-cells with “rest” can enable them to “come back”.  

Currently some cancer immunotherapies can reverse exhaustion, giving T-cells a boost. Unfortunately, terminally exhausted cells do not usually respond to these therapies. However, the team is optimistic that understanding of the “transition from progenitor T-cells to terminal exhaustion”, will promote further advances. Despite this hope it is “unclear” if these cells have “therapeutic potential to gain effector capacity”.  

Co-senior author, Dr Greg Delgoffe of the UPMC Hillman Cancer Centre, stated that in order to “bring the promise of immunotherapy” to more people, scientists need to better understand the process of failure in T-cells. With this goal, the researchers profiled the cells’ epigenome and were “really surprised” to discover that they had “the potential for recovery”.  

In these cells it became apparent that something was “inhibiting gene expression”. They identified that “terminally exhausted T-cells had insufficient co-stimulation”. When addressed with an antibody that binds to a co-stimulatory receptor, 4-1BB, “gene expression increased”.  

Further investigations revealed that hypoxia, “common in the tumour microenvironment”, also influenced gene expression. Thus, when programmed to resist hypoxia, the cells “differentiated into a more functional state”.  

“Our data highlight the convergence of both immunologic signals and pathologic environmental signals that redirect differentiation to exhaustion” 

Dr Delgoffe believes that “restoring oxygen or improving co-stimulation” will push these cells to their “full potential”. The paper concludes with the hope that new approaches could “target hypoxia or co-stimulation pathways”. The ambition is to contribute to therapies that “take full advantage of all subsets of tumour-infiltrating T-cells to eradicate cancer cells”.

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