Oxidative-stress-induced telomere instability drives T cell dysfunction in cancer
Dayana B. Rivadeneira, Sanjana Thosar, Kevin Quann, William Gunn, Victoria Dean, Bingxian Xie, Angelina M. Parise, A McGovern, Kellie Spahr, Konstantinos Lontos, Ryan Barnes, Marcel P. Bruchez, Patricia L. Opresko, Greg M. Delgoffe
Abstract
The tumor microenvironment (TME) imposes immunologic and metabolic stresses sufficient to deviate immune cell differentiation into dysfunctional states. Oxidative stress originating in the mitochondria can induce DNA damage, most notably telomeres. Here, we show that dysfunctional T cells in cancer did not harbor short telomeres indicative of replicative senescence but rather harbored damaged telomeres, which we hypothesized arose from oxidative stress. Chemo-optogenetic induction of highly localized mitochondrial or telomeric reactive oxygen species (ROS) using a photosensitizer caused the accumulation of DNA damage at telomeres, driving telomere fragility. Telomeric damage was sufficient to drive a dysfunctional state in T cells, showing a diminished capability for cytokine production. Localizing the ROS scavenger GPX1 directly to telomeres reduced telomere fragility in tumors and improved the function of therapeutic T cells. Protecting telomeres through expression of a telomere-targeted antioxidant may preserve T cell function in the TME and drive superior responses to cell therapies.