085 Senescent dendritic cells drive ROS-induced DNA damage in CTCL

Abstract

Progressive DNA damage and worsening aneuploidy are associated with the development of highly aggressive CTCL. We immunostained MF skin lesions for the phosphorylated DNA double-strand break repair genes γH2AX and 53BP1 and phosphorylated/activated ATM (pATM) and found that ongoing double-strand DNA breaks were frequent within the malignant T cells even in clinically stable MF skin lesions. IL-6, a product of senescent cells, is the second most highly expressed cytokine in MF. Immunostaining demonstrated the senescence marker p21Cip1 was increased in a stage specific manner in MF and localized to OX40L+CD40L+ dendritic cells. These DC also expressed thioredoxin (TXN), indicating production of reactive oxygen species (ROS) and were found clustered closely together with malignant and benign T cells. ROS production by senescent cells is known to drive ROS-induced DNA damage in neighboring cells. We therefore immunostained T cells near senescent DC for evidence of oxidative stress (TXN) and double-strand DNA breaks (γH2AX). We found a stage specific increase in T cells experiencing oxidative stress and ongoing DNA damage in T cells neighboring senescent DC. Malignant T cells were primarily affected but some CD7+ benign infiltrating T cells showed evidence of DNA damage in later stage MF (IIA, IIB). Our results suggest that ROS produced by senescent DC induces DNA damage in T cells and may drive T cell transformation and tumor progression. These studies suggest a possible role for senolytic therapies in the treatment of CTCL.