T-prolymphocytic leukemia (TPLL) is a rare, poor-prognostic, mature T-cell malignancy associated with an aggressive clinical course in the context of limited therapeutic options. Despite exponentially rising tumor burden, mainly in blood, bone marrow, and spleen, we discovered that many TPLL patients do not show overt neutropenia, but rather elevated neutrophil counts. Such 'neutrophilia' was associated with a shorter overall survival and adverse clinical features. Addressing the role of neutrophils in TPLL, we characterized them to show higher survival ex vivo and elevated migratory activity, both mediated by TPLL cells. Furthermore, TPLL-derived neutrophils enhanced the activation of TPLL cells in co-culture experiments. Additionally, we could show that neutrophils are attracted by TPLL-conditioned medium which is mainly driven by IL8. In line, we found IL8 mRNA to be overexpressed in TPLL cells, which was associated with elevated IL8 levels in TPLL plasma. Based on TCL1A-promoted TCR- and hyper-activated JAK/STAT-signaling as hallmarks of TPLL, we found that TCL1A expression increases IL8 secretion upon TCR engagement. In 48-plex cytokine microarrays, IL8 emerged the second highest cytokine secreted by TCR-activated TPLL cells. Moreover, IL8 promoted hyper-activated JAK/STAT signaling in an autocrine manner. Overall, we propose IL8 acting as an autocrine and paracrine agent in TPLL by attracting neutrophils, thereby mediating survival benefits for neutrophils. Simultaneously, neutrophils enhance the activation of TPLL cells, at least in vitro. Upcoming in-vivo experiments will help to reveal the degrees of dependence on neutrophils in driving initiation and/or clonal sustenance of TPLL.
