CCR10/CCL27 crosstalk contributes to failure of proteasome-inhibitors in multiple myeloma

Abstract

The bone marrow microenvironment plays a decisive role in multiple myeloma progression and drug resistance. Chemokines are soluble mediators of cell migration, proliferation and survival and essentially modulate tumor progression and drug resistance. Here we investigated bone marrow-derived chemokines of naive and therapy-refractory myeloma patients and discovered that high levels of the chemokine CCL27, known so far for its role in skin inflammatory processes, correlated with worse overall survival of the patients. In addition, chemokine levels were significantly higher in samples from patients who became refractory to bortezomib at first line treatment compared to resistance at later treatment lines.In vitro as well as in an in vivo model we could show that CCL27 triggers bortezomib-resistance of myeloma cells. This effect was strictly dependent on the expression of the respective receptor, CCR10, on stroma cells and involved the modulation of IL-10 expression, activation of myeloma survival pathways, and modulation of proteasomal activity. Drug resistance could be totally reversed by blocking CCR10 by siRNA as well as blocking IL-10 and its receptor.From our data we suggest that blocking the CCR10/CCL27/IL-10 myeloma-stroma crosstalk is a novel therapeutic target that could be especially relevant in early refractory myeloma patients.

Impact of Clonal Hematopoiesis on the Carcinogenic Process of Multiple Myeloma

“…Our nding is consistent with previous literature indicating that CCR10/CCL27 myeloma-stroma crosstalk contributes to bortezomib resistance in MM cell lines. 27 In fact, blocking CCR10 signi cantly reduced the proliferative effect of TET2 mutated CH on MM cells, suggesting a potential therapeutic target. Recent surface proteomic analysis also suggests CCR10 as an important molecule in MM.…”

Roles of CCR10/CCL27–CCL28 axis in tumour development: mechanisms, diagnostic and therapeutic approaches, and perspectives

“…Therefore, treatments that enhance the production of these two chemokines have been shown to have anti-cancer properties ( Refs 30,31,32). In contrast, numerous studies have shown that expression of CCL27 and CCL28 was increased in lymphomas, bladder cancer, hepatocellular carcinoma (HCC) and multiple myeloma ( Refs 33,34,35,36,37,38,39,40,41,42,43). Although the underlying mechanisms regarding dysregulation of CCL27/ CCL28 have not yet been defined in all experiments, some studies have indicated possible mechanisms which are discussed in the following.…”

“…It is concluded that blocking the CCR10/CCL27/IL-10-dependent myeloma crosstalk with stroma by siRNAs or antibodies might be a novel and tailored therapeutic target in early refractory myeloma patients (Ref. 43).…”

“…31). The majority of the research on CCR10/CCL27–CCL28's role in cancer has been conducted in vitro, with just a small number of studies conducted in vivo, the majority of which have used animal models (Refs 20, 29, 41, 43, 51). As a result, these findings from in vitro studies will be hard to translate into clinical studies.…”