ISHL10 Abstract P026

Hodgkin cell-derived extracellular vesicles shape fibroblast activity

In Hodgkin lymphoma (HL) the malignant cells are greatly outnumbered by non-malignant immune cells supporting tumor growth and progression. Hodgkin Reed Sternberg (HRS) cells grow highly dependent on the microenvironment, which is actively shaped by a very complex cross-talk between the tumor cells and the reactive infiltrate.

HRS cells secrete cytokines and angiogenic factors capable of recruiting and inducing the proliferation of surrounding cells to finally orchestrate their cellular microenvironment and to inhibit the development of an efficient antitumor immune response. Within this scenario, the role of extracellular vesicles (EVs) released by HRS cells which can communicate with other cells in trans has not been addressed yet. Recently, we demonstrated that EVs released by HRS cells impact on the formation of a tumor supportive niche by stimulating IL-8 release. Here, we investigate the role of tumor cell-derived vesicles on fibroblast activity and thus their impact on creating a tumor favorable surrounding.

With single and co-cultures of the malignant cells and healthy stromal cells, the reciprocal effects on their cellular functions were analyzed. Using Fibroblast mediated eotaxin as a marker we could show that the bi-directional cross-talk is not entirely cell-cell contact dependent. Not only soluble factors, but also EVs had a positive effect on migration and chemotaxis, showing concentration depending effects. EVs released by malignant cells are internalized by fibroblasts and induce an inflammatory phenotype, which resembles the phenotype of cancer associated fibroblasts (CAFs). As a result of EV exposure, fibroblasts show selective changes in the secretome with enhanced expression of pro-inflammatory cytokines and hits related to NFκB-Signaling. Further experiments indicate that in this context, NFκB-Signaling is induced by TNF-α transported via EVs. Results are further supported by in vivo experiments using a HL Xenograft model.

Authors

  • T. Bösl
  • H.P. Hansen
  • A. Engert
  • E. Pogge von Strandmann

Talk

This abstract has been presented as Abstract Talk in “Genetics and Microenvironment