Myeloma-Derived CCL27 Induces Stroma-Dependent Resistance Against Bortezomib via Regulation of IL-10

Karin Joehrer ¹ Shanmugapriya Thangavadivel ¹ Angelika Olivier ¹ Benno Postert ¹ Claudia Zelle-Rieser ¹ Johann Kern ² Gerold Untergasser ^1,2 Andrea Brunner ³ Wolfgang Willenbacher ⁴ Rainer Biedermann ⁵ Richard Greil ⁶

¹Tumor Microenvironment Group, Tyrolean Cancer Research Institut, Austria
²Laboratory for Tumor Biology and Angiogenesis, Department of Internal Medicine V, Medical University Innsbruck, Austria
³Department of Pathology, Medical University Innsbruck, Austria
⁴Department of Internal Medicine V, Medical University Innsbruck, Austria
⁵Department of Orthopedic Surgery, Medical University Innsbruck, Austria
⁶Laboratory for Immunological and Molecular Cancer Research, IIIrd Medical Department of Internal Medicine, Paracelsus Medical University, Austria

Multiple Myeloma is a still incurable plasma cell malignancy and drug-resistance is the major cause for relapse and early death of the patients. The bone marrow microenvironment plays a fundamental role in shaping tumor progression. Chemokines are soluble mediators of cell migration, proliferation and survival and myeloma-derived chemokines might also play an important role in drug-resistance. Here we discovered that the chemokine CCL27 can trigger bortezomib-resistance of myeloma cells.

Briefly, myeloma cells secreted CCL27 and high levels correlated with poor survival in vivo. These cells as well as stromal cells expressed the respective receptor CCR10. Ligand binding led to enhanced adhesion and migration of the malignant cells. In coculture with stromal cells but not in single culture, CCL27 protected myeloma cells from bortezomib-induced cell death but not from melphalan-induced cell death. This was also confirmed in vivo. We found that myeloma-derived CCL27 was further upregulated by bortezomib-treatment and modulated stroma-derived IL-10 levels. In this setting, stromal IL-10 acted as a survival protein for myeloma cells. Knock-down of CCR10 on stromal cells as well as blocking IL-10 and the IL-10 receptor reversed bortezomib resistance in myeloma cells. Modulation of proteasomal activity and immunoglobulin expression levels in the myeloma cells appeared to be involved in this escape mechanism.

In conclusion, from our data we suggest that CCL27 is a novel player involved in bortezomib resistance in multiple myeloma and targeting this system could convert drug resistance and contribute to better therapeutic response in this cancer.