Azzam A. Maghazachi
College of Medicine, University of Sharjah, UAE
Purpose/Objectives: Multiple Sclerosis (MS) is an autoimmune disease, whereas cancer develops in immunodeficient individuals. Natural killer (NK) cells stand at the cross road among treatment of autoimmune diseases and immunodeficient diseases. We reported a new mechanism of action for the drug Copaxone (TEVA Inc.) upon treating multiple sclerosis (MS) patients. NK cells isolated from those patients lysed both immature (i) and mature (m) dendritic cells (DCs) isolated from the same patients. These results were based on previous findings showing that Copaxone ameliorated experimental autoimmune encephalomyelitis (EAE) in mice, corroborated with isolating NK cells that killed both iDCs and mDCs. Similarly, vitamin D3 or FTY720 (Gilenya, Novartis) augmented IL-2-activated NK cells lysis of tumor, iDCs and mDCs. These observations demonstrate that drugs used to treat MS patients activate NK cells to lyse antigen-presenting cells and consequently, impede autoreactive T cell activation. Dimethyl fumarate (DMF) (Biogen, Inc.) is a new drug for treating MS patients. We have examined the effects of DMF and its metabolite monomethyl fumarate (MMF) on various activities of NK cells.
Results: We demonstrate that MMF induces resting CD56+ NK cell lysis of the NK-sensitive K562 cells and the NK-resistant RAJI cells. More recently, we observed that Copaxone and MMF up-regulate the expression of CCR10 on the surface of NK cells. This is corroborated with the ability of NK cells to migrate towards the concentration gradients of CCR10 ligands, namely CCL27 and CCL28.
Conclusions: Our observations are the first to show that MMF converts the non-cytolytic CD56+ NK cells into robust anti-tumor effector cells. They are also the first to show that MMF and Copaxone can be used to direct the anti-tumor effector cells towards tumor cells that secrete the chemokine CCL27 such as melanomas or squamous cell carcinoma, or those secreting CCL28 such as colorectal carcinoma. Hence, drugs used to treat autoimmune diseases can also be used to treat cancer. Clinical protocols using this novel strategy to treat cancer will be discussed.