Effect of Extracellular Survivin and Lymphoma Exosomes on Natural Killer Cells

Tumors alter their microenvironment to promote survival using methods such as angiogenesis promotion, growth signals, and immune suppression. The immune system becomes unresponsive to transformed neoplastic cells through a variety of methods including T cell suppression, increased myeloid-derived suppressor cells (MDSCs), and reduced natural killer (NK) cell activity. NK cells have inherent killing capabilities and thus are among the first responders in recognizing and destroying abnormal cells. However, many types of cancers inhibit the surveillance and cytotoxic abilities of NK cells by releasing exosomes, vesicles that can modulate the tumor microenvironment (TME) and intercellular communication for the purpose of enhancing tumor malignancy. These 30-150 nm sized lipid bound vesicles are secreted by many cell types, including immune cells and tumor cells, and the specific protein, lipid, mRNA and miRNA contents contribute to the complex intercellular communication occurring between malignant and normal cells. Cancer patients often have increased numbers of exosomes circulating through their body, including patients with hematological malignancies, such as lymphoma. The focus of this research was to determine the interactions between B cell lymphoma exosomes and NK cells, and characterize the resultant effects on NK cell function. A specific objective of this research was to determine whether Survivin, an Inhibitor of Apoptosis protein recently found to be localized within exosomes, has a role in modulating NK cells similar to previous findings of T cell modulations. We report that lymphoma exosomes have low levels of internalization into NK cells, and no detectable presence of immune modulating proteins MICA/B or TGF-β. Exposure of NK cells to lymphoma exosomes did not result in observable changes in degranulation or cytotoxic ability. However, treatment with recombinant Survivin protein was able to decrease NKG2D receptor levels in NK cells stimulated with target cells, and decrease protein levels of TNF-α, IFN-γ, perforin, and Granzyme B. A better understanding of the underlying processes by which Survivin or exosomes suppress immune cells in the TME may pave the way to more efficacious immunological therapies against cancer