NKG2D Ligands in Liquid Biopsy: The Importance of Soluble and Vesicle-Bound Proteins for Immune Modulation

The identification of biomarkers allowing diagnostics, prognostics and patient classification is still a challenge in oncological research for patient management. Improvements in patient survival achieved with immunotherapies substantiate that biomarker studies rely not only on cellular pathways contributing to the pathology, but also on the immune competence of the patient. If these immune molecules can be studied in a non-invasive manner, the benefit for patients and clinicians is obvious. The immune receptor Natural Killer Group 2 Member D (NKG2D) represents one of the main systems involved in direct recognition of tumor cells by effector lymphocytes (T and Natural Killer cells), and in immune evasion. The biology of NKG2D and its ligands comprises a complex network of cellular pathways leading to the expression of these tumor-associated ligands on the cell surface or to their release either as soluble proteins, or in extracellular vesicles that potently inhibit NKG2D-mediated responses. Increased levels of NKG2D-ligands in patient serum correlate with tumor progression and poor prognosis; however, most studies did not test the biochemical form of these molecules. Here we review the biology of the NKG2D receptor and ligands, their role in cancer and in patient response to immunotherapies, as well as the changes provoked in this system by non-immune cancer therapies. Further, we discuss the use of NKG2D-L in liquid biopsy, including methods to analyse vesicle-associated proteins. We propose that the evaluation in cancer patients of the whole NKG2D system can provide crucial information about patient immune competence and risk of tumor progression.