TUMOR CELL MEDIATED MODULATION OF NK RECEPTORS AND THEIR ROLE IN CANCER

Abstract

Natural Killer (NK) cells are large granular lymphocytes of the innate immune system with the capacity to kill tumor and virus infected cells without prior sensitization. This is distinct from the mechanism acquired by T-cells to kill target cells, which involves recognition of tumor antigens in a major histocompatibility restricted manner. NK cytotoxicity is regulated by a fine balance between activation and inhibition signals by a multitude of receptors stochastically expressed on each NK cell. NK cells preferentially kill target cells that lack surface expression of major histocompatibility (MHC) class I molecules. Inhibitory NK receptors recognize MHC class I molecules to induce inhibition of NK cell cytotoxicity. IL-2 is the first cytokine to be tested and successfully used as therapeutic agent in cancer. IL-2 stimulation has been shown to cause an expansion of NK cells and T-cells. In the present study, we explored the effect of IL-2 stimulation on proliferation of NK cell population and modulation of NK cell activity. IL-2 stimulation of NK cells resulted in proliferation of NK1.1+ NK population and increase in expression of Ly49A (non-cognate) inhibitory receptor. However neither there was any change in cognate inhibitory receptor, Ly49C nor activating receptor, Ly49D. Hence, IL-2 was found to cause potentiation of NK population but did not result in auto-immunity due to NK activation in absence of tumor. Despite, potential role of immune system in controlling tumor progression, the tumor cells often evolve strategies to escape immunosurveillance. It has been established that tumor cell mediate modulation in the NK cell receptor profile results in effector function against target cells. In the present study, tumor derived factors from NK resistant tumor were tested for NK receptor expression. In this study we showed that membrane derived factors of P815 interfere with the NK cell function by actively modulating the surface expression of NK cell inhibitory receptors, Ly49A and Ly49C. The inhibitory receptor modulation may be responsible for hypoactivity of NK cells against P815 target tumor cells. Thus, identifying the factors responsible for modulation in NK cell receptor expression and frequency will help to optimize the potential of NK cells in current therapies in combinatorial therapies against tumors.

NK cells express a wide range of inhibitory receptors and it was observed that NK inhibitory receptor and non-classical HLA interaction resulted in better inhibition of NK cell cytotoxicity than with classical HLA molecules. In the present study, the basis for this difference in inhibition potential of NK inhibitory receptors was explored. Since each NK cell expresses a multitude of receptors on a single cell; it was difficult to study binding affinities and residues involved in receptor-ligand interaction through experimental studies. Hence, binding affinity of different inhibitory receptors with classical and non-classical HLA molecules was explored through computational approach. The present study conclusively showed that there was greater affinity of NKG2 receptors for their ligands, non-classical HLA molecules due to engagement of more residues at the receptor-ligand interface. NK cells have been used as potential immunotherapeutic agents against tumors. Various NK based therapies such as adoptive cell transfer therapy, chimeric antigen receptors, and cytokines based therapies have shown promising results but did not result in complete regression of tumors in most cases. Our findings would help to design strategies to strengthen the potential of NK cells in current NK based regimens for cancer therapy.