STUDY OF TUMOR DRIVEN ALTERATION OF T AND NK CELL ACTIVITY

Abstract

Both NK cells and T cells play an important role in anti-tumor immunity. T-cells are activated through primary signal constituted by recognition of tumor antigen presented upon self MHC and co-stimulation by other co-stimulatory molecules. Hence tumor cells need both primary and co-stimulatory ligands to be susceptible to T cell cytolysis. NK cells on the other hand do not require MHC mediated antigen presentation and can bind directly to the ligands expressed by the tumors. NK cells express inhibitory receptors which upon binding to HLA molecules send a strong inhibitory signal that prevents NK cell mediated tumor cell lysis. Each NK cell expresses a multitude of activating and inhibitory receptors and a delicate balance of the two opposing signals determines the fate of NK cell stimulation. It has been shown that tumors themselves modulate the activity of T cells and NK cells by altering the expression of different ligands, in order to evade the immune system. In the present study we analyzed the expression levels of both activating as well as inhibitory ligands in various tumors for both NK and T cells. The tumors under consideration were themselves clubbed into two groups based on the levels (high/low) of HLA expression. Our studies showed that in case of the tumors that expressed high levels of HLA, the tumor cells try to actively decrease co-stimulatory signals for T cells in order to evade T cell mediated cytotoxicity. However this also results in increased activation signals in NK cells. Multiple activation signals synergize in NK cells and may also overcome the inhibition through KIR-MHC-I ligation, in such tumors with high MHC expression. These findings suggest that in case of tumors with high MHC expression that are resistant to T cell therapies, a new strategy of combinatorial therapy using co-stimulation of NK cells may prove to be more effective.