Imbalance of activating and inhibitory receptor expression on effector cells in multiple myeloma patients results in immune suppression

Multiple myeloma (MM) is an incurable plasma cell malignancy of the bone marrow (BM). Recent evidence suggests that natural killer (NK) cells are intricately involved in the immunosurveillance of MM and can specifically target malignant plasma cells in the absence of the immunosuppressive BM microenvironment. Immune suppression in MM patients is systemic with total CD4 T cell counts in the peripheral blood significantly lower than healthy donors. We have data showing that the major NK activating receptor NKG2D is significantly reduced in MM patients, whereas inhibitory NKG2A, KIR2DL1 and KIR2DL3 are up-regulated. These inhibitory receptors target HLA-E and C respectively, and dominate over activating signals. Interestingly, we report that NKG2A, KIR2DL1 and KIR2DL3 were also up-regulated on T cells in MM patients. Our subsequent investigations showed that expression of KIR receptors could be induced on CD4 T cells independent of direct cell contact with MM cells. Throughout treatment using an empirical MM drug regimen including an immunomodulatory drug and a corticosteroid, we saw restoration of NKG2D but no change in the expression of inhibitory receptors on NK or T cells in MM patients. Together, this data reveals a novel model of T cell tolerance to MM and highlights to therapeutic potential of KIR blockade to reverse immune suppression.