Kidney cancer is a malignant tumor that accounts for about two percent of all cancers in the United States. African American men and women account for a higher incidence rate of kidney cancer compared to other races. The higher rate of failure of current immunotherapeutic strategies is attributed to the immunosuppressive effects as well as modification of the immune-regulatory circuits brought about by cancers. With the aim of enhancing immune mechanisms against kidney cancer, we undertook a combinatorial approach to reveal the therapeutic potential of adoptive cell transfer regimens using mouse models in conjunction with molecular targeting drugs that sensitize kidney tumor cell-death. The proteasome inhibitor, bortezomib, selectively sensitizes kidney tumor cells to apoptosis by activating caspase-8 in the extrinsic apoptosis pathway. Moreover, our studies thus far have revealed that bortezomib can also enhance natural killer (NK) cell antitumor function. We observed that bortezomib upregulates Fas and NK cell activating receptor NKG2D ligand Rae1-on renal cancer Renca cells in vivo. Moreover, preliminary observations suggest that bortezomib can be combined with adoptive NK cell transfer to provide greater therapeutic benefits with little adverse effects in vivo. These new data predict the potential of combining adoptive NK cell transfer regimens with bortezomib-induced sensitization of kidney tumor cells to induce apoptosis. Such a combinatorial approach of NK cell transfer coupled with bortezomib treatment would have dual effects by sensitizing tumor cells to cell death and improve NK cell effector functions. This could prevent tumor metastasis by eliminating tumor escape variants and significantly benefit tumor immunotherapy efforts in kidney cancer.

Citation Information: Cancer Epidemiol Biomarkers Prev 2011;20(10 Suppl):B107.