Enhanced MHC Class I and II expression induced following staggered combination treatment of human tumor cells with Hsp90 inhibitors and Interferons. (165.16)

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Abstract We have previously shown that Hsp90 inhibitors (iHsp90) can enhance both differentiation antigens and MHC Class I in melanomas and gliomas. To extend these findings, we treated a series of tumors including cancers of the breast, cervix, osteosarcoma and lymphomas to examine the effects of iHsp90 on both Class I and II MHC. Class I MHC was enhanced in most tumors, but induction of MHC Class II antigens was NOT induced in MHC Class II-negative tumors. Since both Types I and II interferon’s (IFN) are known to enhance MHC antigen expression, we wished to determine they would synergize with iHsp90s. However, since iHsp90s can inhibit IFN-signaling, we varied the time of exposure of the tumor cells to the IFNs and iHsp90s to determine if we could circumvent the counteracting effects. While IFN-gamma stimulated strong Class II MHC expression, the simultaneous addition of iHSP90 largely prevented this MHC Class II expression. However, pretreatment for 24 hrs with IFN-gamma allowed iHsp90 to further enhance MHC Class II expression. Similarly, synergistic enhancement of MHC Class I expression was noted if either IFN-beta or IFN-gamma were added prior to addition of iHsp90. Staggering treatment with interferon’s and iHsp90s yielded strong induction of both Class I and II MHC antigens. As both IFN and iHsp90 increased differentiation antigens and MHC, the further increase in MHC expression from the drug combination could be of particular utility in cancer immunotherapy.