|About GSBS | FAQ | Job Opportunities | Search UMDNJ|
Cancer Therapeutics Induce Elevated MHC I Antigen Presentation on Tumor Cells
B.S., Wuhan University - 2005
Thesis Advisor: Leroy F. Liu, Ph.D.
Graduate Program in Cellular & Molecular Pharmacology
Pharmacology Department Conference Room
4th floor, RJWMS Research Tower
Tuesday, May 24, 2011
Cancer therapeutics are known to enhance the antitumor immune response, resulting in increased efficacy of immunotherapies (e.g. dendritic cell- and tumor vaccine-based immunotherapies). Multiple mechanisms such as selective suppression of the T regulatory cells and induction of immunogenic cell death by the cancer therapeutics have been proposed. In the current studies, we demonstrate that topotecan (TPT), a topoisomerase I-targeting drug with a well defined mechanism of action, stimulates MHC I expression in breast cancer cells through activation of type I interferon (IFN) signaling. First, we show that TPT treatment elevates the expression of both total and cell-surface MHC I in breast cancer cells. Second, conditioned media from TPT-treated breast cancer ZR-75-1 cells induce elevated expression of cell-surface MHC I in drug-na´ve recipient cells. Consistently, TPT-treated cells exhibit elevated expression and secretion of multiple cytokines. Third, either knocking down the type I interferon receptor subunit 1 (IFNAR1) or addition of neutralizing antibody against IFN- results in reduced MHC I expression in TPT-treated cells. In the aggregate, these results suggest that TPT induces increased IFN- secretion and activation of type I IFN autocrine/paracrine signaling, resulting in the elevated MHC I expression in tumor cells. Additional studies have demonstrated that other chemotherapeutic agents (e.g. etoposide, cisplatin, paclitaxel and vinblastine) and ionizing radiation also induce elevated expression of IFN- and MHC I. Our results thus suggest that elevated MHC I due to increased IFN- secretion/signaling could represent a common mechanism for increased antitumor immune response during chemo- and radio-therapies.