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A Novel Mechanism for Chemo/Radio-Immune Modulation:
Cancer Therapeutics Induce Elevated MHC I Antigen Presentation on Tumor Cells

by
Shan Wan
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
Piscataway

Tuesday, May 24, 2011
11:00 a.m.


Abstract

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.


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