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Activation of anti‐tumor immune responses using a combination of radiation and 26S proteasome inhibition (LB245)
Author(s) -
Shanderson Ronald,
Cacan Ercan,
Morgan Julie,
Greer Susanna
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.28.1_supplement.lb245
Subject(s) - immune system , cancer research , radiation therapy , apoptosis , cancer , proteasome , breast cancer , programmed cell death , cancer cell , proteasome inhibitor , medicine , combination therapy , pharmacology , immunology , biology , microbiology and biotechnology , biochemistry
Radiation treatment is an effective breast tumor therapy, but its usage is limited by dose and toxicity. Sub‐lethal doses of radiation can modulate tumor gene expression, making tumor cells more susceptible to immune responses, but radiotherapy alone is insufficient to generate strong tumor‐specific immune responses. The proteasome presents a novel target for combination therapies in cancer: it plays a key role in cancer cell proliferation, inhibition of radiation‐induced apoptosis and development of drug resistance. The objective of our study is to investigate the effects of the 26S proteasome inhibitor, Velcade, alone or in combination with radiotherapy, on the expression of immunogenic genes in breast cancer cells. Here, we examined MDA231 breast cancer cells for changes in expression of multiple immuno‐stimulatory molecules and death receptors. Our preliminary data indicates a combination of Velcade and low‐dose radiation significantly increases the sensitivity of MDA231 cells to apoptosis. Furthermore, this novel combination treatment upregulates cell surface expression of multiple death receptors (TNFRSF10A, TNFRSF10B and Fas/APO‐1) and co‐stimulatory molecules (TNFSF4 and TNFRSF9) by increasing their transcriptional activation. These data will guide experiments to determine how this combination therapy can best enhance anti‐tumor immune responses.