Sustained tumour eradication after induced caspase-3 activation and synchronous tumour apoptosis requires an intact host immune response.
AuthorsMelis, M H M
Simpson, Kathryn L
Dovedi, Simon J
Illidge, Timothy M
AffiliationTargeted Therapy, Institute of Cancer Sciences, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK.
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AbstractEffective anticancer treatments often result in the induction of large amounts of tumour cell death. In vivo, such dying tumour cells are a potential source of antigens for T-cell stimulation. Although apoptosis is generally considered nonimmunogenic, recent evidence suggests that some anticancer therapies that induce apoptosis can elicit antitumour immune responses. Here, a doxycycline-inducible, constitutively active caspase-3 ('death switch') was constructed in a murine tumour model to explore the impact of the host immune response to rapid, synchronous and substantial tumour cell apoptosis. In vitro, up to 80% of tumour cells underwent apoptotic cell death within 24 h and death was accompanied by the release of potential 'danger signal' molecules HMGB1 and HSP90. In vivo, death switch induction provoked rapid, pronounced tumour regression in immune-competent and immune-deficient mice, but sustained tumour eradication was observed only in immune-competent mice. Moreover, the majority of mice that were tumour free after death switch induction were protected from further tumour rechallenge. In addition, long-term remission after induction of the death switch was completely abrogated following depletion of CD8 T cells. These data suggest that sustained tumour eradication after substantial tumour apoptosis requires an antitumour host immune response that prevents tumour relapse. In many patients, cancer therapies produce encouraging initial responses that are only short lived. These results provide new insights that may have important implications for further development of strategies that result in long-term tumour clearance after initially effective anticancer treatment.
CitationSustained tumour eradication after induced caspase-3 activation and synchronous tumour apoptosis requires an intact host immune response. 2013, 20 (5):765-73 Cell Death Differ
JournalCell Death and Differentiation