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 Blood, 15 August 2007, Vol. 110, No. 4, pp. 1116-1122.
Prepublished online as a Blood First Edition Paper on May 4, 2007; DOI 10.1182/blood-2007-01-067579.

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CLINICAL TRIALS AND OBSERVATIONS

In vivo p53 response and immune reaction underlie highly effective low-dose radiotherapy in follicular lymphoma

Laurent Knoops1,2, Rick Haas3, Sanne de Kemp4, Donné Majoor1, Annegien Broeks4, Eric Eldering5, Jan Paul de Boer6, Marcel Verheij3, Conny van Ostrom6, Annemieke de Vries6, Laura van't Veer1,4, and Daphne de Jong1

1 Department of Pathology, The Netherlands Cancer Institute, Amsterdam, the Netherlands; 2 Experimental Medicine and Hematology Units, Université Catholique de Louvain, Brussels, Belgium; Departments of3 Radiotherapy, 4 Experimental Therapy and Diagnostic Oncology, and 6Hematology, The Netherlands Cancer Institute, Amsterdam, the Netherlands; 5 Department of Experimental Immunology, Academical Medical Centre, Amsterdam, the Netherlands; 6 Laboratory of Toxicology, Pathology and Genetics, National Institute of Public Health and the Environment, Bilthoven, the Netherlands

Very low-dose irradiation (2 x 2 Gy) is a new, effective, and safe local treatment for follicular lymphoma. To understand the biologic mechanisms of this extremely effective response, we compared by microarray the gene-expression profile of patients' biopsies taken before and after radiation. In all patients, a major and consistent induction of p53 target genes was seen. p53 targets involved in cell-cycle arrest and apoptosis showed the same mode of regulation, indicating that, in vivo, both are activated simultaneously. p53 up-regulation and p53-mediated proliferation arrest and apoptosis were substantiated using immunohistochemistry, with activation of both the intrinsic and the extrinsic apoptotic pathways. The other induced genes revealed a whole set of biologically meaningful genes related to macrophage activation and TH1 immune response. Immunohistochemical analysis suggested a specific activation or differentiation of resident macrophages by apoptotic cells. These biologic insights are important arguments to advocate the use of low-dose radiotherapy as an effective palliative treatment for follicular lymphoma. Moreover, this study is the first in vivo report of the radiation-induced p53 apoptotic response in patients and suggests that this apoptotic response is not immunologically silent.


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