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

Abstract

Very low-dose irradiation (2 ؋ 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 cellcycle 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 radiationinduced p53 apoptotic response in patients and suggests that this apoptotic response is not immunologically silent.

The presence of TP53 mutation at diagnosis of follicular lymphoma identifies a high-risk group of patients with shortened time to disease progression and poorer overall survival

“…Although TP53 mutation is more frequent in older patients, 4 of 12 mutated cases here were younger than 60 years, and nonmyeloablative allogeneic stem cell transplantation may be an option. Radiotherapy would not be predicted to prolong responses, 25 as the majority of mutations observed here were nonfunctional (Table 1).…”

CDC25A, VAV1, TP73, BRCA1 and ZAP70 gene overexpression correlates with radiation response in colorectal cancer

“…the list of discriminating genes included ptgs1, cFB, Anpep, cXcr4, ZAp70, Il8, VAV1, IcAM1, cD59, cAsp1, tp73, BrcA1, cDc25A, rAD51 and tgFB2. In 2007, Knoops et al firstly reported irradiation-induced genes related to macrophage activation and immune response in follicular lymphoma patients (37). According to analysis of the complement and coagulation cascades pathway, previous studies have linked malignant transformation, tumor angiogenesis and metastasis to the generation of clotting intermediates (e.g.…”

Enhancement of T Cell Responses as a Result of Synergy between Lower Doses of Radiation and T Cell Stimulation

“…Total body radiation with 2 Gy or 2 3 2 Gy leads to a .80% response rate in indolent non-Hodgkin lymphoma, with local tumor control for .2 y (9, 10). This radiation dose is expected to be less damaging for tumor cells than high doses, although treatment-related p53-mediated proliferation arrest and apoptosis of follicular lymphoma cells have been reported (11). Low-dose total body, but not localized, radiation of the tumor with 0.2 Gy induced T cell activation and decreased the incidence rate of metastasis in a preclinical tumor model, suggesting broad immune effects (12).…”

“…RT has two well-known immunological links, as follows: one is the need for properly functioning host cellular immune system, especially CD8 + T cells, for maximum benefit from RT (1,2); the second is the much discussed abscopal effect (regression of distant disease following local irradiation) that, in preclinical models (3,4), was proved to be immune mediated. Generally, tumors are treated with a single high dose (8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20) Gy) or multiple fractions of ∼2 Gy radiation, amounting to 60-70 Gy total dose. High-dose RT can provide tumor Ags from dying cells for dendritic cells that then cross-present them to CD8 + T cells.…”