The study of P transposable element repression in Drosophila melanogaster led to the discovery of the trans-silencing effect (TSE), a homology-dependent repression mechanism by which a P-transgene inserted in subtelomeric heterochromatin (Telomeric Associated Sequences) represses in trans, in the female germline, a homologous P-lacZ transgene inserted in euchromatin. TSE shows variegation in ovaries and displays a maternal effect as well as epigenetic transmission through meiosis. In addition, TSE is highly sensitive to mutations affecting heterochromatin components (including HP1) and the Piwi-interacting RNA silencing pathway (piRNA), a homology-dependent silencing mechanism that functions in the germline. TSE appears thus to involve the piRNA-based silencing proposed to play a major role in P repression. Under this hypothesis, TSE may also be established when homology between the telomeric and target loci involves sequences other than P elements, including sequences exogenous to the D. melanogaster genome. We have tested whether TSE can be induced via lacZ sequence homology. We generated a piggyBac-otu-lacZ transgene in which lacZ is under the control of the germline ovarian tumor promoter, resulting in strong expression in nurse cells and the oocyte. We show that all piggyBac-otu-lacZ transgene insertions are strongly repressed by maternally inherited telomeric P-lacZ transgenes. This repression shows variegation between egg chambers when it is incomplete and presents a maternal effect, two of the signatures of TSE. Finally, this repression is sensitive to mutations affecting aubergine, a key player of the piRNA pathway. These data show that TSE can occur when silencer and target loci share solely a sequence exogenous to the D. melanogaster genome. This functionally supports the hypothesis that TSE represents a general repression mechanism which can be co-opted by new transposable elements to regulate their activity after a transfer to the D. melanogaster genome.
5206 Background: The prognostic impact of tumor microenvironment on the survival of lymphoma patients has recently been reported. However, early molecular and cellular responses to immunochemotherapy are unknown. Here, we have compared the tumor-associated macrophage (TAM) and mast cell (MC) contents in the lymphoma tissue in vivo before and after the first immunochemotherapy course in a small cohort of aggressive B-cell lymphoma patients. Patients and methods: The population of this pilot study consisted of seven diffuse large B-cell lymphoma (DLBCL) and three grade IIIB follicular lymphoma (FL) patients treated with rituximab in combination with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone)-like regimen (immunochemotherapy). Paired tumor samples were collected before and a day after the first course of therapy, and evaluated immunohistochemically for CD68+, CD163+ macrophages and tryptase+ MCs. Freshly frozen lymphoma tissue containing enough material for paired mRNA analyses was available from 8 patients. Results: Comparing pre- and post-treatment tissue samples, an increase in the number of CD68+ TAMs was observed (p=0.023), whereas no variation in MC contents was found. If the patients were grouped according to response, i.e. remission (n=7) vs relapse (n=3), the most significant increase after therapy was observed in M2-type CD163+ TAM content (p=0.001). In the exon array analyses, the mRNA levels of both CD68 (p=0.052) and CD163 (p=0.023) genes increased after therapy. Conclusions: Our preliminary data suggest significant changes in macrophage content and their relative subsets in the lymphoma microenvironment after the first course of immunochemotherapy. Disclosures: No relevant conflicts of interest to declare.
2650 Background: Tumor associated macrophages (TAM) have at least two potential roles in promoting tumor growth: suppression of immune responses and potentiation of angiogenesis. In numerous cancer types, including lymphomas, high M2 type TAM content has been associated with worse prognosis. Rarely, high TAM content correlates with better survival. We have recently shown that CD68 positive TAMs in DLBCL contribute to unfavorable survival after high dose chemotherapy. Here we have extended our analyses on M2 type macrophages and questioned how combination of rituximab with chemotherapy influences TAM-associated clinical outcome. Patients and Methods: Expression of CD163 and CCL18, which are primarily expressed in M2 type macrophages, were identified immunohistochemically from samples of 101 de novo DLBCL patients treated with rituximab in combination with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone)-like regimen (immunochemotherapy). With a median follow-up of 65 months, (range 16–114 months), 5-year progression free survival (PFS) was 70% and overall survival (OS) 73%. 29 DLBCL patients previously treated with up front high dose chemotherapy served as a control group. Results: Correlation between CD163 and CCL18 positive TAMs was found (rs=0.427, p<0.001). In the Kaplan-Meier analyses the cutoff level of 67% was found to best discriminate between subgroups with different outcomes. Consistent with previous data, chemotherapy-treated patients with high CD163 or CCL18 positive TAM counts displayed a significantly inferior OS and PFS than the low group (Table). In contrast, after rituximab containing regimen, the patients with high CD163 and CCL18 positive TAM content tended to have favorable survival. Among the patients with low counts in both CD163 and CCL18 positive TAMs, PFS and OS were found to be significantly worse in comparison to others. Conclusions: In contrast to data on chemotherapy treated DLBCL or other lymphoma types, M2 type TAM content is associated with favorable prognosis in DLBCL patients after immunochemotherapy. Disclosures: No relevant conflicts of interest to declare.
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