G. Créhange

Role of STAT3 in CD4+CD25+FOXP3+ Regulatory Lymphocyte Generation: Implications in Graft-versus-Host Disease and Antitumor Immunity

Immunological tolerance is maintained by specialized subsets of T cells including CD4+CD25+FOXP3+ regulatory cells (Treg). Previous studies established that Treg thymic differentiation or peripheral conversion depend on CD28 and Lck signaling. Moreover, foxp3 gene transfer in murine CD4+CD25− T lymphocytes results in the acquisition of suppressive functions. However, molecular pathways leading to FOXP3 expression remain to be described. In this study, we investigated the molecular events driving FOXP3 expression. We demonstrated that CD28 activation in CD4+CD25− T lymphocytes leads to STAT3 Tyr705 phosphorylation in an Lck-dependent manner. STAT3 neutralization during naive peripheral CD4+CD25− T cell conversion into Treg through costimulation with TCR/CD28 and TGF-β1, decreased FOXP3 expression, prevented the acquisition of suppressive functions and restored the ability of the converted lymphocytes to produce IL-2 and IFN-γ. Furthermore, we observed that STAT3 ablation using small interfering RNA strategies inhibited FOXP3 expression and suppressive functions among naturally differentiated CD4+CD25+ T lymphocytes, suggesting a direct role of STAT3 in Treg phenotype and function maintenance. CD4+CD25+ T lymphocytes transduced with specific STAT3 small interfering RNA were devoid of suppressive functions and failed to control the occurrence of acute graft-vs-host disease. Finally, STAT3 inhibition in CD4+ lymphocytes enhanced the anti-tumor immunity conferred by a lymphocyte adoptive transfer. In summary, our findings determine that STAT3 is critical in the molecular pathway required for FOXP3 expression. STAT3 modulation should be taken into account when assessing how regulatory T cells contribute to inflammatory diseases and tumor immunosurveillance.

Safety and efficacy of intensity-modulated radiotherapy in the management of spermatic cord sarcoma

PURPOSE Spermatic cord sarcoma is a rare disease, which management remains controversial due to the lack of guidelines. The standard therapeutic approach is surgical: wide soft-tissue resection with radical inguinal orchidectomy, The diagnosis is made during the analysis of the specimen. The high rate of local recurrence indicates adjuvant radiotherapy of the tumor bed. The aim of this series is to determine the efficacy and safety of postoperative intensity-modulated radiotherapy for spermatic cord sarcomas. PATIENTS AND METHODS Our series included five consecutive cases of spermatic cord sarcoma treated between 2011 and 2014. The indications for radiotherapy were: R1 status after initial surgery, R1 status after wide en bloc resection and orchiectomy, high French federation of cancer centers (FNCLCC) grade, tumor size over 5cm, tumor resection during surgery. RESULTS Median age at diagnosis was 66years (range 46-84years). Median follow-up was 18months (range 6-28months). Four patients had repeat surgery after incomplete removal. All surgeries were orchidectomy with primary ligation of testicular vessels. One patient did not have an in sano margin after the second surgical procedure. The median tumor size was 60mm (range 30-150mm). No recurrence was observed during the follow-up. CONCLUSION No grade 4 toxicities were reported and the most frequent acute toxicity was dermatitis. No recurrence was reported after adjuvant intensity-modulated radiotherapy. The treatment is feasible and well tolerated and seems to provide encouraging results regarding locoregional control of the disease. Dynamic or rotational intensity-modulated radiotherapy is now recommended to decrease acute toxicities while improving the efficacy of this approach.

Chemotherapy: Concurrent Delivery with Radiation Therapy

Preoperative 5-fluorouracil-based chemoradiotherapy has been established as standard treatment for patients with cT3-T4 or N+ resectable rectal cancer by three randomized clinical trials. Local recurrence rates in the range of 6–8% are now common, a figure that was unachievable 15 years ago. However, combined modality treatment does not necessarily translate into a survival gain and induce acute toxicity that may be significant for some patients. The identification of higher risk subgroups of patients from lower risk subgroups of patients is a new paradigm designed to match treatment intensity with risk assessment and clinical outcome. Modern imaging techniques, biomarkers, and gene expression profiling hold promising for selecting future preoperative treatment strategies.