Effect of BLS in Regulatory T cells and its impact on antitumoral immunity

FARIAS ANA; GOLDBAUM FERNANDO; BEROD LUCIANA; BERGUER PAULA; ROSSI ANDRÉS; SPARWASSER TIM

Mar del Plata

Congreso; Reunión Conjunta 2016 entre la Sociedad Argentina de Investigación Clínica (SAIC), la Sociedad Argentina de Inmunología (SAI) y la Sociedad Argentina de Farmacología Experimental (SAFE); 2016

SAI, SAIC, SAFE

Effect of BLS in Regulatory T cells and its impact on antitumoral immunityAna Farias1, Andrés Hugo Rossi1, Luciana Berod2, Fernando Alberto Goldbaum1, Tim Sparwasser2, Paula Mercedes Berguer11 Fundación Instituto Leloir, IIBBA, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina.2 Institute of Infection Immunology, Centre for Experimental and Clinical Infection Research, TWINCORE, Hannover, Germany.Melanoma patients harbor increased numbers of Foxp3(+) regulatory T cells (Treg), impeding the onset of antitumoral response. Treg depletion has been adopted as a promising therapeutic approach however the precise mechanism and receptors involved remains unclear. Brucella spp. lumazine synthase (BLS) is a decameric protein with highly immunogenic properties. We have previously demonstrated that BLS induces a protective antitumoral response in mice with B16 melanoma. We inoculated mice sc with BLS and 20 or 35 days later induced tumor development by sc injecting B16 cells. Treatment significantly inhibited tumor growth and 50% of mice failed to develop a tumor. Furthermore, the protective effect by BLS was abolished in TLR4 deficient mice suggesting the importance in signaling through this receptor. In a first attempt to decipher the mechanism involved, we analyzed the effect of BLS in Treg generation from naïve T cells in vitro under Treg differentiation conditions. BLS decreased the percentage of Foxp3+ Treg, with a marked reduction in the expression of FoxP3. Moreover, the effect of BLS was partially abolished in MyD88-/- mice suggesting that signaling through alternate receptors may be involved. We next evaluated the effect of BLS in Treg in vivo. Our results showed that after 20 days post BLS treatment there is a higher number of CD4+ cells and CD4+Foxp3+ cells in the draining lymph node. However, after 35 days only recruitment of CD4+FoxP3- cells was observed. Thus decrease in Tregs in the tumor microenvironment by FoxP3 downregulation may explain how BLS mechanistically regulates antitumoral responses.