IIBBA   05544
INSTITUTO DE INVESTIGACIONES BIOQUIMICAS DE BUENOS AIRES
Unidad Ejecutora - UE
congresos y reuniones científicas
Título:
Circulating DNA released from brain tumors in response to conditional cytotoxic/immune stimulatory gene therapy induces activation of TLR9 on pDCs, leading to antitumor immunity
Autor/es:
CANDOLFI; YAGIZ; BALASUBRAMANIAN; PUNTEL; KING; MINEHARU; MUHAMMAD; FOULAD; BARNETT; KROEGER; LOWENSTEIN; CASTRO
Lugar:
Orlando, Florida, US
Reunión:
Congreso; American Association for Cancer Research; 2011
Resumen:
Complexes of DNA and proinflammatory proteins are found in serum during
autoimmune responses and activate antigen presenting cells, contributing
to autoimmune pathogenesis. Although circulating DNA has been
extensively evaluated as a biomarker for cancer progression, its role in
the onset of anti-tumor immunity remains elusive. Here we aimed to
evaluate the role of circulating DNA in the induction of anti-tumor
immunity induced by the combination of immune-stimulant Flt3L and
conditionally cytotoxic thymidine kinase (TK), which leads to long-term
survival when delivered into intracranial brain tumor models using
adenoviral vectors (Ad). Treatment of CNS-1 glioblastoma cells with
Ad.TK+GCV led to substantial release of DNA in vitro. Similar results
were observed in vivo; intratumoral treatment of established
intracranial CNS-1 glioblastomas in rats with Ad-TK/GCV+Ad-Flt3L led to
increased levels of circulating DNA in serum when compared to
saline-treated tumor-bearing rats. Since our previous results suggest
that tumor immunity was dependent on the function of activated pDCs, we
aimed to evaluate the hypothesis that circulating tumor DNA induces pDC
activation. Using specific inhibitors, such as DNAse, micrococcal DNAse,
CpG2088 (an inhibitor of TLR9) and cloroquine (an inhibitor of
endocytosis, required for intracellular TLR9 activation), we found that
circulating DNA from treated rats induced TLR9-dependent activation of
pDCs. Taken together, our results suggest that after treatment of brain
tumors with Ad.TK+Ad.Flt3L dying tumor cells release DNA to the general
circulation, which mediate antitumor immunity by acting as
danger-associated molecular patterns, leading to TLR9 signaling and pDC
activation.