B Cells Are Critical to T-cell–Mediated Antitumor Immunity Induced by a Combined Immune-Stimulatory/ Conditionally Cytotoxic Therapy for Glioblastoma

CANDOLFI; CURTIN; YAGIZ; ASSI; WIBOWO; ALZADEH; FOULAD; MUHAMMAD; SALEHI; KEECH; PUNTEL; LIU; SANDERSON; KROEGER; DUNN; MARTINS; CASTRO; LOWENSTEIN

NEOPLASIA

NEOPLASIA PRESS

Lugar: confirmar; Año: 2011 vol. 13 p. 947 - 960

1522-8002

We have demonstrated that modifying the tumor microenvironment through intratumoral administration of adenoviral vectors (Ad) encoding the conditional cytotoxic molecule, i.e., HSV1-TK and the immune-stimulatory cytokine, i.e., fms-like tyrosine kinase 3 ligand (Flt3L) leads to T-cell–dependent tumor regression in rodent models of glioblastoma.We investigated the role of B cells during immune-mediated glioblastoma multiforme regression. Although treatment with Ad-TK+Ad-Flt3L induced tumor regression in 60% of wild-type (WT) mice, it completely failed in B-cell–deficient Igh6−/− mice. Tumor-specific T-cell precursors were detected in Ad-TK+Ad-Flt3L–treated WT mice but not in Igh6−/− mice. The treatment also failed in WT mice depleted of total B cells or marginal zone B cells.Because we could not detect circulating antibodies against tumor cells and the treatment was equally efficient inWT mice and in mice with B-cell–specific deletion of Prdm 1 (encoding Blimp-1), in which B cells are present but unable to fully differentiate into antibody-secreting plasma cells, tumor regression in this model is not dependent on B cells’ production of tumor antigen–specific immunoglobulins. Instead, B cells seem to play a role as antigenpresenting cells (APCs). Treatment with Ad-TK+Ad-Flt3L led to an increase in the number of B cells in the cervical lymph nodes, which stimulated the proliferation of syngeneic T cells and induced clonal expansion of antitumor T cells. Our data show that B cells act as APCs, playing a critical role in clonal expansion of tumor antigen–specific T cells and brain tumor regression