B cells are critical to T-cell mediated anti-tumor immunity induced by a combined immune-stimulatory/conditionally cytotoxic therapy for glioblastoma

MARIANELA CANDOLFI; JAMES F CURTIN; KADER YAGIZ; HIKMAT ASSI; MIA WIBOWO; GABRIELLE E ALZADEH; DAVID FOULAD; AKM GHULAM MUHAMMAD; SOFIA SALEHI; NAOMI KEECH; MARIANA PUNTEL; CHUNYAN LIU; NICHOLAS S SANDERSON; KURT M KROEGER; ROBERT DUNN; GISLAINE MARTINS; PEDRO R LOWENSTEIN; MARIA G CASTRO

NEOPLASIA

NEOPLASIA PRESS

Año: 2011 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 in WT 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 antigen presenting 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.