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

Autor: Marianela Candolfi, James F. Curtin, Kader Yagiz, Hikmat Assi, Mia K. Wibowo, Gabrielle E. Alzadeh, David Foulad, AKM G. Muhammad, Sofia Salehi, Naomi Keech, Mariana Puntel, Chunyan Liu, Nicholas R. Sanderson, Kurt M. Kroeger, Robert Dunn, Gislaine Martins, Pedro R. Lowenstein, Maria G. Castro
Jazyk: angličtina
Rok vydání: 2011
Předmět:
Zdroj: Neoplasia: An International Journal for Oncology Research, Vol 13, Iss 10, Pp 947-960 (2011)
Druh dokumentu: article
ISSN: 1476-5586
1522-8002
DOI: 10.1593/neo.11024
Popis: 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.
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