B cells are critical to t-cell–mediated antitumor immunity induced by a combined immune-stimulatory/ conditionally cytotoxic therapy for glioblastoma

• Autores: Candolfi, Marianela; Curtin, James F.; Yagiz, Kader; Assi, Hikmat; Wibowo, Mia K.; Alzadeh, Gabrielle E.; Foulad, David; Muhammad, AKM G.; Salehi, Sofia; Keech, Naomi; Puntel, Mariana; Liu, Chunyan; Sanderson, Nicholas R.; Kroeger, Kurt; Dunn, Robert; Martins, Gislaine; Castro; Lowenstein, Pedro R.; Castro, Maria G
• Año de publicación: 2011
• Idioma: inglés
• Tipo de recurso: artículo
• Materia: Adenovirus gene therapy; HSV1 Thymidine kinase +Flt3L; B cells; Glioblastoma
• Institución: Consejo Nacional de Investigaciones Científicas y Técnicas

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.
Fil: Candolfi, Marianela. Cedars Sinai Medical Center. Gene Therapeutics Research Institute. Department Of Biomedical Sciences; Estados Unidos. University of California at Los Angeles; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; Argentina
Fil: Curtin, James F.. Cedars Sinai Medical Center. Gene Therapeutics Research Institute. Department Of Biomedical Sciences; Estados Unidos. University of California at Los Angeles; Estados Unidos
Fil: Yagiz, Kader. Cedars Sinai Medical Center. Gene Therapeutics Research Institute. Department Of Biomedical Sciences; Estados Unidos. University of California at Los Angeles; Estados Unidos
Fil: Assi, Hikmat. Cedars Sinai Medical Center. Gene Therapeutics Research Institute. Department Of Biomedical Sciences; Estados Unidos. University of California at Los Angeles; Estados Unidos
Fil: Wibowo, Mia K.. Cedars Sinai Medical Center. Gene Therapeutics Research Institute. Department Of Biomedical Sciences; Estados Unidos. University of California at Los Angeles; Estados Unidos
Fil: Alzadeh, Gabrielle E.. Cedars Sinai Medical Center. Gene Therapeutics Research Institute. Department Of Biomedical Sciences; Estados Unidos. University of California at Los Angeles; Estados Unidos
Fil: Foulad, David. Cedars Sinai Medical Center. Gene Therapeutics Research Institute. Department Of Biomedical Sciences; Estados Unidos. University of California at Los Angeles; Estados Unidos
Fil: Muhammad, AKM G.. Cedars Sinai Medical Center. Gene Therapeutics Research Institute. Department Of Biomedical Sciences; Estados Unidos. University of California at Los Angeles; Estados Unidos
Fil: Salehi, Sofia. Cedars Sinai Medical Center. Gene Therapeutics Research Institute. Department Of Biomedical Sciences; Estados Unidos. University of California at Los Angeles; Estados Unidos
Fil: Keech, Naomi. Cedars Sinai Medical Center. Gene Therapeutics Research Institute. Department Of Biomedical Sciences; Estados Unidos. University of California at Los Angeles; Estados Unidos
Fil: Puntel, Mariana. Cedars Sinai Medical Center. Gene Therapeutics Research Institute. Department Of Biomedical Sciences; Estados Unidos. University of California at Los Angeles; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Liu, Chunyan. Cedars Sinai Medical Center. Gene Therapeutics Research Institute. Department Of Biomedical Sciences; Estados Unidos. University of California at Los Angeles; Estados Unidos
Fil: Sanderson, Nicholas R.. Cedars Sinai Medical Center. Gene Therapeutics Research Institute. Department Of Biomedical Sciences; Estados Unidos. University of California at Los Angeles; Estados Unidos
Fil: Kroeger, Kurt. Cedars Sinai Medical Center. Gene Therapeutics Research Institute. Department Of Biomedical Sciences; Estados Unidos. University of California at Los Angeles; Estados Unidos
Fil: Dunn, Robert. Biogen Idec; Estados Unidos
Fil: Martins, Gislaine. Cedars Sinai Medical Center. Gene Therapeutics Research Institute. Department Of Biomedical Sciences; Estados Unidos
Fil: Castro. Cedars Sinai Medical Center. Gene Therapeutics Research Institute; Estados Unidos
Fil: Lowenstein, Pedro R.. Cedars Sinai Medical Center. Gene Therapeutics Research Institute. Department Of Biomedical Sciences; Estados Unidos. University of California at Los Angeles; Estados Unidos. University of Michigan; Estados Unidos
Fil: Castro, Maria G. Cedars Sinai Medical Center. Gene Therapeutics Research Institute. Department Of Biomedical Sciences; Estados Unidos. University of California at Los Angeles; Estados Unidos. University of Michigan; Estados Unidos