B cells are critical to T-cell-mediated antitumor immunity induced by a combined immune-stimulatory/conditionally cytotoxic therapy for glioblastoma.
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.
Gene Therapeutics Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
Marianela
M
Candolfi
James F
JF
Curtin
Kader
K
Yagiz
Hikmat
H
Assi
Mia K
MK
Wibowo
Gabrielle E
GE
Alzadeh
David
D
Foulad
A K M G
AK
Muhammad
Sofia
S
Salehi
Naomi
N
Keech
Mariana
M
Puntel
Chunyan
C
Liu
Nicholas R
NR
Sanderson
Kurt M
KM
Kroeger
Robert
R
Dunn
Gislaine
G
Martins
Pedro R
PR
Lowenstein
Maria G
MG
Castro
D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology / Q000378:metabolism; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D001932:Brain Neoplasms / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D003602:Cytotoxicity, Immunologic / Q000276:immunology; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D005909:Glioblastoma / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D018259:Herpesvirus 1, Human / Q000201:enzymology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D000074462:Positive Regulatory Domain I-Binding Factor 1; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D013937:Thymidine Kinase / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000276:immunology / Q000378:metabolism
D008565:Membrane Proteins; C513258:Prdm1 protein, mouse; D014157:Transcription Factors; C084881:flt3 ligand protein; D000074462:Positive Regulatory Domain I-Binding Factor 1; D013937:Thymidine Kinase