Spleen but not tumor infiltration by dendritic and T cells is increased by intravenous adenovirus-Flt3 ligand injection

Abstract

Dendritic cell (DC) expansion is regulated by the hematopoietic growth factor fms-like tyrosine kinase 3 ligand (Flt3L). DCs are critical to the control of tumor growth and metastasis, and there is a positive correlation between intratumoral DC infiltration and clinical outcome. In this report, we first demonstrate that single intravenous (i.v.) injections of adenovirus (Adv)-Flt3L significantly increased splenic dendritic, B, T and natural killer (NK) cell numbers in both normal and mammary tumor-bearing mice. In contrast, the numbers of DCs and T cells infiltrating the tumors were not increased. Consistent with the minimal effect on immune cell infiltration, i.v. Adv-Flt3L injections had no therapeutic activity against orthotopic mammary tumors. In addition, we noted tumor and Adv-Flt3L expansion of Gr1 þ CD11b þ immature myeloid suppressor cells (IMSCs), which may inhibit the therapeutic efficacy of Adv-Flt3L-expanded DCs.

Inflammatory cell infiltration of tumors: Jekyll or Hyde

“…This difference is associated with GM-CSF levels such that high levels expand MDSCs numbers [169], reducing clinical vaccine responses, while lower levels augment tumor immunity. Similar effects on MDSCs have been suggested with other GFs, including Flt3L [125], M-CSF [172], and IL-3 [173]. VEGF has also been directly linked with MDSC expansion in a transgenic mammary cancer model in which tumor progression and multiplicity correlated with increased serum levels of VEGF and numbers of MDSCs in the blood and spleen [174].…”

“…In contrast, Flt3L is crucial to steady state pDC and myeloid DC development. Mice lacking Flt3L have low levels of DCs [124] and an injection of Flt3L results in high numbers of circulating and organ-associated DCs and myeloid precursors [125]. The local environment also influences the expansion of DCs, as well as their maturation, further regulating T cell function and tissue-specific response patterns [126].…”

Tumor- and organ-dependent infiltration by myeloid-derived suppressor cells

“…PB, BM, and splenic, single-cell suspensions were prepared and RBCs removed by water lysis, as described previously [19,[30][31][32][33][34]. NPCs from tumors, livers, and lungs were isolated and enriched by collagenase-DNase dissociation and FH density-gradient centrifugation [19,[30][31][32][33][34].…”

Phenotype, development, and biological function of myeloid-derived suppressor cells

“…50 In addition, overexpression of fms-like tyrosine kinase 3 ligand in tumor-bearing mice results in increased MDSCs that inhibit the antitumor activity of effector immune cells. 61 Complement anaphylatoxin C5a increases tumor-infiltrating MDSCs with an immunosuppressive activity through ROS and reactive nitrogen species (RNS) regulation. 62 The factors mediating the apoptosis and proliferation of MDSCs…”