The Flt3L/Flt3 Axis in Dendritic Cell Biology and Cancer Immunotherapy

Abstract

Dendritic cells (DCs) prime anti-tumor T cell responses in tumor-draining lymph nodes and can restimulate T effector responses in the tumor site. Thus, in addition to unleashing T cell effector activity, current immunotherapies should be directed to boost DC function. Herein, we review the potential function of Flt3L as a tool for cancer immunotherapy. Flt3L is a growth factor that acts in Flt3-expressing multipotent progenitors and common lymphoid progenitors. Despite the broad expression of Flt3 in the hematopoietic progenitors, the main effect of the Flt3/Flt3L axis, revealed by the characterization of mice deficient in these genes, is the generation of conventional DCs (cDCs) and plasmacytoid DCs (pDCs). However, Flt3 signaling through PI3K and mTOR may also affect the function of mature DCs. We recapitulate the use of Flt3L in preclinical studies either as a single agent or in combination with other cancer therapies. We also analyze the use of Flt3L in clinical trials. The strong correlation between type 1 cDC (cDC1) infiltration of human cancers with overall survival in many cancer types suggests the potential use of Flt3L to boost expansion of this DC subset. However, this may need the combination of Flt3L with other immunomodulatory agents to boost cancer immunotherapy.

Keywords: Flt3; Flt3L; cancer immunotherapy; dendritic cells.

Figure 1

Expression pattern of Flt3 across mouse hematopoietic lineages. We have simplified the lineage tree generated by Jojic et al. [5]. This tree includes all cell populations identified by the first project of ImmGen to express high levels of Flt3 (relative expression > 1000). In the case of mature cDC1s, cDC2s and pDCs, an average of Flt3 expression has been used to color them, because different populations from different organs were characterized in this consortium.