Abstract
Simple SummaryCancer immunotherapy is currently focused mainly on the enhancement of the effector function of T cells. However, dendritic cells (DCs) are needed to prime T cells, suggesting that DCs can be an attractive target for immunotherapy. Flt3L/Flt3 is an essential pathway for DC development and function, although its potential in cancer immunotherapy is not yet clearly established. Herein, we will review the current evidence which suggests that the stimulation of DCs through the Flt3/Flt3L axis may contribute to improved cancer immunotherapy.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.
Highlights
The development and refinement of immunotherapy constitutes a revolution in the treatment of cancer
Flt3 ligand (Flt3L) is currently being evaluated in multiple clinical trials (e.g., NCT03789097, NCT02839265, NCT01976585) [86], but no clear therapeutic benefit has been reported
The administration of intravenous Flt3L did not show a therapeutic effect, but that might be due to the lack of dendritic cells (DCs) expansion observed in those trials
Summary
The development and refinement of immunotherapy constitutes a revolution in the treatment of cancer. Lymphocyte functions depend on their previous activation by antigen-presenting cells, among which dendritic cells (DCs) stand out. DCs derive from hematopoietic stem cells in the bone marrow (Figure 1) [5]. These can give rise to Lin− IL7Ra− Sca1− cKit+FcgRloCD34+ common myeloid progenitors (CMPs), which can further differentiate into Lin− CX3CR1+CD11b− CSF1R+cKit+Flt3+ macrophage/DC progenitors (MDPs). MDPs can differentiate into Lin− CSF1R+cKitloFlt3+ common DC progenitors (CDPs) which are completely committed to the DC lineage. MDPs can differentiate into Lin–CSF1R+cKitloFlt3+ common DC progenitors (CDPs) which are completely committed to the DC lineage. ofCDPs can give rise to type 1 and type 2 conventional DCs (cDC1s and cDC2s) and plasmacytoid.
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