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.

Metabolites Profiling of Melanoma Interstitial Fluids Reveals Uridine Diphosphate as Potent Immune Modulator Capable of Limiting Tumor Growth

“…Consistent with the hypothesis of UDP acting as an activator of anti-tumor immune response, we also found that in UDP-treated tumors the percentage of TILs CD3 + CD8 + and CD3 + CD4 + were increased (Figures 3G,H). Furthermore, intra-tumoral gene expression analysis of T-cell activation markers showed an increase in the expression of genes functionally linked to anti-tumor immune response, including Flt3 (Bhardwaj et al, 2020;Cueto and Sancho, 2021), Cd40lg (Curran et al, 2015), IFNγ (Gerber et al, 2013), and Il7 (Pellegrini et al, 2009;Figure 3I). Consistent with these observations, we also reported an increase in anti-tumor IFNγ cytokine and a decrease in immunosuppressive IL10 cytokine released within TIF of UDP-treated tumors compared to control (Figure 3J).…”

Fast maturation of splenic dendritic cells upon TBI is associated with FLT3/FLT3L signaling

“…Our expression screening indicated a possible upregulation of FLT3 signaling in association with a cytokine pattern compatible with the involvement of DCs. Considering the well-known role of FLT3/FLT3L in regulating DC immunobiology [65], we sought direct confirmation of enhanced Flt3 engagement in splenic DCs upon TBI and EI/TBI. For this aim, we immunostained thin sections of the spleen from the four treatment groups for the pan-DCs marker CD11c [21], for the pan-leukocyte marker CD45 [66] and for phosphorylated FLT3 (pFLT3, Y589/591; Fig.…”

Plasmacytoid Dendritic Cells and Cancer Immunotherapy

“…Murine cDC1s include two populations: a lymphoid tissue-resident population expressing CD8a, and a non-lymphoid tissue CD103 + population that’s in the periphery [ 12 ]. On the other hand, cDC2s depend on interferon regulatory factor 4 (IRF4) and zinc finger E-box-binding homeobox 2 (ZEB2) for their development, and comprise of heterogeneous populations that are most efficient in priming CD4 T cells after presenting soluble antigens on MHC class II (MHCII), thus regulating immune responses against parasites, extracellular pathogens and allergens [ 8 , 18 ]. However, it should be noted that cDC2s could also cross-present antigens [ 19 , 20 , 21 ] and play a critical role for regulating anti-tumor CD4 and CD8 T cell responses [ 6 , 22 , 23 , 24 ].…”