A four-cell pathway orchestrated by Flt3-L-dependent cDCs controls anti-tumor responses
Authors: Konstantinos Aliazis, Vassiliki A. Boussiotis
Journal: Cell Reports Medicine (2024)

A study by Régnier et al. shows that Flt3-ligand (FL) levels program two distinct mechanisms of anti-tumor immunity. Low FL levels allow recruitment of T effectors and T cell-mediated responses whereas high FL levels support recruitment of classical dendritic cells (cDC) and natural killer (NK) cells and NK-mediated anti-tumor responses. A study by Régnier et al. shows that Flt3-ligand (FL) levels program two distinct mechanisms of anti-tumor immunity. Low FL levels allow recruitment of T effectors and T cell-mediated responses whereas high FL levels support recruitment of classical dendritic cells (cDC) and natural killer (NK) cells and NK-mediated anti-tumor responses. Flt3-ligand (FL) is a cytokine responsible for the expansion and maturation of hematopoietic progenitor cells and is particularly involved in the maturation of classical dendritic cells (cDCs). The tyrosine kinase receptor Flt3 is the natural receptor of FL. Flt3-targeting drugs have revolutionized therapy for acute myelogenous leukemia with Flt3 overexpression or mutation.1Gebru M.T. Wang H.-G. Therapeutic targeting of FLT3 and associated drug resistance in acute myeloid leukemia.J. Hematol. Oncol. 2020; 13: 155-213Crossref Scopus (34) Google Scholar However, although DCs are crucial in anti-tumor immunity, there are conflicting reports regarding the potential role of FL for the treatment of cancer patients.2Lynch D.H. Andreasen A. Maraskovsky E. Whitmore J. Miller R.E. Schuh J.C. Flt3 ligand induces tumor regression and antitumor immune responses in vivo.Nat. Med. 1997; 3: 625-631Crossref PubMed Scopus (278) Google Scholar,3Disis M.L. Rinn K. Knutson K.L. Davis D. Caron D. dela Rosa C. Schiffman K. Flt3 ligand as a vaccine adjuvant in association with HER-2/neu peptide-based vaccines in patients with HER-2/neu–overexpressing cancers. Blood.The Journal of the American Society of Hematology. 2002; 99: 2845-2850Google Scholar In the current issue of Cell Reports Medicine, Régnier et al. demonstrate that the levels of FL can regulate differential mechanisms of anti-tumor responses mediated by the adaptive or the innate immune compartment based on the recruitment of T cells or natural killer (NK) cells to the tumor microenvironment (TME), respectively.4Régnier P. Bansard A. Cagnard N. Podsypanina K. Darrasee-Jèze G. FLT3L-dependent Dendritic Cells Control Tumor Immunity by Modulating Treg and NK Cell Homeostasis.Cell Rep. Med. 2024; 4: 101256Abstract Full Text Full Text PDF Scopus (0) Google Scholar Flt3+ cDCs can present antigen to naive T cells and initiate immune responses but their role in cancer is less well understood. Conventional knowledge says that cDC1s cross-present antigen to CD8+ T cells whereas cDC2s prime CD4+ T cell responses. Although mouse models have shown that FL-dependent cDCs can mount anti-tumor responses, cDCs are also responsible for the induction and proliferation of tolerogenic regulatory T cells (Tregs) to the TME.5Yamazaki S. Dudziak D. Heidkamp G.F. Fiorese C. Bonito A.J. Inaba K. Nussenzweig M.C. Steinman R.M. CD8+ CD205+ splenic dendritic cells are specialized to induce Foxp3+ regulatory T cells.J. Immunol. 2008; 181: 6923-6933Crossref PubMed Google Scholar There is no clear indication as to how the presence of both Tregs and DCs, which have pro- and anti-tumorigenic functions, respectively, can affect immune responses and lead to increased survival of cancer patients. In this study, Régnier and colleagues answer this question by examining the effects of FL depletion or overexpression on DCs in tumors and tumor-draining lymph nodes (dLNs) using the B16 melanoma tumor model.4Régnier P. Bansard A. Cagnard N. Podsypanina K. Darrasee-Jèze G. FLT3L-dependent Dendritic Cells Control Tumor Immunity by Modulating Treg and NK Cell Homeostasis.Cell Rep. Med. 2024; 4: 101256Abstract Full Text Full Text PDF Scopus (0) Google Scholar They generate genetically modified mice which lack expression of FL (FL-KO) and B16 melanoma cells which constitutively express FL (B16-FL). Injection of B16 melanoma cells into wild-type (WT) mice shows an increased accumulation DCs, NK cells, and Tregs in the dLN, as early as day 3. Strikingly, either FL depletion by using the FL-KO mice or FL overexpression by engrafting the B16-FL melanoma cells results in inhibition of tumor growth and increased survival.4Régnier P. Bansard A. Cagnard N. Podsypanina K. Darrasee-Jèze G. FLT3L-dependent Dendritic Cells Control Tumor Immunity by Modulating Treg and NK Cell Homeostasis.Cell Rep. Med. 2024; 4: 101256Abstract Full Text Full Text PDF Scopus (0) Google Scholar The authors find that FL depletion reduces the presence of cDCs and NK cells but also leads to reduced numbers of Tregs and increased frequencies of CD4+Foxp3− T helper (Th) cells in tumors and dLNs. In contrast, activation of Tregs correlates with both the FL levels and the presence of cDCs, indicating that high FL levels recruit cDCs in the TME, which subsequently attract and activate Tregs. Decrease of Tregs in the FL-KO mouse model allows for the activation and enhanced accumulation of Th cells in the dLNs. Furthermore, increased numbers of activated intratumoral Th and CD8+ T cells are present in the FL-KO mice, which have enhanced anti-tumor responses (Figure 1A). The authors show that the absence of DCs positively correlates with the low number of Tregs in the dLN. Interestingly, overexpression of FL allows for activation of Th and CD8+ T cells despite the presence of Tregs in the TME.4Régnier P. Bansard A. Cagnard N. Podsypanina K. Darrasee-Jèze G. FLT3L-dependent Dendritic Cells Control Tumor Immunity by Modulating Treg and NK Cell Homeostasis.Cell Rep. Med. 2024; 4: 101256Abstract Full Text Full Text PDF Scopus (0) Google Scholar To prove that DCs recruit Tregs to the TME, Régnier and colleagues adoptively transfer pre-labelled Tregs into WT, FL-KO, and B16-FL tumor-bearing hosts. This approach reveals that labeled Tregs proliferate only when FL is present in the system, showing that FL-dependent DCs directly recruit and activate Tregs in the TME. In further investigation, Régnier et al. determine that the levels of FL and DCs in both the dLNs and tumor positively correlate with the number of NK cells. FL overexpression also increases NK cell activation. The researchers find that the beneficial effect of FL overexpression on anti-tumor responses is the direct increase of NK cells (Figure 1B). Depletion of NK cells abrogates the beneficial anti-tumor effect induced by B16-FL both in WT mice and NOD scid gamma (NSG) mice, which lack lymphocytes, indicating that the main drivers of tumor control in FL overexpression settings are not the T cells but the NK cells. However, NK cells and NK precursors lack expression of Flt3 and, as a result, cannot be directly regulated by FL.6Yu H. Fehniger T.A. Fuchshuber P. Thiel K.S. Vivier E. Carson W.E. Caligiuri M.A. Flt3 ligand promotes the generation of a distinct CD34+ human natural killer cell progenitor that responds to interleukin-15. Blood.The Journal of the American Society of Hematology. 1998; 92: 3647-3657Google Scholar For this reason, Régnier and colleagues assess indirect effects of FL on NK cells. They use zDCDTR mice, which delete cDCs upon diphtheria toxin administration, and inject them with B16-FL tumors. Deletion of cDCs strongly reduces the number of NK cells in the spleen, dLNs, and tumor sites. These results illustrate that although FL overexpression leads to recruitment of NK cells and Tregs to the tumor site, NK cells are able to exert anti-tumorigenic properties. The authors then hypothesize that FL overexpression and simultaneous depletion of Tregs can be used as an immunotherapeutic approach to enhance anti-tumor therapeutic efficacy. Indeed, either Treg depletion or FL overexpression lead to a similar improvement in survival, but the two therapies combined more prominently increase survival rate.4Régnier P. Bansard A. Cagnard N. Podsypanina K. Darrasee-Jèze G. FLT3L-dependent Dendritic Cells Control Tumor Immunity by Modulating Treg and NK Cell Homeostasis.Cell Rep. Med. 2024; 4: 101256Abstract Full Text Full Text PDF Scopus (0) Google Scholar These findings uncover a previously unappreciated interaction and functional anti-tumor crosstalk among four players: FL, DCs, NK cells, and Tregs. Importantly, Régnier and colleagues use transcriptomic databases to investigate whether this four-way pathway might be identified in samples from various human cancers. They find that FL mRNA levels correlate with increased DCs, Tregs, and NK cells in humans, indicating that this cellular pathway is conserved between mice and humans. However, high levels of FL do not always correlate with increased survival, with some types of cancer showing beneficial and some others showing detrimental effects, confirming the paradoxical effect of cDC numbers on survival in several human tumor types.4Régnier P. Bansard A. Cagnard N. Podsypanina K. Darrasee-Jèze G. FLT3L-dependent Dendritic Cells Control Tumor Immunity by Modulating Treg and NK Cell Homeostasis.Cell Rep. Med. 2024; 4: 101256Abstract Full Text Full Text PDF Scopus (0) Google Scholar Previous studies in mice and humans have reported conflicting results regarding the role of FL in cancer.2Lynch D.H. Andreasen A. Maraskovsky E. Whitmore J. Miller R.E. Schuh J.C. Flt3 ligand induces tumor regression and antitumor immune responses in vivo.Nat. Med. 1997; 3: 625-631Crossref PubMed Scopus (278) Google Scholar,3Disis M.L. Rinn K. Knutson K.L. Davis D. Caron D. dela Rosa C. Schiffman K. Flt3 ligand as a vaccine adjuvant in association with HER-2/neu peptide-based vaccines in patients with HER-2/neu–overexpressing cancers. Blood.The Journal of the American Society of Hematology. 2002; 99: 2845-2850Google Scholar,7Miller G. Pillarisetty V.G. Shah A.B. Lahrs S. DeMatteo R.P. Murine Flt3 ligand expands distinct dendritic cells with both tolerogenic and immunogenic properties.J. Immunol. 2003; 170: 3554-3564Crossref PubMed Google Scholar This could be due to a direct effect of FL on tumor cells, although not all tumors respond to FL.8Serve H. Flesch K. Serve S. Fenski R. Berdel W.E. Expression and function of Flt3/flk2 in human tumor cell lines.Int. J. Oncol. 1999; 14: 765-770PubMed Google Scholar However, the findings of Régnier et al. suggest that FL might be used as a biomarker to decipher which anti-cancer mechanism between the two described in their study would be more likely operative in a certain patient, driving choices for personalized anti-cancer immunotherapies. Therapeutic exploitation of the FL pathway can also be achieved by administration of recombinant FL or FL signaling blockers. Importantly, the study by Régnier et al. indicated that cDC enrichment combined with Treg cell depletion resulted in maximum anti-tumor benefit. Determining how human cancers respond to interventions leading to FL level modulation and dissecting the effects of such interventions to the components of the four-cell pathway identified by Régnier et al. might lead to novel future therapies for multiple cancer types. This work was supported by NIH/NCI grants CA238263 and CA257672 (V.A.B.). The authors declare no competing interests. FLT3L-dependent dendritic cells control tumor immunity by modulating Treg and NK cell homeostasisRégnier et al.Cell Reports MedicineDecember 19, 2023In BriefRégnier et al. examine the role of Flt3L-dependent dendritic cells in cancer and show that both their deficit or excess can paradoxically extend life in mice and humans. They identify their beneficial/adverse/paradoxic roles in 35 human cancers and demonstrate that Treg inhibition and Flt3L synergize to improve cancer survival. Full-Text PDF Open Access