Fms-like tyrosine kinase-3 ligand (Flt3L) uniquely binds the Flt3 (CD135) receptor expressed on hematopoietic stem cells (HSCs), early progenitor cells, immature thymocytes and steady-state dendritic ...cells (DCs) and induces their proliferation, differentiation, development and mobilization in the bone marrow, peripheral blood and lymphoid organs. CDX-301 has an identical amino-acid sequence and comparable biological activity to the previously tested rhuFlt3L, which ceased clinical development over a decade ago. This Phase 1 trial assessed the safety, pharmacokinetic, pharmacodynamic and immunologic profile of CDX-301, explored alternate dosing regimens and examined the impact of rhuFlt3L on key immune cell subsets. Thirty healthy volunteers received CDX-301 (1-75 μg/kg/day) over 5-10 days. One event of Grade 3 community-acquired pneumonia occurred. There were no other infections, dose-limiting toxicities or serious adverse events. CDX-301 resulted in effective peripheral expansion of monocytes, hematopoietic stem and progenitor cells and key subsets of myeloid DCs and plasmacytoid DCs, with no clear effect on regulatory T cells. These data from healthy volunteers support the potential for CDX-301, as monotherapy or in combination with other agents, in various indications including allogeneic HSC transplantation and immunotherapy, but the effects of CDX-301 will need to be investigated in each of these patient populations.
A central mechanism of tumour progression and metastasis involves the generation of an immunosuppressive 'macroenvironment' mediated in part through tumour-secreted factors. Here we demonstrate that ...upregulation of the Inhibitor of Differentiation 1 (Id1), in response to tumour-derived factors, such as TGFβ, is responsible for the switch from dendritic cell (DC) differentiation to myeloid-derived suppressor cell expansion during tumour progression. Genetic inactivation of Id1 largely corrects the myeloid imbalance, whereas Id1 overexpression in the absence of tumour-derived factors re-creates it. Id1 overexpression leads to systemic immunosuppression by downregulation of key molecules involved in DC differentiation and suppression of CD8 T-cell proliferation, thus promoting primary tumour growth and metastatic progression. Furthermore, advanced melanoma patients have increased plasma TGFβ levels and express higher levels of ID1 in myeloid peripheral blood cells. This study reveals a critical role for Id1 in suppressing the anti-tumour immune response during tumour progression and metastasis.
The relationship between cancer and autoimmunity is complex. However, the incidence of solid tumors such as melanoma has increased significantly among patients with previous or newly diagnosed ...systemic autoimmune disease (AID). At the same time, immune checkpoint blockade (ICB) therapy of cancer induces
autoinflammation and exacerbates underlying AID, even without evident antitumor responses. Recently, systemic lupus erythematosus (SLE) activity was found to drive myeloid-derived suppressor cell (MDSC) formation in patients, a known barrier to healthy immune surveillance and successful cancer immunotherapy. Cross-talk between MDSCs and macrophages generally drives immune suppressive activity in the tumor microenvironment. However, it remains unclear how peripheral pregenerated MDSC under chronic inflammatory conditions modulates global macrophage immune functions and the impact it could have on existing tumors and underlying lupus nephritis. Here we show that pathogenic expansion of SLE-generated MDSCs by melanoma drives global macrophage polarization and simultaneously impacts the severity of lupus nephritis and tumor progression in SLE-prone mice. Molecular and functional data showed that MDSCs interact with autoimmune macrophages and inhibit cell surface expression of CD40 and the production of IL27. Moreover, low CD40/IL27 signaling in tumors correlated with high tumor-associated macrophage infiltration and ICB therapy resistance both in murine and human melanoma exhibiting active IFNγ signatures. These results suggest that preventing global macrophage reprogramming induced by MDSC-mediated inhibition of CD40/IL27 signaling provides a precision melanoma immunotherapy strategy, supporting an original and advantageous approach to treat solid tumors within established autoimmune landscapes. SIGNIFICANCE: Myeloid-derived suppressor cells induce macrophage reprogramming by suppressing CD40/IL27 signaling to drive melanoma progression, simultaneously affecting underlying autoimmune disease and facilitating resistance to immunotherapy within preexisting autoimmune landscapes.
Peroxisome proliferator activated receptor-γ (PPARγ) is a lipid-activated nuclear receptor that promotes immune tolerance through effects on macrophages, dendritic cells (DCs), and regulatory T cells ...(Tregs). Granulocyte-macrophage colony stimulating factor (GM-CSF) induces PPARγ expression in multiple myeloid cell types. GM-CSF contributes to both immune tolerance and protection, but the role of PPARγ in these pathways is poorly understood. Here, we reveal an unexpected stimulatory role for PPARγ in the generation of antitumor immunity with irradiated, GM-CSF-secreting tumor-cell vaccines (GVAX). Mice harboring a deletion of
in lysozyme M (LysM)-expressing myeloid cells (KO) showed a decreased ratio of CD8
T effectors to Tregs and impaired tumor rejection with GVAX. Diminished tumor protection was associated with altered DC responses and increased production of the Treg attracting chemokines CCL17 and CLL22. Correspondingly, the systemic administration of PPARγ agonists to vaccinated mice elevated the CD8
T effector to Treg ratio through effects on myeloid cells and intensified the antitumor activity of GVAX combined with cytotoxic T lymphocyte-associated antigen-4 antibody blockade. PPARγ agonists similarly attenuated Treg induction and decreased CCL17 and CCL22 levels in cultures of human peripheral blood mononuclear cells with GM-CSF-secreting tumor cells. Together, these results highlight a key role for myeloid cell PPARγ in GM-CSF-stimulated antitumor immunity and suggest that PPARγ agonists might be useful in cancer immunotherapy.
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Although dendritic cells are known to play a role in atherosclerosis, few studies have examined the contribution of the wide variety of dendritic cell subsets. Accordingly, their roles in ...atherogenesis remain largely unknown. We investigated the ability of different dendritic cell subsets to become foam cells after contact with aggregated low-density lipoprotein (LDL; the predominant form of LDL found in atherosclerotic plaques).
We demonstrate that both murine and human monocyte-derived dendritic cells use exophagy to degrade aggregated LDL, leading to foam cell formation, whereas monocyte-independent dendritic cells are unable to clear LDL aggregates by this mechanism. Exophagy is a catabolic process in which objects that cannot be internalized by phagocytosis (because of their size or association with extracellular structures) are initially digested in an extracellular acidic lytic compartment. Surprisingly, we found that monocyte-derived dendritic cells upregulate exophagy on maturation. This contrasts various forms of endocytic internalization in dendritic cells, which decrease on maturation. Finally, we show that our in vitro results are consistent with dendritic cell lipid accumulation in plaques of an ApoE(-/-) mouse model of atherosclerosis.
Our results show that monocyte-derived dendritic cells use exophagy to degrade aggregated LDL and become foam cells, whereas monocyte-independent dendritic cells are unable to clear LDL deposits. Furthermore, we find that exophagy is upregulated on dendritic cell maturation. Thus, exophagy-mediated foam cell formation in monocyte-derived dendritic cells could play a significant role in atherogenesis.
Since Edward Jenner's discovery that intentional exposure to cowpox could provide lifelong protection from smallpox, vaccinations have been a major focus of medical research. However, while the ...protective benefits of many vaccines have been successfully translated into the clinic, the cellular and molecular mechanisms that differentiate effective vaccines from sub-optimal ones are not well understood. Dendritic cells (DCs) are the gatekeepers of the immune system, and are ultimately responsible for the generation of adaptive immunity and lifelong protective memory through interactions with T cells. In addition to lymph node and spleen resident DCs, a number of tissue resident DC populations have been identified at barrier tissues, such as the skin, which migrate to the local lymph node (migDC). These populations have unique characteristics, and play a key role in the function of cutaneous vaccinations by shuttling antigen from the vaccination site to the draining lymph node, rapidly capturing freely draining antigens in the lymph node, and providing key stimuli to T cells. However, while migDCs are responsible for the generation of immunity following exposure to certain pathogens and vaccines, recent work has identified a tolerogenic role for migDCs in the steady state as well as during protein immunization. Here, we examine the roles and functions of skin DC populations in the generation of protective immunity, as well as their role as regulators of the immune system.
T cell anergy may serve to limit autoreactive T cell responses. We examined early changes in gene expression after antigen-TCR signaling in the presence (activation) or absence (anergy) of B7 ...costimulation. Induced expression of
GRAIL (gene related to anergy in lymphocytes) was observed in anergic CD4
+ T cells. GRAIL is a type I transmembrane protein that localizes to the endocytic pathway and bears homology to RING zinc-finger proteins. Ubiquitination studies in vitro support GRAIL function as an E3 ubiquitin ligase. Expression of GRAIL in retrovirally transduced T cell hybridomas dramatically limits activation-induced IL-2 and IL-4 production. Additional studies suggest that GRAIL E3 ubiquitin ligase activity and intact endocytic trafficking are critical for cytokine transcriptional regulation. Expression of GRAIL after an anergizing stimulus may result in ubiquitin-mediated regulation of proteins essential for mitogenic cytokine expression, thus positioning GRAIL as a key player in the induction of the anergic phenotype.
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