Dr. Akansha Singh
Conference 2024 Live Talk
Talk Title
Adrenergic receptor signaling regulates the CD40-receptor mediated anti-tumor immunity
Authors and Affiliations
Akansha Singh, Ashish Ranjan
Department of Radiation Oncology, UT Southwestern Medical Centre, Dallas, Texas, United States
Abstract
Background
Anti-CD40 agonistic antibody (CD40), an activator of dendritic cells (DC) enhances antigen presentation and engagement with its cognate ligand (CD40L) on T cells. Although promising, systemic administration of CD40 in patients is only moderately effective, and its efficacy depends upon the presence of an immunogenic environment and optimal immune priming. Prior research has shown that 2-adrenergic receptor ( 2AR) expressed on DCs decline its functions. Herein, we determined the implications of -adrenergic signaling on DCs activation and maturation mediated by CD40, and whether propranolol, an FDA approved Pan-Beta blocker can improve local CD40 in-situ immunotherapy of poorly immunogenic head and neck tumors (MOC2).
Methods
Unstimulated CD11c+ cells (nDCs) and MOC2 tumor cell lysate stimulated CD11c+ cells (iDCs) from C57BL/6 female mice were exposed to 2-AR agonist (Isoproterenol, ISO; 1M) and CD40 (10ng/ml). Surface expression of MHC-II, CD86 & CD40 using flow cytometry, NFB activation via western blot and expressed cytokine via RT-PCR & ELISA were determined. Mice bearing MOC2 xenograft in flank region were randomized as follows: (1) Untreated control, (2) CD40, (3) Propranolol (Prop; -AR antagonist) & (4) CD40+Prop. Prop (10mg/kg B.W.) was injected intraperitoneally 5 days post tumor inoculation. 30g CD40 was administrated intratumorally twice 8 days apart at an initial volume of ~50mm3. 4-wks post-inoculation, tumors were profiled for immune cell dynamics using flow cytometry.
Results
2-AR signalling with ISO significantly decreased the expressions of MHC-II, CD86 and CD40 on nDCs and iDCs regardless of CD40 treatment. In addition, CD40+ISO decreased intracellular levels of pIkB (NFB activator) compared to CD40 alone. The modification of intracellular signalling correlated with the decrease of pro-inflammatory cytokines (e.g., IL-6, IL-1b) and increase of anti-inflammatory cytokine (IL-10). In the mice model, combining CD40 with Prop significantly suppress MOC2 tumor growth in murine model compared to monotherapies, with the treated tumors demonstrating significantly higher infiltration of CD8+ T cells, CD8+ GZMB+ cytotoxic T cells, activated DCs (MHC-II CD86 and MHC-II CD40 double positive DCs), and reduced populations of CD4+ FOXP+ Treg cells relative to monotherapies.
Conclusions
-adrenergic signaling negatively impacts CD40 induced DCs activation and maturation mediated. Combining CD40 with propranolol reverses the 2AR signalling suppressed anti-tumor immunity, thereby providing the foundational basis for improving CD40 immunotherapy outcomes in patients using -blockers.
Leave A Comment