4-1BB Ligand Activates Bystander Dendritic Cells To Enhance Immunization in Trans

Abstract

Expression of the co-stimulatory receptor 4-1BB is induced by T cell receptor recognition of antigen, while 4-1BB ligand is highly expressed on activated antigen presenting cells. 4-1BB signalling is particularly important for survival of activated and memory CD8+ T cells. We wished to test whether co-expression of antigen and 4-1BBL by dendritic cells (DC) would be an effective vaccine strategy. We therefore constructed lentiviral vectors (LV) co-expressing 4-1BBL and influenza nucleoprotein (NP). Following subcutaneous immunisation of mice, which targets DC, we found superior CD8+ T cell responses against NP and protection from influenza when 4-1BBL was expressed. However, functionally superior CD8+ T cell responses were obtained when two LV were co-injected, one expressing 4-1BBL, the other expressing NP. This surprising result suggested that 4-1BBL is more effective when expressed in trans, acting on adjacent DC. We therefore investigated the effect of LV expression of 4-1BBL in mouse DC cultures and observed induced maturation of bystander, untransduced cells. Maturation was blocked by anti-4-1BBL antibody, required cell-cell contact and did not require the cytoplasmic signalling domain of 4-1BBL. Greater maturation of untransduced cells could be explained by LV expression of 4-1BBL causing down-regulation of 4-1BB. These data suggest that co-expression of 4-1BBL and antigen by vaccine vectors that target DC may not be an optimal strategy. However, 4-1BBL LV immunisation activates significant numbers of bystander DC in the draining lymph nodes. Transactivation by 4-1BBL/4-1BB interaction following DC/DC contact may therefore play a role in the immune response to infection or vaccination.

CD137 Stimulation Enhances Cetuximab-Induced Natural Killer: Dendritic Cell Priming of Antitumor T-Cell Immunity in Patients with Head and Neck Cancer

“…Moreover, we see an unexpected decrease in the CD80 expression in urelumab alone treated co-culture (Fig. 2D) Altogether, this inability of the CD137 agonist mAb alone to control HNC had been recently proves in a mouse HPV+ HNC model, where stimulatory CD137 neither affected tumor growth nor survival of experimental animals (29, 30). We observed that cetuximab-mediated NK cell activation in the presence of other lymphocytes, i.e in unfractionated PBMC, are sensitive to a second dose of cetuximab, and the cetuximab plus urelumab combination, to induce DC maturation.…”

“…Although in vivo both HPV(+) and HPV(−) tumors display higher expression of CD137 on tumor infiltrating NK cells compared with peripheral NK cells post cetuximab, we notice a higher magnitude of CD137 induction on NK cells infiltrating HPV(+) HNC. Increased susceptibility of HPV (+) HNC to NK cells could be attributed to the previously established antiviral functionality of NK cells (29), which may be differentially boosted by cetuximab in HPV (+) tumors. Thus, HPV (+) HNC may result in better clinical outcomes than HPV (−) HNC when treated with a combination of cetuximab and urelumab.…”

A Distinct Transcriptional Program in Human CAR T Cells Bearing the 4-1BB Signaling Domain Revealed by scRNA-Seq

“…We hypothesize that 4-1BB signaling from the synthetic CAR molecule is strong enough to induce programs that would otherwise not be induced in T cells, such as the MHC class II molecules known to be upregulated after dendritic cell (DC) maturation using 4-1BB/4-1BBL stimulation. 42,43 This may also be in part due to constitutive expression of the 4-1BB intracellular signaling domain when it is part of the CAR, in contrast to the activationdependent expression of the natural 4-1BB molecule.…”

Local Treatment of a Pediatric Osteosarcoma Model with a 4-1BBL Armed Oncolytic Adenovirus Results in an Antitumor Effect and Leads to Immune Memory

“…Moreover, it has been shown that immunization with a 4-1BBL lentivirus activates significant numbers of bystander DC in the draining lymph nodes and lead to more efficacious CD8. In that work the authors showed that transactivation by 4-1BBL/4-1BB interaction following DC-DC contact could participate in the immune response to infection or vaccination (36). Understanding the potential contribution of APCs to the antisarcoma effect shown by Delta-24-ACT could provide clues to improve this therapy One limitation of our work is that adenovirus replication is hindered in murine cell lines.…”