Attacking tumor cells with a dual ligand for innate immune receptors

Nod-like receptors (NLRs) are being implicated in an increasing number of biological processes including carcinogenesis. Whether these innate immune receptors can be exploited in anti-tumor therapies is still uncertain. We have shown that engineered flagellin-bearing tumor cells trigger NLRs which cooperate with Toll-like receptor 5 (TLR5) to induce robust anti-tumor T cell responses and tumor rejection. These findings demonstrate great potential for dual targeting of TLRs and NLRs in the design of optimal cancer vaccines. Pathogen-associated molecular patterns (PAMPs) are microbial structures that signify infection to the immune system upon engaging pattern recognition receptors (PRRs). Among PRRs, the NLRs constitute a recently identified family of cytosolic innate immune receptors that have been implicated in various diseases including cancer [1]. Some of these receptors have the ability to initiate the formation of multiprotein complexes, termed inflammasomes, which induce caspase-1 activation to mediate the proteolytic activation of the pro-inflammatory cytokines interleukin (IL)-1β and IL-18, and can initiate a programmed cell death termed pyroptosis. However, a first signal is needed to stimulate transcription of the precursors pro-IL-1β and pro-IL-18, suggesting that some NLRs can only function in cooperation with other signaling pathways [1]. This signal can efficiently be provided by engagement of another family of innate immune receptors, the Toll-like receptors (TLRs), activation of which leads to cytokine production, T cell co-stimulatory molecule expression, and enhanced antigen presentation [1,2]. While ligands for TLRs have been introduced as adjuvants in vaccine compositions and are currently being tested for use in the clinic, direct manipulation of NLR signaling has not been extensively explored. This will certainly change, however, especially with the recent demonstration that some clinically approved adjuvants rely on inflammasomes to mediate their actions [3]. Among NLR ligands, the bacterial protein flagellin is of particular interest since it is recognized by TLR5 and the NLR NAIP5 (neuronal apoptosis inhibitor protein 5), which partners with the NLR NLRC4 (NLR family, CARD domain containing protein 4) in the cytosol [4,5]. Therefore, sensing flagellin by myeloid cells such as macrophages and dendritic cells (DCs) mobilizes signal transduction downstream of two major families of PRRs, a property that can possibly be exploited in immunotherapy. We tested this possibility by introducing flagellin into different tumor cell lines, a strategy that abrogated tumor development upon subcutaneous or intravenous injection of these flagellin-expressing cells, and induced DC-mediated tumor antigen presentation to CD4 + and CD8 + T cells [6]. When used …