Reprogramming of TLR7 signaling enhances antitumor NK and cytotoxic T cell responses

Abstract

Toll-like receptor (TLR) 7 agonists are effective in topical application for the immunotherapy of skin cancers, but their performance for the systemic treatment of solid tumors is limited by the development of TLR tolerance. In this study, we describe a novel strategy to overcome TLR tolerance and enhance TLR7-dependent antitumor immune responses through reprogramming of TLR signaling pathways. The sensitivity of TLR7 signaling in dendritic cells (DC) was increased by prior stimulation with the dsRNA poly (I:C) that mimics virally induced immune activation. Timing of the stimulations was important, as sequential stimulation with poly(I:C) and the TLR7 agonist R848 interspaced by 24 h induced higher MAPK and NFkB signaling in DC than the simultaneous application of the same ligands. DC activated by sequential poly(I:C)/R848 stimulation efficiently induced Th1 differentiation and primed NK-cell and cytotoxic T-cell responses. We have developed a treatment regimen taking advantage of TLR7 reprogramming that cured over 80% of large immunogenic tumors in mice by the action of NK cells and cytotoxic T cells. These results have direct implications for the use of these clinically established ligands in the immunotherapy of cancer.

Harnessing the immune system to fight cancer with Toll-like receptor and RIG-I-like receptor agonists

“…Indeed, when poly(I:C) and resiquimod, two response modifiers used in clinical trials, were sequentially administered, increased levels of the anti-tumor cytokines IFN- and IL-12p70 were found 44 . This treatment also led to enhanced activation of cytotoxic T cells and differentiation of T helper cells, two cell types of the adaptive immune system involved in fighting cancer 47 . This strategy therefore allowed to overcome TLR tolerance and strengthen TLR7-dependent antitumor immune responses.…”

Amphiphilic nanoparticle delivery enhances the anticancer efficacy of a TLR7 ligand via local immune activation

“…[41,42] We assessed the number of splenic cytotoxic T cells that specifically recognized the immunodominant CT26 tumor antigen gp70 in tumor-bearing mice treated by AmpNP-R848, using a well-described MHC-tetramer assay. [43] R848 delivered by AmpNP generated tumor-specific cytotoxic T cells more efficiently than the equivalent dose of free R848 ( Figure 4A). Additionally, the cytotoxic T cells exhibited higher levels of the activation markers PD1…”

Trial Watch: Toll-like receptor agonists in cancer immunotherapy

“…59 As a family, TLRs are expressed by multiple immune cells, including macrophages, dendritic cells (DCs), B cells, and natural killer (NK) cells, as well as by non-immune cells including epithelial cells, fibroblasts and malignant cells. [60][61][62] Thus, besides controlling the activation, maturation and immunological functions of immune cells (notably cytokine secretion), [63][64][65][66][67][68][69] TLR signaling can influence tumor metabolism, proliferation and dissemination.- 60,62,[70][71][72][73][74][75] Several TLR ligands demonstrated potential therapeutic efficacy against malignant disorders. 70,76 Imiquimod, also called Aldara® (imiquimod 5% cream as commercialized by 3M Pharmaceuticals) or R-837, is a TLR7 agonist that is approved by the US Food and Drug Administration (FDA) for the treatment of actinic keratosis, external genital/perianal warts (condylomata acuminata), and superficial basal cell carcinoma.…”