Dual TLR9 and PD-L1 targeting unleashes dendritic cells to induce durable antitumor immunity

Although immune checkpoint inhibitors have been a breakthrough in clinical oncology, these therapies fail to produce durable responses in a significant fraction of patients. This lack of long-term efficacy may be due to a poor pre-existing network linking innate and adaptive immunity. Here, the team led by GCIR member Prof. Mikael Pittet, in collaboration with Prof. Alfred Zippelius’ group at University Hospital Basel, present an antisense oligonucleotide (ASO)-based strategy that dually targets toll-like receptor 9 (TLR9) and programmed cell death ligand 1 (PD-L1), aiming to overcome resistance to anti-PD-L1 monoclonal therapy.

They designed a high-affinity immunomodulatory IM-TLR9:PD-L1-ASO antisense oligonucleotide (hereafter, IM-T9P1-ASO) targeting mouse PD-L1 messenger RNA and activating TLR9. Then, they performed in vitro and in vivo studies to validate the IM-T9P1-ASO activity, efficacy, and biological effects in tumors and draining lymph nodes. They also performed intravital imaging to study IM-T9P1-ASO pharmacokinetics in the tumor.

IM-T9P1-ASO therapy, unlike PD-L1 antibody therapy, results in durable antitumor responses in multiple mouse cancer models. Mechanistically, IM-T9P1-ASO activates a state of tumor-associated dendritic cells (DCs), referred to here as DC3s, which have potent antitumor potential but express the PD-L1 checkpoint. IM-T9P1-ASO has two roles: it triggers the expansion of DC3s by engaging with TLR9 and downregulates PD-L1, thereby unleashing the antitumor functions of DC3s. This dual action leads to tumor rejection by T cells. The antitumor efficacy of IM-T9P1-ASO depends on the antitumor cytokine interleukin-12 (IL-12), produced by DC3s, and Batf3, a transcription factor required for DC development.

By simultaneously targeting TLR9 and PD-L1, IM-T9P1-ASO amplifies antitumor responses via DC activation, leading to sustained therapeutic efficacy in mice. By highlighting differences and similarities between mouse and human DCs, this study could serve to develop similar therapeutic strategies for patients with cancer.

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Why is it important?

Immune checkpoint inhibitor (ICI) drugs have gained popularity in oncology for their ability to boost a person's immune response against cancer cells. They inhibit cancer immunosuppressive signals and restore cancer immunosurveillance. However, despite the initial clinical success, there is resistance to treatment in many cases, with only a minority of patients showing durable responses and varying between cancer types and individuals. In this study, the authors sought to overcome the limited therapeutic efficacy of these drugs by using a different therapeutic strategy based on antisense oligonucleotides (ASOs) that can stimulate different types of immune cells, including dendritic cells (DCs). This approach demonstrated that the ASO-based technology overcomes resistance to ICIs in mice and provides a mechanistic basis for designing future therapies for treating solid tumours.

May 22, 2023