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

Fernandez-Rodriguez, Laura; Cianciaruso, Chiara; Bill, Ruben; Trefny, Marcel P; Klar, Richard; Kirchhammer, Nicole; Buchi, Mélanie; Festag, Julia; Michel, Sven; Kohler, Rainer H; Jones, Elham; Maaske, Andre; Kashyap, Abhishek S; Jaschinski, Frank; Dixon, Karen O; Pittet, Mikael J; Zippelius, Alfred (2023). Dual TLR9 and PD-L1 targeting unleashes dendritic cells to induce durable antitumor immunity. Journal for immunotherapy of cancer, 11(5) BioMed Central 10.1136/jitc-2023-006714

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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, we 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.


We 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, we performed in vitro and in vivo studies to validate the IM-T9P1-ASO activity, efficacy, and biological effects in tumors and draining lymph nodes. We 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.

Item Type:

Journal Article (Original Article)


04 Faculty of Medicine > Department of Haematology, Oncology, Infectious Diseases, Laboratory Medicine and Hospital Pharmacy (DOLS) > Clinic of Medical Oncology

UniBE Contributor:

Bill, Ruben


600 Technology > 610 Medicine & health




BioMed Central




Rebeka Gerber

Date Deposited:

29 Nov 2023 07:12

Last Modified:

29 Nov 2023 07:12

Publisher DOI:


PubMed ID:


Uncontrolled Keywords:

combined modality therapy dendritic cells immune checkpoint inhibitors immunotherapy





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