Titre
Dual TLR9 and PD-L1 targeting unleashes dendritic cells to induce durable antitumor immunity.
Type
article
Institution
UNIL/CHUV/Unisanté + institutions partenaires
Périodique
Auteur(s)
Fernandez-Rodriguez, L.
Auteure/Auteur
Cianciaruso, C.
Auteure/Auteur
Bill, R.
Auteure/Auteur
Trefny, M.P.
Auteure/Auteur
Klar, R.
Auteure/Auteur
Kirchhammer, N.
Auteure/Auteur
Buchi, M.
Auteure/Auteur
Festag, J.
Auteure/Auteur
Michel, S.
Auteure/Auteur
Kohler, R.H.
Auteure/Auteur
Jones, E.
Auteure/Auteur
Maaske, A.
Auteure/Auteur
Kashyap, A.S.
Auteure/Auteur
Jaschinski, F.
Auteure/Auteur
Dixon, K.O.
Auteure/Auteur
Pittet, M.J.
Auteure/Auteur
Zippelius, A.
Auteure/Auteur
Liens vers les personnes
Liens vers les unités
ISSN
2051-1426
Statut éditorial
Publié
Date de publication
2023-05
Volume
11
Numéro
5
Première page
e006714
Peer-reviewed
Oui
Langue
anglais
Notes
Publication types: Journal Article
Publication Status: ppublish
Publication Status: ppublish
Résumé
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.
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.
PID Serval
serval:BIB_334B6B7FC1F4
PMID
Open Access
Oui
Date de création
2023-05-30T09:44:13.169Z
Date de création dans IRIS
2025-05-20T14:24:55Z
Fichier(s)![Vignette d'image]()
En cours de chargement...
Nom
37208130_BIB_334B6B7FC1F4.pdf
Version du manuscrit
published
Licence
https://creativecommons.org/licenses/by-nc/4.0
Taille
6.84 MB
Format
Adobe PDF
PID Serval
serval:BIB_334B6B7FC1F4.P001
URN
urn:nbn:ch:serval-BIB_334B6B7FC1F40
Somme de contrôle
(MD5):c9294326cade960c6f52f67e25c72c7c