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Preparation of Tumor Antigen-loaded Mature Dendritic Cells for Immunotherapy
Published on: August 1, 2013
Dual TLR9 and PD-L1 targeting unleashes dendritic cells to induce durable antitumor immunity
Laura Fernandez-Rodriguez1, Chiara Cianciaruso2,3,4, Ruben Bill2,3,4
1Department of Biomedicine, University of Basel and University Hospital of Basel, Basel, Switzerland.
Background:
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.
Methods:
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.
Results:
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.
Conclusions:
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.
Insights
A novel antisense oligonucleotide therapy simultaneously targets toll-like receptor 9 (TLR9) and programmed cell death ligand 1 (PD-L1) to overcome cancer treatment resistance. This dual-action approach enhances anti-tumor immune responses for durable efficacy in preclinical models.
Area of Science:
- Immunology
- Oncology
- Molecular Biology
Background:
- Immune checkpoint inhibitors (ICIs) offer breakthroughs in cancer treatment but often fail to induce durable responses in many patients.
- Resistance to ICIs may stem from inadequate communication between innate and adaptive immune systems.
- There is a critical need for novel therapeutic strategies to overcome ICI resistance.
Purpose of the Study:
- To develop and validate a novel antisense oligonucleotide (ASO)-based strategy to overcome resistance to anti-PD-L1 therapy.
- To investigate a dual-targeting approach combining toll-like receptor 9 (TLR9) activation and programmed cell death ligand 1 (PD-L1) inhibition.
- To assess the efficacy and mechanisms of action of the novel immunomodulatory ASO in preclinical cancer models.
Main Methods:
- Design of a high-affinity immunomodulatory antisense oligonucleotide (IM-TLR9:PD-L1-ASO) targeting mouse PD-L1 mRNA and activating TLR9.
- In vitro and in vivo studies to evaluate IM-T9P1-ASO activity, efficacy, and biological effects in tumors and draining lymph nodes.
- Intravital imaging to determine IM-T9P1-ASO pharmacokinetics within the tumor microenvironment.
Main Results:
- IM-T9P1-ASO therapy demonstrated durable antitumor responses in multiple mouse cancer models, outperforming PD-L1 antibody therapy.
- The ASO activates tumor-associated dendritic cells (DCs), termed DC3s, which possess potent antitumor capabilities.
- IM-T9P1-ASO simultaneously expands DC3s via TLR9 engagement and downregulates PD-L1, thereby unleashing DC3-mediated antitumor functions.
- Therapeutic efficacy relies on DC3-produced interleukin-12 (IL-12) and the transcription factor Batf3, essential for DC development.
Conclusions:
- Simultaneous targeting of TLR9 and PD-L1 with IM-T9P1-ASO amplifies antitumor responses through DC activation, leading to sustained therapeutic efficacy in mice.
- This dual-action strategy holds promise for overcoming resistance to current immunotherapies.
- Further research comparing mouse and human DCs could facilitate the development of similar therapeutic strategies for cancer patients.
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