Intratumoral delivery of mRNA encoding the endogenous TLR2/6 agonist UNE-C1 induces immunogenic cell death and enhances antitumor activity

Front Immunol. 2024 Nov 28:15:1454504. doi: 10.3389/fimmu.2024.1454504. eCollection 2024.

Abstract

Introduction: Recent investigations have highlighted the intratumoral administration of Toll-like receptor (TLR) ligands as a promising approach to initiate localized immune responses and enhance antitumor immunity. However, the clinical application of these ligands is limited by their rapid dissemination from the tumor microenvironment, raising concerns about reduced effectiveness and systemic toxicity.

Methods: To address these challenges, our study focused on the intratumoral delivery of mRNA encoding UNE-C1, a TLR2/6 ligand known for its efficacy and low toxicity profile. We explored the potential of UNE-C1 to induce immunogenic cell death (ICD) through autocrine mechanisms, facilitated by the release of damage-associated molecular patterns (DAMPs) triggered by TLR2 activation.

Results: Our findings indicate that sensitivity to UNE-C1-induced cell death is dependent on the expression levels of TLR2 and the Fas-associated death domain (FADD) in cancer cells. Furthermore, we investigated the paracrine activation of dendritic cells (DCs) by UNE-C1 via TLR2 signaling, which primes a CD8+ T cell response essential for tumor regression.

Discussion: Our results advocate for the intratumoral delivery of UNE-C1 via mRNA therapy as a promising strategy for innovative antitumor treatments.

Keywords: cancer immunotherapy; immunogenic cell death; intratumoral treatment; mRNA therapeutics; toll-like receptor; tumor microenvironment.

MeSH terms

  • Alarmins / metabolism
  • Animals
  • CD8-Positive T-Lymphocytes / immunology
  • Cell Line, Tumor
  • Dendritic Cells / immunology
  • Female
  • Humans
  • Immunogenic Cell Death* / drug effects
  • Mice
  • Mice, Inbred C57BL
  • RNA, Messenger* / genetics
  • Toll-Like Receptor 2* / agonists
  • Toll-Like Receptor 2* / genetics
  • Toll-Like Receptor 6* / agonists
  • Toll-Like Receptor 6* / genetics
  • Tumor Microenvironment / immunology

Substances

  • Toll-Like Receptor 2
  • RNA, Messenger
  • Toll-Like Receptor 6
  • Tlr2 protein, mouse
  • Alarmins

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korean government (Ministry of Science and ICT (MSIT)) (2021R1A3B1076605), NRF grant funded by Korean government (MSIT) (2021R1C1C1006496), NRF grant funded by the Korean government (MSIT) (2021R1C1C1013332), NRF grant funded by the Korean Government (MSIT) (2022R1C1C1013481), and Yonsei University Research Fund (2024-22-0060).