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Updated: Jun 7, 2026
Experimental Melanoma Immunotherapy Model Using Tumor Vaccination with a Hematopoietic Cytokine
Published on: February 24, 2023
Additive melanoma suppression with intralesional phospholipid-conjugated TLR7 agonists and systemic IL-2
Tomoko Hayashi1, Michael Chan, John T Norton
1aRebecca and John Moores UCSD Cancer Center bDepartment of Medicine, University of California, San Diego, La Jolla, California, USA.
Abstract:
There remains a compelling need for the development of treatments for unresectable melanoma. Agents that stimulate the innate immune response could provide advantages for cell-based therapies. However, there are conflicting reports concerning whether toll-like receptor (TLR) signaling controls tumor growth. The objective of this study was to evaluate the effect of intralesional administration of a TLR7 agonist in melanoma therapy. B16cOVA melanoma was implanted to TLR7 mice to evaluate the roles of stromal TLR7 on melanoma growth. To capitalize on the potential deleterious effects of TLR7 stimulation on the tumor growth, we injected melanoma tumor nodules with a newly developed and potent TLR7 agonist. B16 melanoma nodules expanded more rapidly in TLR7-deficient and MyD88 mice compared with TLR9 and wild type mice. Repeated injections with low doses of unconjugated TLR7 agonist were more effective at attenuating nodule size than a single high dose injection. To improve the efficacy we conjugated the agonist to phospholipid or phospholipids-polyethylene glycol, which retained TLR7 specificity. The phospholipid conjugate was indeed more effective in reducing lesion size. Furthermore, intralesional administration of the phospholipid TLR7 agonist conjugate enhanced the antimelanoma effects of systemic treatment with interleukin (IL)-2 and prolonged the survival of mice compared with IL-2 alone. Our study showed that: (1) TLR7/MyD88 signaling in the stroma is involved in melanoma growth; and (2) intralesional administration of a TLR7 agonist reduces the growth of melanoma nodules and enhances the antimelanoma effects of IL-2.
Insights
Toll-like receptor 7 (TLR7) signaling in melanoma stroma influences tumor growth. Intralesional TLR7 agonist administration effectively reduces melanoma nodule size and enhances anti-melanoma effects when combined with interleukin-2 therapy.
Area of Science:
- Immunology
- Oncology
- Pharmacology
Background:
- Unresectable melanoma necessitates novel treatment strategies.
- Stimulating the innate immune response offers potential for cell-based therapies.
- The role of toll-like receptor (TLR) signaling in tumor growth remains debated.
Purpose of the Study:
- To investigate the effect of intralesional TLR7 agonist administration in melanoma therapy.
- To evaluate the role of stromal TLR7 in melanoma growth using a B16cOVA model.
- To assess the efficacy of a novel potent TLR7 agonist, including conjugated forms.
Main Methods:
- Implantation of B16cOVA melanoma in TLR7-deficient and wild-type mice.
- Intralesional injection of a novel TLR7 agonist, both unconjugated and conjugated to phospholipids.
- Combination therapy with intralesional TLR7 agonist conjugate and systemic interleukin-2 (IL-2).
Main Results:
- Melanoma nodules grew faster in TLR7-deficient and MyD88 mice, indicating stromal TLR7 involvement in growth.
- Repeated low-dose TLR7 agonist injections were more effective than single high doses.
- Phospholipid-conjugated TLR7 agonist significantly reduced lesion size and enhanced IL-2's anti-melanoma effects, prolonging survival.
Conclusions:
- TLR7/MyD88 signaling in the tumor stroma plays a role in melanoma progression.
- Intralesional administration of a TLR7 agonist is a promising strategy for melanoma treatment.
- Combination therapy with TLR7 agonist conjugates and IL-2 demonstrates enhanced anti-melanoma efficacy.
