Jayden Olson

Background: Melanoma is the most aggressive and deadliest skin cancer, with an increasing incidence in recent decades.¹ Melanomas typically present as darkly pigmented lesions but can also be the same shade of the patient’s skin, making early detection difficult.^2,3 Therapeutic options range anywhere from surgical resections to radiation therapy to topical creams.⁴ The newest advancements in treatment are immune checkpoint blockades which address the complex pathology of melanoma; however, relapses are still being seen in most of the patient population.⁵  To address this issue studies were conducted on the role of plasmacytoid dendritic cells (pDC) on tumorigenesis and found that properly activated pDCs cause melanoma regression, presenting TLR and STING agonists as potential new line of treatment in combination with existing immunotherapies.⁵

Objective: In this literature review, we explored impairment of pDCs by the melanoma tumor microenvironment (TME) and how these mechanisms can be targeted for immunotherapy.

Search Methods: An online search in the PubMed database was conducted from 2018 to 2024 using the following keywords: “melanoma”, “tumor microenvironment”, “immunometabolism”, “plasmacytoid dendritic cells”, “TLR agonist”, “STING agonist”.

Results: Production of immunosuppressive cytokines (PGE2, IL-10, and TGF-beta), oncometabolites (lactic acid), and IFN inhibitory receptor ligand by the melanoma TME, inhibited IFN-alpha production of pDC’s which caused immunosuppression.⁵ In a study evaluating TLR agonist, rMBP- NAP, dendritic cell maturation markers (CD40, CD80, MHC I and II) were elevated in spleen and tumor tissues.⁶ Additionally, infiltration of tumor tissues with CD4⁺ and CD8⁺ T cells was significantly higher in the agonist treatment group. Treated mice also had upregulated mRNA expression of granzyme B and perforin in tumor tissues, exhibiting greater cytotoxic efects.⁶ In another study looking at STING agonists, Western blotting analysis indicated high levels of phosphorylated proteins associated with the cGAS-STING pathway indicating activation. Crucial factors such as IFN-beta were seen at high levels in the experimental group showing dendritic cell maturation and immunological activation. An increase in the percentage of mature dendritic cells was measured in tumor draining lymph nodes with a similar trend seen in intratumoral CD8⁺ T cell infiltration.⁷  A combination study with DMXAA + 522 treatment showed enhanced stimulation of  proinflammatory cytokines, such TNF-alpha, IL-6, and IL-12, and decreased murine tumor volume.⁸ Excised tumors after treatment were stained to quantify caspase-3 levels, higher percentages of caspase-3-stained areas were seen with the combination treatment, illustrating an increase in the induction of apoptosis of tumor cells.⁸

Conclusions: pDCs play a crucial role in the immune system but are being rendered inactive by the tumor microenvironment. The studied TLR agonist, rMBP-NAP, promotes development of DCs and amplifies T-cell response, demonstrating it’s valuable for innate and adaptive immunity and making it a potential immunotherapy. Experimental cGAS-STING pathway stimulation aids DC maturation, activating T cells and inducing a systemic antitumor immune response, showing another potential immunotherapy. The combination treatment, DMXAA+522, was more effective than a singular agonist at excitation of pro-inflammatory cytokines and co-stimulatory molecules which led to greater CD8+ T cell priming and anti-tumor effects. This shows the individual strengths and gaps of the separate adjuvants, illustrating that when combined they filled some of the holes and amplified similar strengths. This emphasizes the need for further experimentation and combination of immunotherapies.

Works Cited:

1. Teixido C, Castillo P, Martinez-Vila C, Arance A, Alos L. Molecular Markers and Targets in Melanoma. Cells. 2021; 10(9):2320. https://doi-org.srv-proxy1.library.tamu.edu/10.3390/cells10092320
2. Strashilov S, Yordanov A. Aetiology and Pathogenesis of Cutaneous Melanoma: Current Concepts and Advances. International Journal of Molecular Sciences. 2021; 22(12):6395. https://doi-org.srv-proxy1.library.tamu.edu/10.3390/ijms22126395
3. Long GV, Swetter SM, Menzies AM, Gershenwald JE, Scolyer RA. Cutaneous melanoma. The Lancet. 2023;402(10400):485-502. doi:https://doi.org/10.1016/s0140-6736(23)00821-8
4. ‌Di Raimondo C, Lozzi F, Di Domenico PP, Campione E, Bianchi L. The Diagnosis and Management of Cutaneous Metastases from Melanoma. International Journal of Molecular Sciences. 2023; 24(19):14535. https://doi-org.srv-proxy1.library.tamu.edu/10.3390/ijms241914535
5. Monti M, Ferrari G, Grosso V, et al. Impaired activation of plasmacytoid dendritic cells via toll-like receptor 7/9 and STING is mediated by melanoma-derived immunosuppressive cytokines and metabolic drift. Front Immunol. 2024;14:1227648. Published 2024 Jan 3. doi:10.3389/fimmu.2023.1227648
6. Liu J, Ding C, Wang X, Yang L, Liu X, Kang Q. TLR agonist rMBP-NAP inhibits B16 melanoma tumor growth via induction of DCs maturation and T-cells cytotoxic response. Cytotechnology. 2022;74(4):459-467. doi:10.1007/s10616-022-00532-4
7. Feng Y, Wang G, Li W, et al. PhotoPyro-Induced cGAS-STING Pathway Activation Enhanced Anti-Melanoma Immunotherapy via a Manganese-Coordinated Nanomedicine. Adv Healthc Mater. 2024;13(6):e2302811. doi:10.1002/adhm.202302811
8. Bhatnagar S, Revuri V, Shah M, et al. Combination of STING and TLR 7/8 Agonists as Vaccine Adjuvants for Cancer Immunotherapy. Cancers (Basel). 2022;14(24):6091. Published 2022 Dec 11. doi:10.3390/cancers14246091