Dataset Information

Nanoparticles with rough surface improve the therapeutic effect of photothermal immunotherapy against melanoma.

ABSTRACT: Photothermal therapy has been intensively investigated for treating cancer in recent years. However, the long-term therapeutic outcome remains unsatisfying due to the frequently occurred metastasis and recurrence. To address this challenge, immunotherapy has been combined with photothermal therapy to activate anti-tumor immunity and relieve the immunosuppressive microenvironment within tumor sites. Here, we engineered silica-based core‒shell nanoparticles (JQ-1@PSNs-R), in which silica cores were coated with the photothermal agent polydopamine, and a bromodomain-containing protein 4 (BRD4) inhibitor JQ-1 was loaded in the polydopamine layer to combine photothermal and immune therapy for tumor elimination. Importantly, to improve the therapeutic effect, we increased the surface roughness of the nanoparticles by hydrofluoric acid (HF) etching during the fabrication process, and found that the internalization of JQ-1@PSNs-R was significantly improved, leading to a strengthened photothermal killing effect as well as the increased intracellular delivery of JQ-1. In the animal studies, the multifunctional nanoparticles with rough surfaces effectively eradicated melanoma via photothermal therapy, successfully activated tumor-specific immune responses against residual tumor cells, and further prevented tumor metastasis and recurrence. Our results indicated that JQ-1@PSNs-R could serve as an innovative and effective strategy for combined cancer therapy.

SUBMITTER: Xue J

PROVIDER: S-EPMC9214318 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:Photothermal therapy (PTT) can be an effective antitumor therapy, but it may not completely eliminate tumor cells, leading to the risk of recurrence or metastasis. Here we describe nanocarriers that allow combination therapy involving PTT and immunotherapy. Nanocarriers are prepared by coating Al2O3 nanoparticles with non-toxic, biodegradable polydopamine, which shows high photothermal efficiency. A near-infrared laser irradiation can kill the majority of tumor tissues, resulting in the release of tumor-associated antigens. The Al2O3 within the nanoparticles, together with CpG, acts as an adjuvant to trigger robust cell-mediated immune responses that can help eliminate the residual tumor cells and reduce the risk of tumor recurrence. Methods: The characteristics and photothermal performance of polydopamine-coated Al2O3 nanoparticles were examined after one-step preparation. Then we studied their internalization, photothermal toxicity and immunostimulatory activity in vitro. For in vivo experiments, these nanocarriers were injected directly into B16F10 melanoma allografts in mice to ensure specific localization. After photothermal irradiation on day 0, mice were subcutaneously injected with CpG adjuvant on day 1, 3 and 5. Tumor volumes and number of living mice were recorded every two days. Moreover, various immune responses induced by our combined therapy were tested for mechanism research. Results: 50% of mice after our combined treatment successfully achieved the goal of tumor eradication, and survived for 120 days, which was the end point of the experiment. Mechanism studies demonstrated the combined therapy efficiently led to dendritic cell maturation, resulting in the secretion of antibodies and cytokines as well as the proliferation of splenocytes and lymphocytes for anti-tumor immunotherapy. Conclusion: Taken together, these results demonstrated the promise of our combined photothermal therapy and immunotherapy for tumor shrinkage, which merited further research.

Project description:The therapeutic effect of immune checkpoint blockers, especially the neutralizing antibodies of programmed cell death (PD-1) and its ligand programmed death ligand 1 (PD-L1), has been well verified in melanoma. Nevertheless, the dissatisfactory response rate and the occurrence of resistance significantly hinder the treatment effect. Inflammation-related molecules like A20 are greatly implicated in cancer immune response, but the role of tumorous A20 in antitumor immunity and immunotherapy efficacy remains elusive. The association between tumorous A20 expression and the effect of anti-PD-1 immunotherapy was determined by immunoblotting, immunofluorescence staining and flow cytometry analysis of primary tumor specimens from melanoma patients. Preclinical mouse model, in vitro coculture system, immunohistochemical staining and flow cytometry analysis were employed to investigate the role of A20 in regulating the effect of anti-PD-1 immunotherapy. Bioinformatics, mass spectrum analysis and a set of biochemical analyzes were used to figure out the underlying mechanism. We first discovered that upregulated A20 was associated with impaired antitumor capacity of CD8+T cells and poor response to anti-PD-1 immunotherapy in melanoma patients. Subsequent functional studies in preclinical mouse model and in vitro coculture system proved that targeting tumorous A20 prominently improved the effect of immunotherapy through the invigoration of infiltrating CD8+T cells via the regulation of PD-L1. Mechanistically, A20 facilitated the ubiquitination and degradation of prohibitin to potentiate STAT3 activation and PD-L1 expression. Moreover, tumorous A20 expression was highly associated with the ratio of Ki-67 percentage in circulating PD-1+CD8+T cells to tumor burden. Together, our findings uncover a novel crosstalk between inflammatory molecules and antitumor immunity in melanoma, and highlight that A20 can be exploited as a promising target to bring clinical benefit to melanomas refractory to immune checkpoint blockade.

Dataset Information

Nanoparticles with rough surface improve the therapeutic effect of photothermal immunotherapy against melanoma.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets