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Celastrol nanoemulsion induces immunogenicity and downregulates PD-L1 to boost abscopal effect in melanoma therapy.

ABSTRACT: Programmed cell death-ligand 1 (PD-L1)-based immune checkpoint blockade therapy using the anti-PD-L1 antibody is effective for a subset of patients with advanced metastatic melanoma but about half of the patients do not respond to the therapy because of the tumor immunosuppressive microenvironment. Immunogenic cell death (ICD) induced by cytotoxins such as doxorubicin (DOX) allows damaged dying tumor cells to release immunostimulatory danger signals to activate dendritic cells (DCs) and T-cells; however, DOX also makes tumor cells upregulate PD-L1 expression and thus deactivate T-cells via the PD-1/PD-L1 pathway. Herein, we show that celastrol (CEL) induced not only strong ICD but also downregulation of PD-L1 expression of tumor cells. Thus, CEL was able to simultaneously activate DCs and T-cells and interrupt the PD-1/PD-L1 pathway between T-cells and tumor cells. In a bilateral tumor model, intratumorally (i.t.) injected celastrol nanoemulsion retaining a high tumor CEL concentration activated the immune system efficiently, which inhibited both the treated tumor and the distant untreated tumor in the mice (i.e., abscopal effect). Thus, this work demonstrates a new and much cost-effective immunotherapy strategy - chemotherapy-induced immunotherapy against melanoma without the need for expensive immune-checkpoint inhibitors.

SUBMITTER: Qiu N

PROVIDER: S-EPMC8601126 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:PD-L1 expression in the tumor immune microenvironment is recognized as both a prognostic and predictive biomarker in patients with cutaneous melanoma, a finding closely related to its adaptive (IFN-?-mediated) mechanism of expression. Approximately 35% of cutaneous melanomas express PD-L1, however, the expression patterns, levels, and prevalence in rarer melanoma subtypes are not well described. We performed immunohistochemistry for PD-L1 and CD8 on 200 formalin-fixed paraffin-embedded specimens from patients with acral (n=16), mucosal (n=36), uveal (n=103), and chronic sun-damaged (CSD) (n=45) melanomas (24 lentigo maligna, 13 'mixed' desmoplastic, and 8 'pure' desmoplastic melanomas). CD8+ tumor-infiltrating lymphocyte (TIL) densities were characterized as mild, moderate, or severe, and their geographic association with PD-L1 expression was evaluated. Discrete lymphoid aggregates, the presence of a spindle cell morphology, and the relationship of these features with PD-L1 expression were assessed. PD-L1 expression was observed in 31% of acral melanomas, 44% of mucosal melanomas, 10% of uveal melanomas, and 62% of CSD melanomas (P<0.0001). Compared to our previously characterized cohort of cutaneous melanomas, the proportion of PD-L1(+) tumors was lower in uveal (P=0.0002) and higher in CSD (P=0.0073) melanomas, while PD-L1 expression in the acral and mucosal subtypes was on par. PD-L1 expression in all subtypes correlated with a moderate-severe grade of CD8+ TIL (all, P<0.003), supporting an adaptive mechanism of expression induced during the host antitumor response. The tumor microenvironments observed in CSD melanomas segregated by whether they were the pure desmoplastic subtype, which showed lower levels of PD-L1 expression when compared to other CSD melanomas (P=0.047). The presence of lymphoid aggregates was not associated with the level of PD-L1 expression, while PD-L1(+) cases with spindle cell morphology demonstrated higher levels of PD-L1 than those with a nested phenotype (P<0.0001). Our findings may underpin the reported clinical response rates for anti-PD-1 monotherapy, which vary by subtype.

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Celastrol nanoemulsion induces immunogenicity and downregulates PD-L1 to boost abscopal effect in melanoma therapy.

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