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PD-1 blockade mitigates surgery-induced immunosuppression and increases the efficacy of photodynamic therapy for malignant pleural mesothelioma

ABSTRACT: Surgical resection can influence tissue behavior and immune interactions, leading to an altered inflammatory state. Our clinical trial delivers intraoperative photodynamic therapy (PDT) to the thoracic cavity after macroscopic complete resection of malignant pleural mesothelioma (MPM) tumors. We have previously published evidence of systemic inflammation via increases in circulating levels of IL-6 after surgical resection. Thus, we expect surgery to alter local signal transduction in the resection field by the time that PDT is delivered. To detect these signaling changes, RNA sequencing analysis was performed on tumor tissue isolated at different time intervals during the surgery (and prior to PDT) from 33 MPM patients. We discovered several pathways associated with tumor behavior and immune function were activated over the course of surgery.

ORGANISM(S): Homo sapiens

PROVIDER: GSE272176 | GEO | 2025/04/29

REPOSITORIES: GEO

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Project description:Photodynamic therapy (PDT) of solid cancers comprises the administration of a photosensitizer followed by illumination of the photosensitizerreplete tumor with laser light. This induces a state of local oxidative stress, culminating in the destruction of tumor tissue and microvasculature and induction of an anti-tumor immune response. However, some tumor types, including perihilar cholangiocarcinoma, are relatively refractory to PDT, which may be attributable to the activation of survival pathways in tumor cells following PDT (i.e., activator protein 1 (AP-1)-, nuclear factor of kappa light polypeptide gene enhancer in B-cells (NF-ÎºB)-, hypoxia-inducible factor 1-alpha (HIF-1Î±)-, nuclear factor (erythroid-derived 2)-like 2 (NFE2L2), and unfolded protein response-mediated pathways). To assess the activation of survival pathways after PDT, human perihilar cholangiocarcinoma (SK-ChA-1) cells were subjected to PDT with zinc phthalocyanine (ZnPC)-encapsulating liposomes. Following a 30-minute incubation with liposomes, the cells were either left untreated or treated at low (50 mW) or high (500 mW) laser power (cumulative light dose of 15 J/cm2). Cells were harvested 90 minutes post-PDT and whole genome expression analysis was performed using Illumina HumanHT-12 v4 expression beadchips. Hilar cholangiocarcinoma (SK-ChA-1) cells were incubated with PBS (control group) or 500 Î¼M zinc phthalocyanine (ZnPC)-encapsulating liposomes (ZnPC-ITLs, final lipid concentration). After 30 minutes, cells that were incubated with ZnPC-ITLs were either kept in the dark (ITL group) or were treated with 500-mW (ITL 500) or 50-mW (ITL 50) laser light (n = 3 per group, cumulative light dose of 15 J/cm2). Ninety minutes after photodynamic therapy, total cellular RNA was isolated and gene expression levels were analyzed by using the Illumina HumanHT-12 v4 platform. The data was analyzed in the context of survival signalling and comparisons were made with the control group.

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PD-1 blockade mitigates surgery-induced immunosuppression and increases the efficacy of photodynamic therapy for malignant pleural mesothelioma

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