Lung-sparing radical pleurectomy with intraoperative photodynamic therapy (PDT) demonstrates remarkable survival for patients with pleural mesothelioma. Nevertheless, most patients treated with this multimodal approach will develop local tumor recurrence. An understanding of potential causes of treatment failure is central to developing mitigation strategies. Surgery importantly reduces disease burden but also produces tumor-promoting inflammation, as demonstrated through transcriptomic analysis of pleural mesothelioma specimens. Using preclinical models in the setting of combination therapy, we separated the benefit of surgical resection from its counterproductive effects on therapeutic outcome. Specifically, we evaluated mechanisms by which surgically induced inflammation can be therapy-limiting in a murine model of tumor incision (TI) introduced by a surgical cut across the tumor. In this TI model, we identified distinct TI-altered patterns in innate and adaptive inflammatory cells in murine mesothelioma tumors, and we studied changes in these patterns with the addition of [ photodynamic therapy (PDT) ]. TI introduction of an immunosuppressive environment is established via upregulation of PD-1/PD-L1 expression on tumor cells, T cells, and myeloid cells that is partially resolved by [ photodynamic therapy (PDT) ]. Immune dysfunction is further mitigated by the addition of PD-1 blockade, leading to curative potential in a process that requires Ly6G+ neutrophils and CD8+ T cells. Overall, these studies suggest that, without [ photodynamic therapy (PDT) ], surgical modulation of immune cell trafficking and functionality leads to systemic immunosuppression. This immunosuppressive state potentially interferes with the generation of antitumor immunity by [ photodynamic therapy (PDT) ]. However, targeted inhibition of surgery-induced signaling in the PD-l/PD-L1 pathway counteracts surgery’s immunosuppressive outcomes to enhance [ photodynamic therapy (PDT) ] efficacy in the intraoperative setting.
Introduction
The etiology of pleural mesothelioma (PM) commonly consists of asbestos embedment in the pleura of the lungs, triggering a chronic inflammatory response and mesothelial carcinogenesis. This process is supported by high levels of reactive oxygen species–producing phagocytic cells, inflammasome activation, and amplified growth factor signaling (1–3). Years after exposure, this can progress to PM, a relatively rare and highly aggressive cancer of the pleura. Histologic and biologic heterogeneities in PM within and between patients necessitate a treatment plan that is multidisciplinary and adaptive. Typically, this includes systemic therapy; in surgical candidates, definitive options include combinations of radiotherapy with cytoreduction through extrapleural pneumonectomy or extended pleurectomy/decortication (4). As local recurrence is common even with multimodal treatment, additional strategies to improve control of tumor could include fluorescence-guided resection to improve surgical efficacy (5), cytotoxic therapies such as hyperthermic intraoperative chemotherapy (6), and immunotherapies to boost immune response (7).
For patients with PM, surgical resection can reduce tumor burden to mitigate symptoms and facilitate adjuvant cytotoxic or immune-stimulating therapies. However, surgical debulking results in altered cytokine levels, such as decreases in IL-2 signaling and increases in IL-1/6/8/10 signaling, as well as the release of growth factors, clotting factors, and stress hormones (8) that lead to the expansion of regulatory and suppressive immune cells, including myeloid-derived suppressor cells (MDSC) and tumor-associated macrophages (TAM; refs. 9, 10). Although accumulation of these regulatory immune cells is essential in the context of wound healing, the resulting amplified expression of PD-1/CTLA-4 immune checkpoints, decreased T-cell proliferation, and impaired NK cell cytotoxicity result in an overall state of immunosuppression (11–13). This potentially contributes to tumor relapse. However, it may also be possible to reset the tumor microenvironment from a protumor to antitumor state by introducing adjuvant therapies during key windows of opportunity in the perioperative or postsurgical setting.
We are evaluating photodynamic therapy (PDT) as an adjuvant to surgery for PM in a randomized phase II trial of intraoperative[ photodynamic therapy (PDT)] (NCT02153229) following encouraging results with earlier intraoperative [ photodynamic therapy (PDT) ] trials for PM (NCT01673074 and NCT02159742; ref. 14). [ photodynamic therapy (PDT) ] is a cytotoxic therapy that leads to immunogenic cell death using visible wavelengths of light to activate reactive oxygen species–producing photosensitizers localized within tumor cells (15). In addition to directly causing tumor cell death, [ photodynamic therapy (PDT) ] also releases large quantities of cytokines and cellular debris that are a source of tumor antigens, initiates an influx of neutrophils followed by other myeloid cells, and subsequently generates an adaptive immune response (16–18).
[Article continues at original source]
Asbestos & Mesothelioma Information
Asbestos-Mesothelioma Case Evaluation
Free. Confidential. No Obligation.