Treatment of malignant pleural mesothelioma remains palliative in nature, and consists of surgical resection in order to achieve local control. More recently, surgical procedures which spare the lung (radical pleurectomy) have been coupled with photodynamic therapy (PDT) of residual disease to achieve better local control. Due to increasing evidence of the effects of surgery on both host immunity and residual tumor cells, we investigated the contribution of injuries sustained during surgery to efficacy of photodynamic therapy in a mouse model of malignant mesothelioma. We previously observed that surgical injury prior to PDT inhibits long-term response in vivo. As it relates to PDT outcome, we are now investigating neutrophil profiles in the presence and absence of surgical injury. Our results demonstrate that neutrophil influx into the tumor and lymph node occur sooner when PDT is preceded by surgical injury, as demonstrated by higher neutrophil counts in the respective tissue. Through in vivo imaging using luminol chemiluminescence as a marker of neutrophil activation, we show a role of neutrophil-secreted myeloperoxidase activity in producing long-term response after PDT. However, myeloperoxidase deposition in the lymph node is known to suppress dendritic cell migration, activation, and antigen uptake. Thus, we are currently investigating if early influx and activation of neutrophils in tumor draining lymph nodes results in a loss of establishment of PDT-mediated immunity. Taken together, these studies will describe potential immunomodulatory roles for myeloperoxidase in responses to intraoperative PDT.
The onset of inflammation is a well-known physiology in tumors treated with photodynamic therapy (PDT). After PDT, the release of danger signals causes an influx of neutrophils, activation of dendritic cells, and an eventual initiation of the adaptive immune response. However, inflammation also lies at a crucial fulcrum for treatment outcome, as it can stimulate the expression of resistance factors. Therefore, effective treatment with PDT requires an understanding of the holistic contribution of inflammation. Within, we outline two means of studying tumor inflammation in the setting of PDT. Experiments are conducted in murine models of mesothelioma, including those that incorporate surgery prior to PDT or pleural propagation of the disease. First, we use a chemiluminescent agent, luminol, to detect the influx of neutrophils by in vivo molecular imaging. This longitudinal approach allows for the repeated non-invasive monitoring of PDT-induced neutrophil influx. Data clearly identify protocol-specific differences in tumor-associated neutrophil activity. Second, we describe the application of cone-beam CT to detect the fibrosis associated with murine orthotropic mesothelioma models. This approach incorporates novel methods in image segmentation to accurately identify diffuse disease in the thoracic cavity. These studies lay the foundation for future research to correlate long-term response with local PDT-induced inflammation. Such methods in monitoring of inflammation or tumor burden will enable characterization of the consequences of combinatorial therapy (e.g., intraoperative PDT). Resulting data will guide the selection of pharmacological agents or molecular imaging techniques that respectively exploit inflammation for therapeutic or monitoring purposes.