The migratory and functional contribution of pleural space immune cells during inflammation and cancer

• Applicant: Professor Dr. Georg Weber
• Subject Area: General and Visceral Surgery
• Term: from 2019 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 433570747

The immune cell pool in the body cavities contribute to disease related damages during trauma, inflammation and cancer. Peritoneal macrophages relocate into the liver parenchyma during liver injury to induce potent tissue repair while pleural space innate response activator (IRA) B cells extravasate into the lungs to protect against airway infection. Although these mechanisms suggest an important function of serosal cavity immune cells during inflammation and cancer, the immunological role of other pleural space cells in the immune response to bacterial or viral lung infections, their function in mediating innate into adaptive immune responses as well as the role of other residing pleural space cells during lung cancer disease remain largely unknown. Within the last years we (i) elucidated the function of pleural space IRA B cells in the second phase of airway inflammation; (ii) explored the generation of IRA B cells through various other extra- and intracellular mediators (TLR 1/2/4/9; IRAK4); (iii) investigated the trafficking of pleural space cells during steady state and inflammatory conditions; and (iv) analyzed the impact of GM-CSF dependent lung macrophages for antibody mediated immunotherapy in a lung tumor model. Our results indicate that (i) IRA B cells influence the amount of dendritic cells (DCs) and T cells in the lungs and draining lymph nodes during bacterial lung infection; that (ii) IRAK4 mediates the development of IRA B cells; that (iii) the pleural space serves as a cellular hub for T cells during lung inflammation; and that (iv) GM-CSF production is an important feature for macrophage mediated anti-tumor antibody activity. This leads to several new and important questions that are in the focus of this proposal. To investigate the role of pleural space T cells in the innate and adaptive immune responses we will conduct trafficking and functional analysis. Mechanistically, we will explore the role of tumor necrosis factor α-producing parietal pleural membrane cells as well as IRA B cells on T cell migration and function for effective protection during lung inflammation. In a model of colorectal cancer lung metastasis as well as in a xenograft model for primary lung cancer we will investigate the impact of pleural space (IRA) B cells and macrophages in tumor development and progression.

• DFG Programme: Research Grants