HMGB1 Promotes Myeloid Egress and Limits Lymphatic Clearance of Malignant Pleural Effusions

Abstract

Pleural effusions, when benign, are attributed to cardiac events and suffusion of fluid within the pleural space. When malignant, lymphatic obstruction by tumor and failure to absorb constitutively produced fluid is the predominant formulation. The prevailing view has been challenged recently, namely that the lymphatics are only passive vessels, carrying antigenic fluid to secondary lymphoid sites. Rather, lymphatic vessels can be a selective barrier, efficiently coordinating egress of immune cells and factors within tissues, limiting tumor spread and immune pathology. An alternative explanation, offered here, is that damage associated molecular pattern molecules, released in excess, maintain a local milieu associated with recruitment and retention of immune cells associated with failed lymphatic clearance and functional lymphatic obstruction. We found that levels of high mobility group box 1 (HMGB1) were equally elevated in both benign and malignant pleural effusions (MPEs) and that limited diversity of T cell receptor expressing gamma and delta chain were inversely associated with these levels in MPEs. Acellular fluid from MPEs enhanced γδ T cell proliferation in vitro, while inhibiting cytokine production from γδ T cells and monocytes as well as restricting monocyte chemotaxis. Novel therapeutic strategies, targeting HMGB1 and its neutralization in such effusions as well as direct delivery of immune cells into the pleural space to reconstitute normal physiology should be considered.

Isoforms of Neuropilin-2 Denote Unique Tumor-Associated Macrophages in Breast Cancer

“…Immunophenotyping was performed on fresh single-cell homogenates of mouse tissues or cryopreserved cellular fraction of pleural effusions as described previously ( 21 – 24 ). Detection of NRP2 Total (extracellular labeling) and NRP2b (intracellular labeling) was performed simultaneously along with macrophage phenotyping under standardized conditions.…”

Fighting Fire With Fire: Oncolytic Virotherapy for Thoracic Malignancies

“…Thus, lymphatics play a critical role in regulating viral infection, both by minimizing its spread throughout the body and by promoting an adaptive immune response, 37 , 38 allowing us to consider that they play a major role in limiting fluid egress from the thoracic cavity in the setting of benign and malignant pleural effusions. 39 …”

“…Thus, lymphatics play a critical role in regulating viral infection, both by minimizing its spread throughout the body and by promoting an adaptive immune response, 37,38 allowing us to consider that they play a major role in limiting fluid egress from the thoracic cavity in the setting of benign and malignant pleural effusions. 39 The following sections have been divided by the major epithelial thoracic malignancies for which OVs might be used (lung cancer, esophageal cancer, and metastatic malignant pleural effusions) in both preclinical studies and clinical trials. In addition to single-agent therapy, combination therapies (e.g., checkpoint inhibitors with OV) are included because they have shown promise, with potential to modulate the immunologic TME and promote a more effective host response.…”