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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.
Highlights
At advanced stages, many types of cancer can infiltrate the pleural cavity, disrupting the normal mechanism of fluid secretion and absorption, resulting in an unopposed collection of cancer containing fluid termed malignant pleural effusion (MPE)
Previous studies have shown that transudative effusions resulting from congestive heart failure or liver cirrhosis had significantly lower levels of high mobility group box 1 (HMGB1) when compared with exudative effusions arising from infection or malignancy [29, 30]
We found, compared to reference cohorts from sera of both healthy controls and metastatic clear cell renal cell carcinoma (ccRCC) patients, that intrapleural HMGB1 levels in both MPEs and benign pleural effusion (BPE) were significantly elevated
Summary
Many types of cancer can infiltrate the pleural cavity, disrupting the normal mechanism of fluid secretion and absorption, resulting in an unopposed collection of cancer containing fluid termed malignant pleural effusion (MPE). HMGB1 in Pleural Effusions life expectancy, and often heralding the terminal stages of cancer [1,2,3,4]. Our understanding of the phenotypes of immune cells, their tumor specificity, and how they are impacted by the MPE environment are only beginning to be understood. The lymphatics themselves, regulating pleural fluid dynamics, are not just passive conduits. They emerged after the appearance of cartilaginous fish, with organized lymph nodes found later, primarily in mammals and in some birds. In the pleural space of sheep, where it has been measured, effusions can be completely removed by the lymphatics in a linear manner at a rate of 0.28 mL/kg/h, ∼28 times greater than the rate of pleural fluid formation
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