Cyclic adenosine monophosphate (cAMP) serves cells of all life forms as a signaling messenger and to regulate gene expression. Regulatory T cells (Treg) transfer cAMP to other immune cells to suppress their function (J. Exp. Med 2007). In melanomas, melanoma cells acidify their environment by lactate, which instigates cAMP production in monocytes, suppressing their anti-tumor activities (Nat. Immunol. 2018).

We have collaborated with colleagues in chemistry and immunology to develop nanoparticulate micelles that release an cAMP (Adenylate cyclase) inhibitor in tumor tissue.  Local application of such inhibitor-loaded particles suppresses melanoma growth through metabolic reprogramming of infiltrating immune cells. We are currently further improving the cAMP inhibitor particles to make them systemically and thus clinically applicable. At the same time, we continue to investigate the molecular basis of cAMP-mediated reprogramming of the immune system to identify alternative, cell-specific intervention points.

Regulatory T cells (Treg) have -in addition to their role in suppressing immune responses- an important and non-redundant role in tissue repair. The cellular and molecular mechanisms underlying the development and function of 'repair Treg' in injured tissue are poorly defined.

We recently identified a specialized population of Treg that develops in venous blood clots and controls clot resolution by potentiating monocyte recruitment, differentiation and matrix metalloproteinase (MMP) activity through the matricellular protein, secreted protein acidic and rich in cysteine (SPARC) (Shahneh et al., 2020). We believe that 'clot Treg‘ and their products offer new therapeutic opportunities for the treatment of sterile tissue inflammation, such as in vascular diseases and tumors.

Chronic venous insufficiency (CVI) is a very common health problem. The most common manifestations of chronic venous disease are dilated skin veins and varicose veins. The exact etiology of CVI remains unclear, but inflammatory processes are thought to be of critical importance. Varicose veins have a larger infiltrate of inflammatory cells than normal veins, and monocytes are a major component.

Varicose veins removed during surgery to correct venous dysfunction or for cosmetic reasons and their healthy counterpart used in cardiac bypass surgery provide an exceptional opportunity to understand the activities of human vascular monocytes.

We are exploring the specific function of monocytes in inflamed venous tissue and expect to contribute to the understanding of CVI pathology and, moreover, chronic tissue inflammation.