Platelet–CD40 ligand interaction with melanoma cell and monocyte CD40 enhances cellular procoagulant activity

Abstract

Platelet-tumor cell interactions are believed to be important in tumor metastasis. Tumor cell tissue factor (TF) expression enhances metastasis and angiogenesis, and is primarily responsible for tumor-induced thrombin generation and the formation of tumor cell-platelet aggregates. Activated platelets express and release CD40 ligand (CD40L), which induces endothelial TF expression by ligation to CD40. We investigated the effect of platelet-derived CD40L on the TF activity of human CD40-positive melanoma cells and monocytes by incubating supernatants from activated or resting platelets with tumor cells or monocytes, and by bringing resting or activated platelets into close apposition with tumor cell monolayers. CD40L was present on the surface of activated (but not resting) platelets and was also released following platelet activation. Both recombinant soluble CD40L (rsCD40L) and activated platelet supernatants increased procoagulant activity (PCA) and TF antigen in tumor cells and monocytes. The increase in TF activity induced by both rsCD40L and activated platelet supernatants was inhibited by anti-CD40L antibody. Furthermore, contact of activated platelets with tumor cells increased cellular PCA, and this effect was also inhibited by anti-CD40L. In malignancy, the increase in cellular TF activity via CD40 (tumor cell)-CD40L (platelet) interaction may possibly enhance intravascular coagulation and hematogenous metastasis.

Soluble CD40 Ligand Plasma Levels in Lung Cancer

“…Although it is conceivable to hypothesize that a procoagulant activity released from lung cancer cells might stimulate platelet activation and the release of sCD40L, we should also consider the possibility that platelet-released sCD40L may engage interactions with other cell types expressing CD40, including tumor-associated monocytes/macrophages and lung cancer cells (1,24). This hypothesis is in agreement with the findings by Amirkhosravi et al (6), who suggested recently that CD40/CD40L interaction through tumor cell CD40 and platelet CD40L may potentially promote clotting activation by enhancing TF expression on A375 human melanoma cells.…”

“…Both membrane-bound and sCD40L interact with CD40 expressed on vascular cells, resulting in inflammatory and prothrombotic responses (3,5). Recently, it has been suggested that activation of the CD40/CD40L pathway may enhance the procoagulant activity of tumor cells through an up-regulation of tissue factor (TF) expression, the natural activator of the extrinsic pathway of coagulation (6). Thrombin generation and peritumoral fibrin deposition are known to be involved in angiogenesis, and there is evidence that TF-mediated thrombin generation may play a predominant role in the mechanisms for tumor-induced platelet activation (7).…”

Modulation of Autoimmunity and Atherosclerosis – Common Targets and Promising Translational Approaches Against Disease –

“…91 This may be logical, considering that most of the CD40L in blood is expressed on platelets, not T cells. 92 In experimental atherosclerosis, CD40-CD40L interactions induce a proinflammatory response, thus accelerating the disease, 93,94 whereas CD40L blockade is associated with atheroprotection. 95 Notably, anti-CD40L has been proposed to influence plaque size and stability through the induction of collagen.…”

Anti-CD40L Immune Complexes Potently Activate Platelets In Vitro and Cause Thrombosis in FCGR2A Transgenic Mice

“…Given that the majority of circulating CD40L is contained not in T cells but in platelets (16), there is an urgent need to identify the molecular mechanisms that link platelets and CD40L to thrombosis with anti-CD40L mAbs. Only by unraveling these complex interactions can the goal of delivering safe and effective anti-CD40L immunotherapy to patients be fully realized.…”