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Primary effusion lymphoma (PEL) is an aggressive malignancy with poor prognosis even under chemotherapy. Kaposi sarcoma–associated herpesvirus (KSHV), one of the human oncogenic viruses, is the principal causative agent. Currently, there is no specific treatment for PEL; therefore, developing new therapies is of great importance. Sphingolipid metabolism plays an important role in determining the fate of tumor cells. Our previous studies have demonstrated that there is a correlation between sphingolipid metabolism and KSHV+ tumor cell survival. To further develop sphingolipid metabolism-targeted therapy, after screening a series of newly synthesized ceramide analogs, here, we have identified compounds with effective anti-PEL activity. These compounds induce significant PEL apoptosis, cell-cycle arrest, and intracellular ceramide production through regulation of ceramide synthesizing or ceramide metabolizing enzymes and dramatically suppress tumor progression without visible toxicity in vivo. These new compounds also increase viral lytic gene expression in PEL cells. Our comparative transcriptomic analysis revealed their mechanisms of action for inducing PEL cell death and identified a subset of novel cellular genes, including AURKA and CDCA3, controlled by sphingolipid metabolism, and required for PEL survival with functional validation. These data provide the framework for the development of promising sphingolipid-based therapies against this virus-associated malignancy.

In this issue of Blood, de Stoppelaar et al further unravel the relevance of platelets in a mouse model of pneumonia-derived sepsis by illustrating how platelets dynamically modulate infection and the inflammatory response.

The platelet glycoprotein (GP) Ib-IX receptor complex is expressed exclusively on the surface of platelets and is well characterized as a primary adhesion receptor supporting normal hemostasis and pathologic thrombosis. Beyond hemostasis and thrombosis, platelets can also participate in the innate immune response and inflammation. While the platelet as a contributor to the immune continuum is recognized, many aspects of the molecular mechanisms whereby platelets influence the immune response are still undefined. Here, we report studies using a murine model of GP Ib-IX deficiency linking GP Ib-IX to the immune response associated with polymicrobial sepsis, as modeled by cecal ligation and puncture (CLP). In the CLP model, genetic absence of the major GP Ib-IX hemostatic ligand, von Willebrand factor (VWF), improves survival following CLP when compared to control wild-type animals (p= 0.003, Logrank analysis). This suggests a VWF role in thrombosis contributes to survival outcome following CLP. In contrast, genetic absence of the VWF platelet receptor, GP Ib-IX, does not improve survival with no statistical difference comparing wild-type animals to GPIb-IX deficient animals. The molecular basis to explain improved survival in VWF-deficient (ligand deficient) but not GPIb-IX deficient (receptor deficient) animals was pursued. We tested the hypothesis GPIb-IX has normal physiologic and pathophysiologic functions beyond platelet adhesion influencing infection and an inflammatory response. Indeed, GPIb-IX influencing the innate immune response is not completely unexpected since a hallmark structural feature of each subunit of the GPIb-IX receptor is leucine rich repeats, the common motif to all members of the toll like receptor family (TLRs). Whether structural similarities are a consequence of ancestral origins for GPIb-IX and TLRs is unknown. We first documented in the absence of murine platelet GP Ib-IX there are reduced platelet-neutrophil and platelet-monocyte interactions under normal conditions and following CLP in whole blood. Whether there are physiologic consequences for disrupting a platelet/monocyte and/or platelet/neutrophil axis was determined via multianalyte profiling of circulating cytokine levels on a Luminex analyzer following CLP. In the absence of GP Ib-IX there is a robust and statistically significant increase 24 hrs following CLP in some of the major proinflammatory cytokines produced by monocytes and macrophages, including TNFα, MCP-1, MIP-β, IL-6, and IL-15. Increases in cytokines, such as IL-5 and IL-13, associated with other immune cells were also observed. These results highlight a coagulation/inflammation interface where the platelet, and specifically GP Ib-IX, contributes to the pathophysiology of CLP. On the one hand, absence of platelet GPIb-IX reduces thrombotic potential, but it occurs at the expense of upregulation of inflammatory cytokine release leading to a reduced survival in CLP. Clearly, survival outcomes in CLP reflect a complex dysregulation of coagulation and inflammation where platelet GPIb-IX likely contributes to both processes with physiologic consequences. Understanding dysregulation of the coagulation/ inflammation interface and identifying a platelet receptor (GPIb-IX) critical to both adds new information to this complex set of pathophysiologic events Sharing the common structural motifs, leucine rich repeats, with the well characterized family of toll-like receptors, platelet GPIb-IX should now be considered an active participant in the inflammatory cascade. Disclosures: No relevant conflicts of interest to declare.