Targeting phosphatidylserine for Cancer therapy: prospects and challenges

Abstract

Cancer is a leading cause of mortality and morbidity worldwide. Despite major improvements in current therapeutic methods, ideal therapeutic strategies for improved tumor elimination are still lacking. Recently, immunotherapy has attracted much attention, and many immune-active agents have been approved for clinical use alone or in combination with other cancer drugs. However, some patients have a poor response to these agents. New agents and strategies are needed to overcome such deficiencies. Phosphatidylserine (PS) is an essential component of bilayer cell membranes and is normally present in the inner leaflet. In the physiological state, PS exposure on the external leaflet not only acts as an engulfment signal for phagocytosis in apoptotic cells but also participates in blood coagulation, myoblast fusion and immune regulation in nonapoptotic cells. In the tumor microenvironment, PS exposure is significantly increased on the surface of tumor cells or tumor cell-derived microvesicles, which have innate immunosuppressive properties and facilitate tumor growth and metastasis. To date, agents targeting PS have been developed, some of which are under investigation in clinical trials as combination drugs for various cancers. However, controversial results are emerging in laboratory research as well as in clinical trials, and the efficiency of PS-targeting agents remains uncertain. In this review, we summarize recent progress in our understanding of the physiological and pathological roles of PS, with a focus on immune suppressive features. In addition, we discuss current drug developments that are based on PS-targeting strategies in both experimental and clinical studies. We hope to provide a future research direction for the development of new agents for cancer therapy.

Keywords: T lymphocytes; bavituximab; cancer; immunotherapy; phosphatidylserine.

Figure 1

An illustration of PS synthesis. PS synthesis in the MAM from PC by PSS-1 or PE by PSS-2. After synthesis, some of the PS transported into mitochondria is decarboxylated to PE by PSD. The remaining synthesized PS in the MAM is transported to other organelles, such as the plasma membrane and the Golgi. MAM, mitochondria associated membranes; PC, phosphatidylcholine; PE, phosphatidylethanolamine; PSS-1/2, phosphatidylserine synthase 1/2; PSD, phosphatidylserine decarboxylase.

Figure 2

An illustration of PS receptors and their functions in immune suppression. TAM interacts with PS through Gla domain-containing proteins, Gas6 or Pros1. Ca²⁺ also participates in effective PS binding and receptor activation. PS binds to TAM to regulate the feedback inhibition of the innate immune response in immune cells. The TIM protein forms a narrow cavity or pocket that PS binds to and plays a critical role in regulating immune responses. Stabilin-1/2 interacts with PS through four clusters (each cluster includes an EGF-like domain, an atypical EGF-like domain, a FAS domain and/or a link domain), which in turn activate a series of signals that lead to immune suppression.

Figure 3

An illustration of PS exposure on tumor cells and vesicles inducing immune suppression. PS exposure on tumor cells induces immune suppression by ligation of PS to receptors on macrophages and T cells. PS binds to PSR on macrophages to promote maturation of M2-like macrophages, which are able to secrete the anti-inflammatory cytokines IL-10 and TGF-β. IL-10 and TGF-β are immunosuppressive cytokines that inhibit T cell activation. Additionally, ligation of PS to receptors on T cells inhibits T cell activation via GPR174-mediated M2 macrophage maturation. Conversely, PS exposed on tumor-derived microvesicles (externalized PS on microvesicles) increase the removal of apoptotic cells via phagocytes to prevent an undesirable inflammatory response and maintain an anti-inflammatory status in tumor microenvironments. GPR174, G protein-coupled receptor 174; M1Mф, M1-like macrophages; M2Mф, M2-like macrophages.

Figure 4

Cancer therapeutics related to PS. The graph shows the approved and promising drugs designed to target PS for cancer therapy. 1) Naked antibodies bind to PS. 2) Antibody-drug conjugates bind to PS. 3) Liposomal carriers bind to PS.