PS is redistributed or flipped to the outer leaflet of the plasma membrane during or as result of certain cellular contexts or processes, the most well-described of which is apoptosis. PS is asymmetrically distributed to the inner leaflet of the plasma membrane in a highly conserved ATP-dependent process. While PS is a minor constituent in eukaryotic cells, PS-induced processes are highly conserved and have significant physiological functions. Other phospholipids, which are less abundant but integral to membrane function and homeostasis are phosphatidylinositol (PI), PS, and phosphatidic acid (PA). The major phospholipids in the cell include phosphatidylcholine (PC) and phosphatidylethanolamine (PE), which make up 45–50% and 30–40% of the phospholipids in cell, respectively. Phospholipid bilayers account for almost three-quarters of mammalian cell content. Lipid bilayers envelop eukaryotic cells and organelles to subdivide the cell into distinct working compartments. This review will cover the current literature of targeting PS and PSRs by monoclonal antibodies for the treatment of cancer. Research has shown targeting PS or PS-receptors (PSR) with monoclonal antibodies (mAb) can alter PS-mediated immunosuppression and facilitate the induction of an innate and adaptive anti-tumor immune response. Phosphatidylserine (PS), an anionic phospholipid present in all mammalian cells has been studied for the past two decades as a critical immunosuppressive feature that tumors use to mask their presence from the immune system. To expand the impact of immunotherapy, signaling pathways that drive tumor evasion of immune surveillance are under robust investigation. Immunotherapy is now first line therapy for some cancers and the immunotherapy options have grown substantially, to include vaccines, immune checkpoint blockade, immune agonists and chimeric antigen receptor (CAR) T-cell therapy. The realization that the immune system can be harnessed to fight a patients’ own disease has provided a new arsenal of strategies for cancer therapy. Since 1965, life-changing advancements in chemotherapy design and utilization have been made but hurdles for the systemic treatment of cancer remain. Michele Peyrone in 1845 described a molecule that had anti-cancer activity called “Peyrone salt,” Alfred Werner in 1893 deduced the structure of the salt, and Barnett Rosenberg in 1965 discovered the biological effects of this salt, a substance that the field of oncology now knows as cisplatin.
This review will highlight the development of mAbs targeting PS, TIM-3 and the TAM receptors. The TIM (T-cell/transmembrane, immunoglobulin, and mucin) and TAM (Tyro3, AXL, and MerTK) family of receptors are PSRs that have been shown to drive PS-mediated immune suppression in tumors. Monoclonal antibodies (mAbs) targeting PS or PSRs have been developed and are in preclinical and clinical testing. In the tumor microenvironment (TME) PS-mediated immune suppression is often termed apoptotic mimicry. Externalized PS can drive efferocytosis or engage PS receptors (PSRs) to promote local immune suppression. PS is a membrane lipid that flips to the outer surface of the cell membrane during apoptosis and/or cell stress. Phosphatidylserine (PS) signaling is exploited by tumors to enhance tumor immune evasion and thus strategies to inhibit PS-mediated immune suppression have potential to increase the efficacy of immunotherapy. To increase the breadth of patients that benefit from immunotherapy, new strategies that combat the immunosuppressive microenvironment of tumors are needed. Immunotherapy for cancer is making impressive strides at improving survival of a subset of cancer patients.
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