Abstract
Immunotherapy for cancer is making impressive strides at improving survival of a subset of cancer patients. To increase the breadth of patients that benefit from immunotherapy, new strategies that combat the immunosuppressive microenvironment of tumors are needed. 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. PS is a membrane lipid that flips to the outer surface of the cell membrane during apoptosis and/or cell stress. Externalized PS can drive efferocytosis or engage PS receptors (PSRs) to promote local immune suppression. In the tumor microenvironment (TME) PS-mediated immune suppression is often termed apoptotic mimicry. Monoclonal antibodies (mAbs) targeting PS or PSRs have been developed and are in preclinical and clinical testing. 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. This review will highlight the development of mAbs targeting PS, TIM-3 and the TAM receptors.4HLjmLqfELMkdkVsK3_rALVideo
Highlights
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 knows as cisplatin [1, 2]
It should be noted that no current TIM-1 or TIM-4 Monoclonal antibodies (mAbs) clinical trials are ongoing antibody-drug conjugates (ADCs) targeting these receptors are being developed [47]
The mAb appeared to induce antibody dependent cellular cytotoxicity (ADCC) directed towards endothelial cells and this effect was magnified in the presence of chemotherapy [113]. These results suggest that chemotherapy induces increased PS externalization and that PS-targeting mAbs alter immune cell phenotype as macrophages in the tumor microenvironment (TME) typically are not capable of performing Antibody-dependent cellular cytotoxicity (ADCC)
Summary
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 knows as cisplatin [1, 2]. 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.
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