A Hypothetical, Universal Cancer Vaccine, 2019
References
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Over 150 mammalian protein types performing diverse functions specifically localize to leaflets on the outer cell membrane surface through glycophosphatidylinositol (GPI)-anchor mediated glypiation (1). The GPI anchor is assembled in the endoplasmic reticulum and attached to the C-terminus of proteins tagged with an anchor signal sequence, resulting in their export to the cell surface (1). Although GPI-anchoring is a post-translational addition of a glycolipid, the anchor signal sequence arises at the level of DNA and may therefore be substituted as an end-sequence for, theoretically, almost any protein (2). Due to the ability of purified, recombinant, exogenously-applied GPI-anchored proteins to integrate into mammalian outer cell membranes and retain full functionality, including the membranes of cancer cells (3), local delivery of novel GPI-anchored proteins permits a direct tethering of biochemical reaction networks onto cell types and tissue regions of interest. Likewise, localized delivery may better flag cancer cells for immune recognition.
Tumor immune escape has been found to occur in a variety of ways, such as through a lack of functional MHC molecules (4, 5, 6), resulting in T-cell avoidance. Local delivery of GPI- anchored protein antigens may offer a novel route of flagging tumors for destruction while bypassing MHC presentation, by directly tethering one or multiple immune effector modules to tumor cells, including macrophage-mediated antibody-dependent cellular phagocytosis (ADCP) (7, 8) and NK cell-mediated antibody-dependent cellular cytotoxicity (ADCC) (7, 9).
Macrophage-mediated ADCP and NK cell-mediated ADCC target antibody-coated extracellular pathogens through Fc receptors on their outer membranes, which bind to Fc (constant) regions on antibodies and are activated through cross-linking upon contact with antibody aggregations on a pathogen. Both macrophages (7, 8) and NK cells (7, 9) are known to play roles in tumor clearance, and both possess the Fc receptor CD16(A), which binds selectively to antibody subclasses IgG1 and IgG3 (10, 11). GPI-anchored protein antigens specific to IgG1 and/or IgG3 isotopes will therefore be incorporated into cancer cell membranes to evaluate therapeutic efficacy. Although this pilot will initially be performed in- vitro, it possesses multiple potential advantages for in-vivo application. Such includes 1) bypassing MHC presentation and the need for T-cell harvesting, as well as the possibility of 2) reliance on immune memory against antigens that the target has received a prior vaccination against. Both an advantage and disadvantage of this therapeutic regimen is that GPI-anchors will integrate into almost any mammalian cell types, including any cancer line, which results in the need for local delivery (e.g. nanoparticle delivery vehicles, magnetic manipulation systems, etc.) or synthetic anchor sequences. Still, due to a cross-linking based activation mechanism of Fc receptors on NK cells and macrophages requiring the presence of clustered, pathogen- bound antibodies, low levels of off-target anchored antigens may potentially be tolerated without triggering a response.