Radiation-induced tumor neoantigens: imaging and therapeutic implications

Abstract

Exposure of tumor cells to ionizing radiation (IR) is widely known to induce a number of cellular changes. One way that IR can affect tumor cells is through the development of neoantigens which are new molecules that tumor cells express at the cell membrane following some insult or change to the cell. There have been numerous reports in the literature of changes in both tumor and tumor vasculature cell surface molecule expression following treatment with IR. The usefulness of neoantigens for imaging and therapeutic applications lies in the fact that they are differentially expressed on the surface of irradiated tumor cells to a greater extent than on normal tissues. This differential expression provides a mechanism by which tumor cells can be "marked" by radiation for further targeting. Drug delivery vehicles or imaging agents conjugated to ligands that recognize and interact with the neoantigens can help to improve tumor-specific targeting and reduce systemic toxicity with cancer drugs. This article provides a review of the molecules that have been reported to be expressed on the surface of tumor cells in response to IR either in vivo or in vitro. Additionally, we provide a discussion of some of the methods used in the identification of these antigens and applications for their use in drug delivery and imaging.

Figure 1

Ionizing radiation leads to the upregulation of surface molecules in tumor endotheiiai cells that can be targeted for drug delivery. A schematic illustrating a generalized mechanism by which irradiation can be used to deliver tumor targeted therapies. 1) Ionizing radiation is incident upon the tumor from an external source. 2) Radiation induces the upregulation of the neoantigen and its subsequent translocation to the cell surface. 3) Intravascular nanoparticles conjugated with a targeting moiety bind to the irradiated tumor endotheiiai cell surface. 4) The nanoparticle is endocytosed and the drug contents are released to the surrounding tumor cells.

Figure 2

GIRLRG-targeted nanoparticle drug delivery system causes tumor growth delay in vivo. MDA-MB-231 (a) or GL261 (b) tumor cells were implanted in the hind limbs of nude mice or C57/BI6, respectively. Once tumors reached 300 mm³ in volume, mice were treated with 3 Gy radiation daily for 3 days, or were left as untreated controls. On the 2^nd day, mice were injected with either systemic paclitaxel, paclitaxel nanoparticle conjugated with the RILGGR scrambled peptide, or paclitaxel nanoparticle conjugated with the GIRLRG targeted peptide at a concentration of 10 mg/kg (n=5) (a) or 20 mg/kg (n=3) (b). Tumor volumes were monitored throughout using calipers. Reprinted with permission [12].