Exploiting Immunogenic Modulation in Chordoma: Sublethal Radiation Increases EGFR Expression and Sensitizes Tumor Cells to Cetuximab

Abstract

Chordoma is a rare primary spinal neoplasm for which standard therapy consists of surgery and radiation. However, the high dose of radiation required to kill chordoma is not always possible given their proximity to the brain and spinal cord. Cancer cells surviving radiation often have phenotypic changes making them more susceptible to immunotherapy, a process termed immunogenic modulation. Among these phenotypic changes is the upregulation of surface markers for which FDA approved monoclonal antibodies exist, such as trastuzumab (Anti‐HER2), rituximab (anti‐CD20), and cetuximab (anti‐EGFR). Upregulation of monoclonal antibody targets have previously been shown to increase natural killer (NK) cell lysis by antibody dependent cell‐mediated cytotoxicity (ADCC) in both chordoma and other carcinoma types. It is known that approximately 80% of chordomas express Epidermal Growth Factor Receptor (EGFR), though to varying degrees of positivity. We hypothesized that sublethal radiation of chordoma cells would increase EGFR expression and enhance the therapeutic effects of cetuximab. Three distinct chordoma cell lines were exposed to sublethal doses of radiation and changes in surface EGFR expression were monitored via flow cytometry. ADCC assays were then performed using NK cells from normal donors and cetuximab. We show here that chordoma cells surviving low dose ionizing radiation express increased EGFR levels. The functional consequence of this upregulation is significantly decreased proliferation compared to either radiation or cetuximab alone. ADCC assays also show increased killing in cells that have been irradiated compared to those which have not. While both radiotherapy and cetuximab have had mixed results as monotherapies for chordoma, our results suggest that cetuximab in combination with radiation will produce a more complete response than either therapy alone.Support or Funding InformationNational Cancer Institute