Chordoma, a rare bone tumor derived from the notochord, has been shown to be 
resistant to conventional therapies. Checkpoint inhibition has shown great 
promise in immune-mediated therapy of diverse cancers. The anti-PD-L1 mAb 
avelumab is unique among checkpoint inhibitors in that it is a fully human IgG1 
capable of mediating antibody-dependent cell-mediated cytotoxicity (ADCC) of 
PD-L1-expressing tumor cells. Here, we investigated avelumab as a potential 
therapy for chordoma. We examined 4 chordoma cell lines, first for expression of 
PD-L1, and in vitro for ADCC killing using NK cells and avelumab. PD-L1 
expression was markedly upregulated by IFN-γ in all 4 chordoma cell lines, which 
significantly increased sensitivity to ADCC. Brachyury is a transcription factor 
that is uniformly expressed in chordoma. Clinical trials are ongoing in which 
chordoma patients are treated with brachyury-specific vaccines. Co-incubating 
chordoma cells with brachyury-specific CD8+ T cells resulted in significant 
upregulation of PD-L1 on the tumor cells, mediated by the CD8+ T cells' IFN-γ 
production, and increased sensitivity of chordoma cells to avelumab-mediated 
ADCC. Residential cancer stem cell subpopulations of chordoma cells were also 
killed by avelumab-mediated ADCC to the same degree as non-cancer stem cell 
populations. These findings suggest that as a monotherapy for chordoma, avelumab 
may enable endogenous NK cells, while in combination with T-cell immunotherapy, 
such as a vaccine, avelumab may enhance NK-cell killing of chordoma cells via 
ADCC.