Abstract
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.
Highlights
Chordoma is a rare bone cancer thought to arise from remnants of the embryonic notochord
For the first time, we demonstrate the potential of anti-programmed death-ligand 1 (PD-L1) antibody therapy for chordoma and report that (a) PD-L1 expression induced by IFN-γ increased the sensitivity of chordoma cells to lysis by natural killer (NK) cells via avelumab-mediated antibody-dependent cell-mediated cytotoxicity (ADCC); (b) tumor antigenspecific CD8+ T cells indirectly induced PD-L1 expression on chordoma cells; (c) upregulated PD-L1 expression on chordoma cells indirectly induced by brachyury-specific CD8+ T cells increased the sensitivity of chordoma cells to avelumab-mediatedADCC; and (d) residential cancer stem cell (CSC) populations in chordoma cells were killed by avelumab-mediated ADCC to the same degree as nonCSC populations within the cells
We first examined whether IFN-γ could modulate expression of MHC-I and PD-L1 in chordoma cell lines established from 4 chordoma patients [18,19,20,21]
Summary
Chordoma is a rare bone cancer thought to arise from remnants of the embryonic notochord. 300 new cases per year are diagnosed in the United States, accounting for 20% of primary spine tumors and 1%-4% of all malignant bone tumors [1, 2]. Reported 5- and 10-year survival rates are about 70% and 40%, respectively, a reflection of the slow-growing nature of the disease. Surgery followed by radiotherapy is the standard of care for primary tumors. Based on anatomic location and tumor size on presentation, a wide curative excision is rarely feasible [2]. Incidence of disease recurrence is common and metastases have been reported in up to 40% of cases. Median survival is about 1 year [1]. There is an urgent need for novel therapeutic modalities for this disease
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