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Affect of Interferon Gamma on Chordoma Cells

ABSTRACT: IFN-g-induced gene expression profiles of UM-Chor1 cells were assessed by microarray analysis Chordoma is a rare bone tumor derived from notochord, which has shown to be resistant to conventional therapy, including chemotherapy and radiotherapy. Immunotherapy has the potential to be effective in cancers with resistance to conventional therapy. Checkpoint inhibition, including Programmed cell Death 1 (PD-1)/Programmed cell Death protein 1 (PD-L1) blockade has shown great promise in treating diverse cancers. The purpose of this study was to investigate the potential of anti-PD-L1 antibody therapy for chordoma. To this end, using 4 chordoma cell lines, we examined the expression of PD-L1 and performed in vitro NK cells killing assay for antibody-dependent cell-mediated cytotoxicity (ADCC) activity mediated by the anti-PD-L1 antibody, avelumab. Here, the expression of PD-L1 was markedly upregulated by IFN-g in all 4 chordoma cell lines, which resulted in increasing the sensitivity to ADCC. Next, to model a patient that received a tumor-antigen specific vaccine, chordoma cells were co-incubated with brachyury specific CD8+ T cells, culminating in significant upregulation of PD-L1 on the tumor cells mediated by CD8+ T cells IFN-g production. The functional consequence was the sensitivity of chordoma cells to ADCC mediated by avelumab. Finally, residential cancer stem cell subpopulations of chordoma cells were killed by avelumab-mediated ADCC to the same degree as non-cancer stem cell populations. Our findings show the potential of avelumab therapy in chordoma; a) alone, to enable endogenous NK cells to kill chordoma cells via ADCC, or b) in conjunction with T cells immunotherapy such a vaccine, to exploit enhanced NK cell killing of chordoma cells via ADCC.

ORGANISM(S): Homo sapiens

PROVIDER: GSE77732 | GEO | 2017/01/01

SECONDARY ACCESSION(S): PRJNA311327

REPOSITORIES: GEO

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Project description:The paper describes a model of ADCC. Created by COPASI 4.26 (Build 213) This model is described in the article: A mathematical model of antibody-dependent cellular cytotoxicity (ADCC) F. Hoffman, D. Gavaghan, J. Osborne, I.P. Barrett, T. You, H. Ghadially, R. Sainson, R.W. Wilkinson, H.M. Byrne Journal of Theoretical Biology 436 (2018) 39–50 Abstract: Immunotherapies exploit the immune system to target and kill cancer cells, while sparing healthy tis- sue. Antibody therapies, an important class of immunotherapies, involve the binding to specific antigens on the surface of the tumour cells of antibodies that activate natural killer (NK) cells to kill the tu- mour cells. Preclinical assessment of molecules that may cause antibody-dependent cellular cytotoxicity (ADCC) involves co-culturing cancer cells, NK cells and antibody in vitro for several hours and measuring subsequent levels of tumour cell lysis. Here we develop a mathematical model of such an in vitro ADCC assay, formulated as a system of time-dependent ordinary differential equations and in which NK cells kill cancer cells at a rate which depends on the amount of antibody bound to each cancer cell. Numerical simulations generated using experimentally-based parameter estimates reveal that the system evolves on two timescales: a fast timescale on which antibodies bind to receptors on the surface of the tumour cells, and NK cells form complexes with the cancer cells, and a longer time-scale on which the NK cells kill the cancer cells. We construct approximate model solutions on each timescale, and show that they are in good agreement with numerical simulations of the full system. Our results show how the processes involved in ADCC change as the initial concentration of antibody and NK-cancer cell ratio are varied. We use these results to explain what information about the tumour cell kill rate can be extracted from the cytotoxicity assays. To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models . To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

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Affect of Interferon Gamma on Chordoma Cells

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