ASTX660, an antagonist of cIAP1/2 and XIAP, increases antigen processing machinery and can enhance radiation-induced immunogenic cell death in preclinical models of head and neck cancer
Inhibitor of apoptosis protein (IAP) antagonists have shown activity in preclinical models of head and neck squamous cell carcinoma (HNSCC), and work across several cancer types has demonstrated diverse immune stimulatory effects including enhancement of T cell, NK cell, and dendritic cell function....
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2020-01-01
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| Series: | OncoImmunology |
| Subjects: | |
| Online Access: | http://dx.doi.org/10.1080/2162402X.2019.1710398 |
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| author | Wenda Ye Sreenivasulu Gunti Clint T. Allen Youji Hong Paul E. Clavijo Carter Van Waes Nicole C. Schmitt |
| author_facet | Wenda Ye Sreenivasulu Gunti Clint T. Allen Youji Hong Paul E. Clavijo Carter Van Waes Nicole C. Schmitt |
| author_sort | Wenda Ye |
| collection | DOAJ |
| description | Inhibitor of apoptosis protein (IAP) antagonists have shown activity in preclinical models of head and neck squamous cell carcinoma (HNSCC), and work across several cancer types has demonstrated diverse immune stimulatory effects including enhancement of T cell, NK cell, and dendritic cell function. However, tumor-cell-intrinsic mechanisms for this immune upregulation have been largely unexplored. In this study, we show that ASTX660, an antagonist of cIAP1/2 and XIAP, induces expression of immunogenic cell death (ICD) markers in sensitive HNSCC cell lines in vitro. Experiments in syngeneic mouse models of HNSCC showed that ASTX660 can also enhance radiation-induced ICD in vivo. On a functional level, ASTX660 also enhanced killing of multiple murine cell lines by cytotoxic tumor-infiltrating lymphocytes, and when combined with XRT, stimulated clonal expansion of antigen-specific T lymphocytes and expression of MHC class I on the surface of tumor cells. Flow cytometry experiments in several human HNSCC cell lines showed that MHC class I (HLA-A,B,C) was reliably upregulated in response to ASTX660 + TNFα, while increases in other antigen processing machinery (APM) components were variable among different cell lines. These findings suggest that ASTX660 may enhance anti-tumor immunity both by promoting ICD and by enhancing antigen processing and presentation. |
| first_indexed | 2024-12-18T02:26:56Z |
| format | Article |
| id | doaj.art-eb5025ec4fbc4aa0aa02084fdf22ed8a |
| institution | Directory Open Access Journal |
| issn | 2162-402X |
| language | English |
| last_indexed | 2024-12-18T02:26:56Z |
| publishDate | 2020-01-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | OncoImmunology |
| spelling | doaj.art-eb5025ec4fbc4aa0aa02084fdf22ed8a2022-12-21T21:24:02ZengTaylor & Francis GroupOncoImmunology2162-402X2020-01-019110.1080/2162402X.2019.17103981710398ASTX660, an antagonist of cIAP1/2 and XIAP, increases antigen processing machinery and can enhance radiation-induced immunogenic cell death in preclinical models of head and neck cancerWenda Ye0Sreenivasulu Gunti1Clint T. Allen2Youji Hong3Paul E. Clavijo4Carter Van Waes5Nicole C. Schmitt6National Institute on Deafness and Other Communication Disorders, National Institutes of HealthNational Institute on Deafness and Other Communication Disorders, National Institutes of HealthNational Institute on Deafness and Other Communication Disorders, National Institutes of HealthNational Institute on Deafness and Other Communication Disorders, National Institutes of HealthNational Institute on Deafness and Other Communication Disorders, National Institutes of HealthNational Institute on Deafness and Other Communication Disorders, National Institutes of HealthNational Institute on Deafness and Other Communication Disorders, National Institutes of HealthInhibitor of apoptosis protein (IAP) antagonists have shown activity in preclinical models of head and neck squamous cell carcinoma (HNSCC), and work across several cancer types has demonstrated diverse immune stimulatory effects including enhancement of T cell, NK cell, and dendritic cell function. However, tumor-cell-intrinsic mechanisms for this immune upregulation have been largely unexplored. In this study, we show that ASTX660, an antagonist of cIAP1/2 and XIAP, induces expression of immunogenic cell death (ICD) markers in sensitive HNSCC cell lines in vitro. Experiments in syngeneic mouse models of HNSCC showed that ASTX660 can also enhance radiation-induced ICD in vivo. On a functional level, ASTX660 also enhanced killing of multiple murine cell lines by cytotoxic tumor-infiltrating lymphocytes, and when combined with XRT, stimulated clonal expansion of antigen-specific T lymphocytes and expression of MHC class I on the surface of tumor cells. Flow cytometry experiments in several human HNSCC cell lines showed that MHC class I (HLA-A,B,C) was reliably upregulated in response to ASTX660 + TNFα, while increases in other antigen processing machinery (APM) components were variable among different cell lines. These findings suggest that ASTX660 may enhance anti-tumor immunity both by promoting ICD and by enhancing antigen processing and presentation.http://dx.doi.org/10.1080/2162402X.2019.1710398iap antagonistsmac mimetichead and neck cancerimmunogenic cell deathantigen processing machinery |
| spellingShingle | Wenda Ye Sreenivasulu Gunti Clint T. Allen Youji Hong Paul E. Clavijo Carter Van Waes Nicole C. Schmitt ASTX660, an antagonist of cIAP1/2 and XIAP, increases antigen processing machinery and can enhance radiation-induced immunogenic cell death in preclinical models of head and neck cancer OncoImmunology iap antagonist smac mimetic head and neck cancer immunogenic cell death antigen processing machinery |
| title | ASTX660, an antagonist of cIAP1/2 and XIAP, increases antigen processing machinery and can enhance radiation-induced immunogenic cell death in preclinical models of head and neck cancer |
| title_full | ASTX660, an antagonist of cIAP1/2 and XIAP, increases antigen processing machinery and can enhance radiation-induced immunogenic cell death in preclinical models of head and neck cancer |
| title_fullStr | ASTX660, an antagonist of cIAP1/2 and XIAP, increases antigen processing machinery and can enhance radiation-induced immunogenic cell death in preclinical models of head and neck cancer |
| title_full_unstemmed | ASTX660, an antagonist of cIAP1/2 and XIAP, increases antigen processing machinery and can enhance radiation-induced immunogenic cell death in preclinical models of head and neck cancer |
| title_short | ASTX660, an antagonist of cIAP1/2 and XIAP, increases antigen processing machinery and can enhance radiation-induced immunogenic cell death in preclinical models of head and neck cancer |
| title_sort | astx660 an antagonist of ciap1 2 and xiap increases antigen processing machinery and can enhance radiation induced immunogenic cell death in preclinical models of head and neck cancer |
| topic | iap antagonist smac mimetic head and neck cancer immunogenic cell death antigen processing machinery |
| url | http://dx.doi.org/10.1080/2162402X.2019.1710398 |
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