@article{580e434c12ce4fe091ca22a6bbaa5ba5,
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",
abstract = "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.",
keywords = "IAP antagonist, SMAC mimetic, antigen processing machinery, head and neck cancer, immunogenic cell death",
author = "Wenda Ye and Sreenivasulu Gunti and Allen, {Clint T.} and Youji Hong and Clavijo, {Paul E.} and {Van Waes}, Carter and Schmitt, {Nicole C.}",
note = "Funding Information: Astex Pharmaceuticals provided ASTX660 and research funding to Dr. Schmitt and Dr. Van Waes under a Cooperative Research and Development Agreement (CRADA) with NIDCD, NIH. Funding Information: The authors acknowledge Christopher Silvin and Yvette Robbins for technical assistance, James Mitchell and his lab for assistance with irradiation treatments, James Hodge and Wojciech Mydlarz for critical review of the manuscript, and the NIH Medical Arts team for illustration of Figure 6 . This research was made possible in part through the NIH Medical Research Scholars Program, a public-private partnership supported jointly by the NIH and contributions to the Foundation for the NIH from the Doris Duke Charitable Foundation (DDCF Grant #2014194), the American Association for Dental Research, the Colgate-Palmolive Company, Genentech, Elsevier, and other private donors. Figure 6. ASTX660 combined with TNFα differentially alters APM across various human HNSCC cell lines. UMSCC-74A (HPV-), −11B(HPV-), −47(HPV+), −46 (HPV-) cells were treated with IFN-γ (10 ng/mL, positive control), TNFα (20 ng/mL), ASTX660 (500 nM or 1 μM), and ASTX660 (250 nM, 500 nM, or 1 μM) + TNFα for 48 hours prior to staining and analysis by flow cytometry. Data are represented as mean + SEM, n = 6–9 from at least 2 independent experiments. * p < .05 versus control. APM, antigen processing machinery; IFN-γ, interferon-γ; TNFα, tumor necrosis factor α; MFI, mean fluorescence intensity. Funding Information: Supported by NIDCD intramural projects [ZIA-DC-DC000087 and ZIA-DC-DC000090]; Astex Pharmaceuticals. The authors acknowledge Christopher Silvin and Yvette Robbins for technical assistance, James Mitchell and his lab for assistance with irradiation treatments, James Hodge and Wojciech Mydlarz for critical review of the manuscript, and the NIH Medical Arts team for illustration of Figure 6. This research was made possible in part through the NIH Medical Research Scholars Program, a public-private partnership supported jointly by the NIH and contributions to the Foundation for the NIH from the Doris Duke Charitable Foundation (DDCF Grant #2014194), the American Association for Dental Research, the Colgate-Palmolive Company, Genentech, Elsevier, and other private donors.Figure 6. ASTX660 combined with TNF? differentially alters APM across various human HNSCC cell lines. UMSCC-74A (HPV-), ?11B(HPV-), ?47(HPV+), ?46 (HPV-) cells were treated with IFN-? (10?ng/mL, positive control), TNF? (20?ng/mL), ASTX660 (500?nM or 1 ?M), and ASTX660 (250?nM, 500?nM, or 1 ?M) + TNF? for 48?hours prior to staining and analysis by flow cytometry. Data are represented as mean + SEM, n?=?6?9 from at least 2 independent experiments. *p ?<?.05 versus control. APM, antigen processing machinery; IFN-?, interferon-?; TNF?, tumor necrosis factor ?; MFI, mean fluorescence intensity. Publisher Copyright: {\textcopyright} 2020, {\textcopyright} 2020 The Author(s). Published with license by Taylor & Francis Group, LLC.",
year = "2020",
month = jan,
day = "1",
doi = "10.1080/2162402X.2019.1710398",
language = "English (US)",
volume = "9",
journal = "OncoImmunology",
issn = "2162-4011",
publisher = "Landes Bioscience",
number = "1",
}