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

• Authors: Wenda Ye, National Institutes of Health; Sreenivasulu Gunti, National Institutes of Health; Clint T. Allen, National Institutes of Health; Youji Hong, National Institutes of Health; Paul E. Clavijo, National Institutes of Health; Carter Van Waes, National Institutes of Health; Nicole Schmitt, Emory University
• Journal Title: OncoImmunology
• Volume: Volume 9, Number 1
• Publisher: Taylor & Francis: STM, Behavioural Science and Public Health Titles | 2020-01-01, Pages 1710398-1710398
• Type of Work: Article | Final Publisher PDF
• Publisher DOI: http://doi.org/10.1080/2162402X.2019.1710398
• Subjects: Health Sciences, Oncology; Health Sciences, Immunology
• Keywords: IAP antagonist; SMAC mimetic; antigen processing machinery; head and neck cancer; immunogenic cell death

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.