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.

中文翻译：

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在头颈癌的临床前模型中，ASTX660 是 cIAP1/2 和 XIAP 的拮抗剂，可增加抗原加工机制并增强辐射诱导的免疫原性细胞死亡。

凋亡蛋白抑制剂 (IAP) 拮抗剂已在头颈部鳞状细胞癌 (HNSCC) 的临床前模型中显示出活性，并且在几种癌症类型中的工作已证明具有多种免疫刺激作用，包括增强 T 细胞、NK 细胞和树突细胞功能. 然而，这种免疫上调的肿瘤细胞内在机制在很大程度上尚未探索。在这项研究中，我们展示了 cIAP1/2 和 XIAP 的拮抗剂 ASTX660 在体外诱导敏感 HNSCC 细胞系中免疫原性细胞死亡 (ICD) 标志物的表达。HNSCC 同基因小鼠模型的实验表明，ASTX660 还可以增强体内辐射诱导的 ICD。在功能层面上，ASTX660 还增强了细胞毒性肿瘤浸润淋巴细胞对多种鼠细胞系的杀伤，当与 XRT 结合时，刺激抗原特异性 T 淋巴细胞的克隆扩增和肿瘤细胞表面 MHC I 类的表达。在几种人类 HNSCC 细胞系中进行的流式细胞术实验表明，MHC I 类（HLA-A、B、C）在响应 ASTX660 + TNFα 时可靠上调，而其他抗原加工机制（APM）成分的增加在不同细胞系中是可变的. 这些发现表明，ASTX660 可以通过促进 ICD 和增强抗原加工和呈递来增强抗肿瘤免疫。而其他抗原加工机器（APM）成分的增加在不同细胞系中是可变的。这些发现表明，ASTX660 可以通过促进 ICD 和增强抗原加工和呈递来增强抗肿瘤免疫。而其他抗原加工机器（APM）成分的增加在不同细胞系中是可变的。这些发现表明，ASTX660 可以通过促进 ICD 和增强抗原加工和呈递来增强抗肿瘤免疫。