Means to cause an immunogenic cell death could lead to significant insight into how cancer escapes immune control. In this study, we screened a library of five pyrrole–imidazole polyamides coding for different DNA sequences in a model of B-cell lymphoma for the upregulation of surface calreticulin, a pro-phagocytosis signal implicated in immunogenic cell death. We found that hairpin polyamide 1 triggers the release of the damage-associated molecular patterns calreticulin, ATP and HMGB1 in a slow necrotic-type cell death. Consistent with this signaling, we observed an increase in the rate of phagocytosis by macrophages after the cancer cells were exposed to polyamide 1. The DNA sequence preference of polyamide 1 is 5′-WGGGTW-3′ (where W = A/T), indicated by the pairing rules and confirmed by the Bind-n-Seq method. The close correspondence of this sequence with the telomere-repeat sequence suggests a potential mechanism of action through ligand binding at the telomere. This study reveals a chemical means to trigger an inflammatory necrotic cell death in cancer cells.

中文翻译：

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序列特异性 DNA 结合小分子触发 B 细胞淋巴瘤模型中免疫原性信号的释放和吞噬作用

导致免疫原性细胞死亡的方法可能会导致对癌症如何逃脱免疫控制的重要见解。在这项研究中，我们在 B 细胞淋巴瘤模型中筛选了编码不同 DNA 序列的五种吡咯-咪唑聚酰胺文库，用于上调表面钙网蛋白，这是一种与免疫原性细胞死亡有关的促吞噬信号。我们发现发夹式聚酰胺1在缓慢的坏死型细胞死亡中触发损伤相关分子模式钙网蛋白、ATP 和 HMGB1 的释放。与该信号一致，我们观察到癌细胞暴露于聚酰胺后巨噬细胞的吞噬率增加1. 聚酰胺的 DNA 序列偏好1是 5′-WGGGTW-3′（其中W= A/T)，由配对规则指示并由 Bind-n-Seq 方法确认。该序列与端粒重复序列的密切对应表明通过端粒处的配体结合的潜在作用机制。这项研究揭示了一种化学方法来触发癌细胞中的炎症性坏死细胞死亡。