Adoptive cell therapy (ACT) with tumor-specific memory T cells has shown increasing efficacy in regressing solid tumors. However, tumor antigen heterogeneity represents a longitudinal challenge for durable clinical responses due to the therapeutic selective pressure for immune escape variants. Here, we demonstrated that delivery of the class I histone deacetylase inhibitor MS-275 promoted sustained tumor regression by synergizing with ACT in a coordinated manner to enhance cellular apoptosis. We found that MS-275 altered the tumor inflammatory landscape to support antitumor immunoactivation through the recruitment and maturation of cross-presenting CD103⁺ and CD8⁺ DCs and depletion of Tregs. Activated endogenous CD8⁺ T cell responses against nontarget tumor antigens were critically required for the prevention of tumor recurrence. Importantly, MS-275 altered the immunodominance hierarchy by directing epitope spreading toward the endogenous retroviral tumor–associated antigen p15E. Our data suggest that MS-275 in combination with ACT multimechanistically enhanced epitope spreading and promoted long-term clearance of solid tumors.

中文翻译：

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HDACi促进肿瘤微环境的炎症重塑以增强表位扩散和抗肿瘤免疫

使用肿瘤特异性记忆 T 细胞的过继细胞疗法 (ACT) 在实体瘤消退方面显示出越来越高的功效。然而，由于免疫逃逸变体的治疗选择压力，肿瘤抗原异质性代表了持久临床反应的纵向挑战。在这里，我们证明了 I 类组蛋白去乙酰化酶抑制剂 MS-275 的递送通过与 ACT 协同作用以增强细胞凋亡来促进持续的肿瘤消退。我们发现 MS-275 通过交叉呈递 CD103 ⁺和 CD8 ⁺ DCs 的募集和成熟以及 Tregs 的消耗改变了肿瘤炎症环境以支持抗肿瘤免疫激活。活化的内源性 CD8 ⁺针对非靶肿瘤抗原的 T 细胞反应是预防肿瘤复发的关键。重要的是，MS-275 通过引导表位向内源性逆转录病毒肿瘤相关抗原 p15E 扩散来改变免疫优势等级。我们的数据表明，MS-275 与 ACT 联合多机制增强了表位扩散并促进了实体瘤的长期清除。