HDACi-dependent Microenvironmental Normalization Overcomes Tumor Burden–induced T-cell Exhaustion

癌症研究 生物 重编程 肿瘤微环境 免疫疗法 CD8型 细胞毒性T细胞 T细胞 转录组 细胞 免疫学 免疫系统 生物化学 基因表达 基因 体外 遗传学
作者
Andrew Nguyen,Dominique Brown,Ramya Krishnan,Donald Bastin,Li Deng,Lan Chen,Omar Salem,Scott Walsh,Jonathan L. Bramson,Yonghong Wan
出处
期刊:Clinical Cancer Research [American Association for Cancer Research]
卷期号:29 (20): 4289-4305
标识
DOI:10.1158/1078-0432.ccr-22-2181
摘要

Abstract Purpose: T-cell exhaustion limits immunotherapy for the treatment of solid tumors. Although immune checkpoint blockade and adoptive T-cell therapy (ACT) can mediate tumor regression, their potency is often determined by tumor burden. Here, we identified tumor burden–related pathway changes that are conducive to T-cell exhaustion. We then determined whether microenvironmental reprogramming via epigenetic modulation could reverse T-cell exhaustion and improve immunotherapeutic responsiveness. Experimental Design: We developed a murine syngeneic tumor model wherein an increased burden ablated therapeutic responsiveness to ACT, which corresponded with systemic induction of T-cell exhaustion. Transcriptome analysis of these large tumors allowed us to characterize changes to immunosuppressive pathway expression during class I histone deacetylase inhibitor MS-275 treatment. We then measured the therapeutic impact of MS-275 during ACT and assessed T-cell exhaustion by transcriptome/phenotypic analysis. Results: ACT durably regressed small tumors but failed to control large tumors, which were associated with systemic T-cell exhaustion and ablation of T-cell responses. Large tumors were defined by an immunosuppressive pathway signature. MS-275 reversed this pathway signature and promoted durable regression of large tumors during ACT. Prototypical exhaustion marker Tim-3 was selectively upregulated in transferred T cells despite displaying a reduced exhaustion signature. Instead, we observed enhanced activation-dependent signaling correlating with enrichment of the IL2–STAT5 signaling axis. Activated CD8+ T-cell responses were predominantly skewed toward terminal effector cell–like CD44+ Tim-3hi TCF1− CD127− KLRG1+ differentiation. Conclusions: Tumor burden–induced pathway changes can be reversed through epigenetic reprogramming, enabling the conversion from T-cell exhaustion to effector lineage differentiation.
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