Adoptive T Cell Therapy Targeting Different Gene Products Reveals Diverse and Context-Dependent Immune Evasion in Melanoma
Adoptive T Cell Therapy Targeting Different Gene Products Reveals Diverse and Context-Dependent Immune Evasion in Melanoma
复制标题
DOI：
10.1016/j.immuni.2020.07.007
复制
发表时间：
2020-09-15
期刊：
影响因子：
32.4
通讯作者：
Hoelzel, Michael
中科院分区：
文献类型：
--
作者：
Effern, Maike;Glodde, Nicole;Hoelzel, Michael
肿瘤免疫逃逸限制了对T细胞疗法的持久应答。在这里，我们研究了为CD 8（+）T细胞抗肿瘤免疫提供靶表位的基因产物的调节和功能如何影响治疗效果和耐药性。我们在同源黑色素瘤模型中使用基于CRISPR-Cas9的方法（CRISPitope）将相同的模型CD 8（+）T细胞表位融合到不同内源性基因产物的C末端。通过过继性细胞转移（ACT）相同表位特异性CD 8（+）T细胞靶向黑素体蛋白或致癌CDK 4（R24 C）（细胞周期蛋白依赖性激酶4），揭示了不同的遗传和非遗传免疫逃逸机制。ACT针对黑素体蛋白，但不针对CDK 4（R24 C），促进黑色素瘤去分化，并增加骨髓细胞浸润。CDK 4（R24 C）抗原持续性与高干扰素和富含T细胞的肿瘤微环境相关，允许免疫检查点抑制作为挽救治疗。因此，靶抗原的选择决定了复发性黑色素瘤的表型和免疫结构，对癌症免疫疗法的设计有影响。
Tumor immune escape limits durable responses to T cell therapy. Here, we examined how regulation and function of gene products that provide the target epitopes for CD8(+) T cell anti-tumor immunity influence therapeutic efficacy and resistance. We used a CRISPR-Cas9-based method (CRISPitope) in syngeneic melanoma models to fuse the same model CD8(+) T cell epitope to the C-termini of different endogenous gene products. Targeting melanosomal proteins or oncogenic CDK4(R24C )(Cyclin-dependent kinase 4) by adoptive cell transfer (ACT) of the same epitope-specific CD8(+) T cells revealed diverse genetic and non-genetic immune escape mechanisms. ACT directed against melanosomal proteins, but not CDK4(R24C), promoted melanoma dedifferentiation, and increased myeloid cell infiltration. CDK4(R24C) antigen persistence was associated with an interferon-high and T-cell-rich tumor microenvironment, allowing for immune checkpoint inhibition as salvage therapy. Thus, the choice of target antigen determines the phenotype and immune contexture of recurrent melanomas, with implications to the design of cancer immunotherapies.