Holden Comprehensive Cancer Center, University of Iowa, Iowa City, Iowa.
Department of Anatomy and Cell Biology, University of Iowa, Iowa City, Iowa.
Cancer Immunol Res. 2020 Sep;8(9):1206-1214. doi: 10.1158/2326-6066.CIR-20-0056. Epub 2020 Jul 1.
T-cell-mediated cancer immunotherapies, including anti-PD-1 and T cells expressing chimeric antigen receptors (CAR-T cells), are becoming standard treatments for many cancer types. CAR-T therapy, in particular, has been successful in treating circulating, but not solid, tumors. One challenge limiting immunotherapy success is that tumors lacking T-cell infiltration do not respond to treatment. Therefore, one potential strategy to overcome resistance is to enhance the ability of T cells to traffic into tumors. Here, we describe an unbiased genetic screen approach utilizing the mutagenesis system to identify candidate genes in T cells that might be modified to drive intratumoral T-cell accumulation. This screen identified over 400 candidate genes in three tumor models. These results indicated substantial variation in gene candidate selection, depending on the tumor model and whether or not mice were treated with anti-PD-1, yet some candidate genes were identified in all tumor models and with anti-PD-1 therapy. Inhibition of the most frequently mutated gene, , affected chemokine receptor expression and enhanced T-cell trafficking and Screen candidates should be further validated as therapeutic targets, with particular relevance to enhancing infiltration of adoptively transferred T cells into solid tumors.
T 细胞介导的癌症免疫疗法，包括抗 PD-1 和表达嵌合抗原受体（CAR-T 细胞）的 T 细胞，正在成为许多癌症类型的标准治疗方法。特别是 CAR-T 疗法在治疗循环肿瘤方面取得了成功，但对实体肿瘤效果不佳。限制免疫疗法成功的一个挑战是，缺乏 T 细胞浸润的肿瘤对治疗没有反应。因此，克服耐药性的一种潜在策略是增强 T 细胞进入肿瘤的能力。在这里，我们描述了一种利用诱变系统的无偏基因筛选方法，以确定可能被修饰以驱动肿瘤内 T 细胞积累的 T 细胞候选基因。该筛选在三种肿瘤模型中鉴定了超过 400 个候选基因。这些结果表明，候选基因的选择存在很大差异，这取决于肿瘤模型以及是否用抗 PD-1 治疗，但在所有肿瘤模型和抗 PD-1 治疗中都鉴定出了一些候选基因。最常突变基因的抑制，影响趋化因子受体表达并增强 T 细胞迁移和筛选候选物应进一步作为治疗靶点进行验证，特别是与增强过继转移的 T 细胞渗透到实体肿瘤中有关。
