Rank aggregation of independent genetic screen results highlights new strategies for adoptive cellular transfer therapy of cancer.
Rank aggregation of independent genetic screen results highlights new strategies for adoptive cellular transfer therapy of cancer.
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DOI：
10.3389/fimmu.2023.1235131
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发表时间：
2023
影响因子：
7.3
通讯作者：
中科院分区：
文献类型：
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过继转移细胞在肿瘤内的有效渗透是过继细胞转移(ACT)疗法有效治疗实体瘤的重要障碍。我们最近的正向遗传学全基因组筛查确定了可能改善肿瘤对T细胞的渗透的T细胞内在基因候选。在这里，结果与五个独立的遗传筛选相结合，使用等级聚合来提高精确度。这导致了总共1,523个候选基因-包括1,464个目前未被评估为治疗靶点的基因-可能会改善肿瘤对T细胞的渗透。对已发表的人类数据集的基因集浓缩分析表明，这些候选基因在肿瘤浸润性疾病中的表达与循环中的T细胞相比存在差异，支持翻译潜力。重要的是，过继将过表达功能增强候选T细胞(AAK1EHADHN125、Δ1B和EHHADH)转移到荷瘤小鼠体内会增加T细胞对肿瘤的侵袭。这些新的候选基因可能被认为是潜在的治疗候选基因，可以辅助过继细胞治疗改善T细胞对实体瘤的渗透。
Efficient intratumoral infiltration of adoptively transferred cells is a significant barrier to effectively treating solid tumors with adoptive cellular transfer (ACT) therapies. Our recent forward genetic, whole-genome screen identified T cell-intrinsic gene candidates that may improve tumor infiltration of T cells. Here, results are combined with five independent genetic screens using rank aggregation to improve rigor. This resulted in a combined total of 1,523 candidate genes – including 1,464 genes not currently being evaluated as therapeutic targets - that may improve tumor infiltration of T cells. Gene set enrichment analysis of a published human dataset shows that these gene candidates are differentially expressed in tumor infiltrating compared to circulating T cells, supporting translational potential. Importantly, adoptive transfer of T cells overexpressing gain-of-function candidates (AAK1ΔN125 , SPRR1B, and EHHADH) into tumor-bearing mice resulted in increased T cell infiltration into tumors. These novel gene candidates may be considered as potential therapeutic candidates that can aid adoptive cellular therapy in improving T cell infiltration into solid tumors.
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