RNAseq of Rpl18*-specific T cells from MC38 tumor and draining lymph node

The protein PI3K-interacting protein (PIK3IP1), or transmembrane inhibitor of PI3K (TrIP), is highly expressed by T cells and can modulate PI3K activity in these cells. Several studies have also revealed that TrIP is rapidly downregulated following T cell activation and can play important roles in T cell differentiation. We have generated mice with CD8-specific TrIP deficiency. Here we provide data detailing that activated TrIP KO CD8 T cells display an increased inflammatory transcriptional profile in the absence of TrIP. Consistent with these effects, we also show that knockout of TrIP specifically in CD8 T cells resulted in reduced growth of syngeneic tumors. When characterizing the tumor-infiltrating cells, we found that TrIP KO led to an increase in the number of tumor-infiltrating T cells, as well as a delay in the acquisition of an exhausted phenotype, based on phenotypic and transcriptomic analyses. Finally, our data suggest that TrIP regulates the diversity of T cell clonal responses to tumors, since we observed an increase in the number of distinct T cell clonotypes responding to a tumor neoantigen. Taken together, we show that TrIP intrinsically restricts the CD8 T cell response to tumors, and that targeting TrIP may augment the anti-tumor response in a way that is distinct from established checkpoint therapies. Tumor and tumor draining lymph nodes (TDLN) from WT and CD8-specific TrIP knockout mice were harvested 10 days after MC38 tumor injection. CD8+ Rpl18 Tetramer+ cells were sorted from both tissues and prepared for sequencing.

蛋白质PI3K相互作用蛋白（PI3K-interacting protein, PIK3IP1），又称PI3K跨膜抑制剂（transmembrane inhibitor of PI3K, TrIP），在T细胞中呈高表达状态，可调控此类细胞内的PI3K活性。多项研究亦证实，TrIP在T细胞活化后会快速下调，并在T细胞分化过程中发挥重要作用。我们构建了CD8特异性TrIP缺陷小鼠。本数据集提供的数据表明，在缺失TrIP的情况下，活化的TrIP敲除（knockout, KO）CD8 T细胞呈现出增强的炎症转录谱特征。与上述效应一致，我们还证实，CD8 T细胞特异性敲除TrIP可使同基因肿瘤的生长减缓。在对肿瘤浸润细胞进行表征时，我们通过表型与转录组分析发现，TrIP敲除不仅可增加肿瘤浸润T细胞的数量，还能延缓耗竭表型的获得。最后，我们的数据提示TrIP可调控T细胞针对肿瘤的克隆应答多样性——我们观察到，针对肿瘤新抗原的不同T细胞克隆型数量有所增加。综上，我们证实TrIP可内在性限制CD8 T细胞对肿瘤的应答，而靶向TrIP或许可通过一种区别于现有免疫检查点疗法（checkpoint therapies）的方式增强抗肿瘤应答。野生型（wild type, WT）与CD8特异性TrIP敲除小鼠的肿瘤及肿瘤引流淋巴结（tumor draining lymph nodes, TDLN）在MC38肿瘤接种后10天被采集。从两种组织中分选CD8+ Rpl18四聚体（tetramer）阳性细胞，并制备样本用于测序。