Murter Benjamin M, Kane Lawrence P
Department of Immunology, Graduate Program in Microbiology and Immunology, University of Pittsburgh, Pittsburgh, PA 15213.
bioRxiv. 2025 Jul 15:2025.07.10.664200. doi: 10.1101/2025.07.10.664200.
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 generated mice with CD8-specific TrIP deficiency. We then implanted these mice, and Cre-only control animals, with B16 melanoma or MC38 colon carcinoma tumors. Tumor growth and anti-tumor immunity were then followed. We also assessed the effects of TrIP deficiency on transcriptional programs in CD8 T cells stimulated in vivo or derived from tumor-bearing mice.
We found that activated TrIP KO CD8 T cells display an increased inflammatory transcriptional profile in the absence of TrIP. Consistent with these effects, we also found that knockout of TrIP specifically in CD8 T cells resulted in reduced growth of syngeneic tumors. When characterizing the tumor-infiltrating cells, 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, our findings demonstrate 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.
蛋白质PI3K相互作用蛋白（PIK3IP1），即PI3K的跨膜抑制剂（TrIP），在T细胞中高度表达，并可调节这些细胞中的PI3K活性。多项研究还表明，TrIP在T细胞激活后会迅速下调，并在T细胞分化中发挥重要作用。
我们构建了CD8特异性TrIP缺陷的小鼠。然后将这些小鼠以及仅含Cre的对照动物植入B16黑色素瘤或MC38结肠癌肿瘤。随后监测肿瘤生长和抗肿瘤免疫情况。我们还评估了TrIP缺陷对体内刺激的或源自荷瘤小鼠的CD8 T细胞转录程序的影响。
我们发现，在没有TrIP的情况下，活化的TrIP基因敲除CD8 T细胞表现出炎症转录谱增加。与这些效应一致，我们还发现特异性敲除CD8 T细胞中的TrIP会导致同基因肿瘤生长减缓。在对肿瘤浸润细胞进行表征时，基于表型和转录组分析，TrIP基因敲除导致肿瘤浸润T细胞数量增加，以及耗竭表型的获得延迟。最后，我们的数据表明TrIP调节T细胞对肿瘤的克隆反应多样性，因为我们观察到对肿瘤新抗原作出反应的不同T细胞克隆型数量增加。
综上所述，我们的研究结果表明，TrIP本质上限制了CD8 T细胞对肿瘤的反应，并且靶向TrIP可能以一种不同于既定检查点疗法的方式增强抗肿瘤反应。
