Differential PI3Kδ Signaling in CD4+ T-cell Subsets Enables Selective Targeting of T Regulatory Cells to Enhance Cancer Immunotherapy

To modulate T-cell function for cancer therapy, one challenge is to selectively attenuate regulatory but not conventional CD4(+) T-cell subsets [regulatory T cell (Treg) and conventional T cell (Tconv)]. In this study, we show how a functional dichotomy in Class IA PI3K isoforms in these two subsets of CD4(+) T cells can be exploited to target Treg while leaving Tconv intact. Studies employing isoform-specific PI3K inhibitors and a PI3K delta-deficient mouse strain revealed that PI3K alpha and PI3K beta were functionally redundant with PI3K delta in Tconv. Conversely, PI3K delta was functionally critical in Treg, acting there to control T-cell receptor signaling, cell proliferation, and survival. Notably, in a murine model of lung cancer, coadministration of a PI3K delta-specific inhibitor with a tumor-specific vaccine decreased numbers of suppressive Treg and increased numbers of vaccine-induced CD8 T cells within the tumor microenvironment, eliciting potent antitumor efficacy. Overall, our results offer a mechanistic rationale to employ PI3K delta inhibitors to selectively target Treg and improve cancer immunotherapy. (C) 2017 AACR.

为了调节T细胞功能用于癌症治疗，一个挑战是选择性地减弱调节性CD4(+) T细胞亚群而非常规的CD4(+) T细胞亚群[调节性T细胞（Treg）和常规T细胞（Tconv）]。在这项研究中，我们展示了如何利用这两种CD4(+) T细胞亚群中IA类PI3K异构体的功能二分性来靶向Treg同时保持Tconv完好无损。采用异构体特异性PI3K抑制剂和PI3Kδ缺陷型小鼠品系的研究表明，在Tconv中，PI3Kα和PI3Kβ与PI3Kδ在功能上是冗余的。相反，PI3Kδ在Treg中在功能上至关重要，在其中发挥作用以控制T细胞受体信号传导、细胞增殖和存活。值得注意的是，在一个肺癌小鼠模型中，将一种PI3Kδ特异性抑制剂与一种肿瘤特异性疫苗共同给药，减少了肿瘤微环境中抑制性Treg的数量，并增加了疫苗诱导的CD8 T细胞的数量，引发了强大的抗肿瘤功效。总体而言，我们的结果为使用PI3Kδ抑制剂选择性靶向Treg并改善癌症免疫治疗提供了一种机制上的理论依据。（C）2017美国癌症研究协会