PI3Kδ inhibitors are approved for the therapy of B cell malignancies, but their clinical use has been limited by unpredictable autoimmune toxicity, despite promising efficacy and evidence that toxicity is associated with improved clinical outcomes. Prior phenotypic evaluation by CyTOF has identified increases in activated CD8 T cells with activation of Th17 T cells, as well as decreases in Tregs, particularly in patients with toxicity. Here we sought to further understand the effects of idelalisib and duvelisib in vitro, and demonstrate that both idelalisib and duvelisib can inhibit T cell proliferation as well as Th1 and Treg differentiation in vitro, while promoting Th2 and Th17 differentiation. We further demonstrate directly using intracellular flow cytometry that autoimmune toxicity in patients is associated with higher absolute numbers of CD4 and CD8 T cells with Th17 differentiation in peripheral blood prior to therapy, and that gastrointestinal tissues from patients with active autoimmune complications of PI3Kδ inhibitors show infiltration with Th17+ T cells. These same tissues show depletion of Tregs as compared to CLL patients without toxicity, suggesting that loss of Tregs may be permissive for Th17 activation to lead to autoimmune toxicity. Clinical trials to restore this balance are warranted.
PI3Kδ抑制剂已获批用于治疗B细胞恶性肿瘤，尽管其疗效显著且有证据表明毒性反应与临床结局改善相关，但其临床应用仍受难以预测的自身免疫毒性所限制。此前通过质谱流式细胞技术进行的表型评估发现，毒性反应患者体内活化的CD8 T细胞与Th17 T细胞的激活水平升高，同时Treg细胞数量减少。本研究旨在进一步探讨艾代拉里斯和杜韦利西布在体外的作用，证实两者均能抑制T细胞增殖以及Th1和Treg细胞的分化，同时促进Th2和Th17细胞的分化。我们进一步通过细胞内流式细胞术直接证实，患者的自身免疫毒性反应与治疗前外周血中Th17分化的CD4和CD8 T细胞绝对数量较高相关，且在发生PI3Kδ抑制剂自身免疫并发症的患者胃肠道组织中观察到Th17+ T细胞的浸润。与未出现毒性的慢性淋巴细胞白血病患者相比，这些组织中Treg细胞明显减少，提示Treg细胞的缺失可能为Th17细胞的活化创造条件，从而导致自身免疫毒性。有必要开展临床试验以恢复这种免疫平衡。
Circulating Th17 T cells at treatment onset predict autoimmune toxicity of PI3Kδ inhibitors
肿瘤(癌症)患者之家