IDO1 inhibition potentiates vaccine-induced immunity against pancreatic adenocarcinoma
IDO1 inhibition potentiates vaccine-induced immunity against pancreatic adenocarcinoma
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DOI：
10.1172/jci124077
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发表时间：
2019-04-01
影响因子：
15.9
通讯作者：
Zheng, Lei
中科院分区：
文献类型：
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作者：
Blair, Alex B.;Kleponis, Jennifer;Zheng, Lei
胰腺导管腺癌（PDAC）是一种免疫静止的肿瘤，对免疫检查点抑制剂具有抗性。此前，我们的研究小组已经表明，分泌粒细胞 - 巨噬细胞集落刺激因子（GM - CSF）的同种异体胰腺肿瘤细胞疫苗（GVAX）可能通过诱导肿瘤内T细胞浸润来激活肿瘤微环境。在此，我们发现未经治疗的PDACs表达极少量的吲哚胺 - 2,3 - 双加氧酶（IDO1）；然而，GVAX治疗可诱导肿瘤上皮以及疫苗诱导的三级淋巴聚集体表达IDO1。IDO1的表达在调节PDAC肿瘤中Th1、Th17以及可能的调节性T细胞的极化方面发挥作用。在PDAC小鼠模型中，IDO1抑制剂增强了GVAX的抗肿瘤功效。疫苗和IDO1抑制剂的组合增强了肿瘤内T细胞的浸润和功能，但在该组合中添加抗PD - L1抗体并没有产生进一步的协同作用，实际上可能产生了负面相互作用，减少了肿瘤内效应T细胞的数量。此外，在疫苗治疗存在的情况下，IDO1抑制剂在数量上没有显著调节肿瘤内髓源性抑制细胞，但减弱了它们对CD8(+)增殖的抑制作用。我们的研究支持IDO1抑制剂和疫苗治疗的组合；然而，对于像接受疫苗治疗的PDACs这类T细胞炎症性肿瘤，不支持IDO1抑制剂和抗PD - 1/PD - L1抗体的组合。
Pancreatic ductal adenocarcinoma (PDAC) represents an immune quiescent tumor that is resistant to immune checkpoint inhibitors. Previously, our group has shown that a GM-CSF-secreting allogenic pancreatic tumor cell vaccine (GVAX) may prime the tumor microenvironment by inducing intratumoral T cell infiltration. Here, we show that untreated PDACs express minimal indoleamine-2,3-dioxygenase (IDO1); however, GVAX therapy induced IDO1 expression on tumor epithelia as well as vaccine-induced tertiary lymphoid aggregates. IDO1 expression plays a role in regulating the polarization of Th1, Th17, and possibly T regulatory cells in PDAC tumors. IDO1 inhibitor enhanced antitumor efficacy of GVAX in a murine model of PDACs. The combination of vaccine and IDO1 inhibitor enhanced intratumoral T cell infiltration and function, but adding anti-PD-L1 antibody to the combination did not offer further synergy and in fact may have had a negative interaction, decreasing the number of intratumoral effector T cells. Additionally, IDO1 inhibitor in the presence of vaccine therapy did not significantly modulate intratumoral myeloid-derived suppressor cells quantitatively, but diminished their suppressive effect on CD8(+) proliferation. Our study supports the combination of IDO1 inhibitor and vaccine therapy; however, it does not support the combination of IDO1 inhibitor and anti-PD-1/PD-L1 antibody for T cell-inflamed tumors such as PDACs treated with vaccine therapy.