美国奥古斯塔大学David H. Munn团队的研究显示，抑制BTK-IDO-mTOR通路可促进单核细胞来源树突状细胞(DC)的分化以及提高抗肿瘤T细胞的免疫能力。该项研究成果发表在2021年10月5日出版的《免疫》上。

研究人员探究了抑制炎性骨髓细胞分化靶向通路如何影响抗肿瘤免疫。使用药物抑制Bruton酪氨酸激酶(BTK)和色氨酸降解酶吲哚胺2,3-双加氧酶(IDO)或Btk或Ido1的缺失在化疗期间显著有利于炎性Ly6c⁺CD103⁺ DC的分化、促进抗肿瘤T细胞反应并抑制肿瘤生长。未成熟的Ly6c⁺c-kit⁺前体细胞具有与传统DC前体相似的表观遗传特征；Btk或Ido1的缺失促进了这些细胞的分化。

从机制上讲，BTK-IDO通路抑制了由GATOR2和mTORC1诱导的色氨酸敏感分化途径，并且单核细胞谱系前体中GATOR2的缺失阻止了其在体内分化为炎性DC。表达IDO的DC和单核细胞存在于一系列人类肿瘤中。因此，在化疗期间BTK-IDO轴通过抑制炎性DCs的分化从而影响靶向治疗的效果。 

据悉，单核细胞系炎性Ly6c⁺CD103⁺树突状细胞促进抗肿瘤免疫，但这些DC在肿瘤中很少见，即使在化疗时也是如此。

附：英文原文

Title: Inhibition of the BTK-IDO-mTOR axis promotes differentiation of monocyte-lineage dendritic cells and enhances anti-tumor T cell immunity

Author: Madhav D. Sharma, Rafal Pacholczyk, Huidong Shi, Zuzana J. Berrong, Yousef Zakharia, Austin Greco, Chang-Sheng S. Chang, Sudharshan Eathiraj, Eugene Kennedy, Thomas Cash, Roni J. Bollag, Ravindra Kolhe, Ramses Sadek, Tracy L. McGaha, Paulo Rodriguez, Jessica Mandula, Bruce R. Blazar, Theodore S. Johnson, David H. Munn

Issue&Volume: 2021-10-05

Abstract: Monocytic-lineage inflammatory Ly6c+CD103+ dendritic cells (DCs) promote antitumor immunity, but these DCs are infrequent intumors, even upon chemotherapy. Here, we examined how targeting pathways that inhibitthe differentiation of inflammatory myeloid cells affect antitumor immunity. Pharmacologicinhibition of Bruton’s tyrosine kinase (BTK) and the tryptophan-degrading enzyme indoleamine2,3-dioxygenase (IDO) or deletion of Btk or Ido1 allowed robust differentiation of inflammatory Ly6c+CD103+ DCs during chemotherapy, promoting antitumor T cell responses and inhibiting tumorgrowth. Immature Ly6c+c-kit+ precursor cells had epigenetic profiles similar to conventional DC precursors; deletionof Btk or Ido1 promoted differentiation of these cells. Mechanistically, a BTK-IDO axis inhibiteda tryptophan-sensitive differentiation pathway driven by GATOR2 and mTORC1, and disruptionof the GATOR2 in monocyte-lineage precursors prevented differentiation into inflammatoryDCs in vivo. IDO-expressing DCs and monocytic cells were present across a range of human tumors.Thus, a BTK-IDO axis represses differentiation of inflammatory DCs during chemotherapy,with implications for targeted therapies.

DOI: 10.1016/j.immuni.2021.09.005

Source: https://www.cell.com/immunity/fulltext/S1074-7613(21)00390-3