Clever David, Roychoudhuri Rahul, Constantinides Michael G, Askenase Michael H, Sukumar Madhusudhanan, Klebanoff Christopher A, Eil Robert L, Hickman Heather D, Yu Zhiya, Pan Jenny H, Palmer Douglas C, Phan Anthony T, Goulding John, Gattinoni Luca, Goldrath Ananda W, Belkaid Yasmine, Restifo Nicholas P
Surgery Branch, National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD 20892, USA; Medical Scientist Training Program, The Ohio State University College of Medicine, Columbus, OH 43210, USA.
Surgery Branch, National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD 20892, USA; Laboratory of Lymphocyte Signaling and Development, Babraham Institute, Cambridge CB22 3AT, UK.
Cell. 2016 Aug 25;166(5):1117-1131.e14. doi: 10.1016/j.cell.2016.07.032.
Cancer cells must evade immune responses at distant sites to establish metastases. The lung is a frequent site for metastasis. We hypothesized that lung-specific immunoregulatory mechanisms create an immunologically permissive environment for tumor colonization. We found that T-cell-intrinsic expression of the oxygen-sensing prolyl-hydroxylase (PHD) proteins is required to maintain local tolerance against innocuous antigens in the lung but powerfully licenses colonization by circulating tumor cells. PHD proteins limit pulmonary type helper (Th)-1 responses, promote CD4(+)-regulatory T (Treg) cell induction, and restrain CD8(+) T cell effector function. Tumor colonization is accompanied by PHD-protein-dependent induction of pulmonary Treg cells and suppression of IFN-γ-dependent tumor clearance. T-cell-intrinsic deletion or pharmacological inhibition of PHD proteins limits tumor colonization of the lung and improves the efficacy of adoptive cell transfer immunotherapy. Collectively, PHD proteins function in T cells to coordinate distinct immunoregulatory programs within the lung that are permissive to cancer metastasis. PAPERCLIP.
癌细胞必须逃避免疫反应才能在远处形成转移灶。肺是常见的转移部位。我们假设肺特异性免疫调节机制为肿瘤定植创造了一个免疫许可环境。我们发现，氧感应脯氨酰羟化酶（PHD）蛋白在T细胞内的表达对于维持肺部对无害抗原的局部耐受性是必需的，但却有力地促进了循环肿瘤细胞的定植。PHD蛋白限制肺部辅助性T（Th）1型反应，促进CD4（+）调节性T（Treg）细胞的诱导，并抑制CD8（+）T细胞效应功能。肿瘤定植伴随着PHD蛋白依赖的肺部Treg细胞诱导以及IFN-γ依赖的肿瘤清除抑制。T细胞内PHD蛋白的缺失或药物抑制可限制肺部肿瘤定植，并提高过继性细胞转移免疫疗法的疗效。总的来说，PHD蛋白在T细胞中发挥作用，协调肺部内有利于癌症转移的不同免疫调节程序。回形针。
