Sharma Madhav D, Shinde Rahul, McGaha Tracy L, Huang Lei, Holmgaard Rikke B, Wolchok Jedd D, Mautino Mario R, Celis Esteban, Sharpe Arlene H, Francisco Loise M, Powell Jonathan D, Yagita Hideo, Mellor Andrew L, Blazar Bruce R, Munn David H
Cancer Center, Georgia Regents University, Augusta, GA 30912, USA. ; Department of Pediatrics, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912, USA.
Cancer Center, Georgia Regents University, Augusta, GA 30912, USA.
Sci Adv. 2015 Nov 6;1(10):e1500845. doi: 10.1126/sciadv.1500845. eCollection 2015 Nov.
The tumor microenvironment is profoundly immunosuppressive. We show that multiple tumor types create intratumoral immune suppression driven by a specialized form of regulatory T cell (Treg) activation dependent on the PTEN (phosphatase and tensin homolog) lipid phosphatase. PTEN acted to stabilize Tregs in tumors, preventing them from reprogramming into inflammatory effector cells. In mice with a Treg-specific deletion of PTEN, tumors grew slowly, were inflamed, and could not create an immunosuppressive tumor microenvironment. In normal mice, exposure to apoptotic tumor cells rapidly elicited PTEN-expressing Tregs, and PTEN-deficient mice were unable to maintain tolerance to apoptotic cells. In wild-type mice with large established tumors, pharmacologic inhibition of PTEN after chemotherapy or immunotherapy profoundly reconfigured the tumor microenvironment, changing it from a suppressive to an inflammatory milieu, and tumors underwent rapid regression. Thus, the immunosuppressive milieu in tumors must be actively maintained, and tumors become susceptible to immune attack if the PTEN pathway in Tregs is disrupted.
肿瘤微环境具有很强的免疫抑制作用。我们发现多种肿瘤类型会产生肿瘤内免疫抑制，这种抑制由一种特殊形式的调节性T细胞（Treg）激活所驱动，而该激活依赖于PTEN（磷酸酶和张力蛋白同源物）脂质磷酸酶。PTEN在肿瘤中起到稳定Treg的作用，阻止它们重编程为炎性效应细胞。在PTEN特异性缺失的Treg小鼠中，肿瘤生长缓慢、出现炎症，且无法形成免疫抑制性肿瘤微环境。在正常小鼠中，暴露于凋亡肿瘤细胞会迅速诱导表达PTEN的Treg，而PTEN缺陷小鼠无法维持对凋亡细胞的耐受性。在患有大型已形成肿瘤的野生型小鼠中，化疗或免疫治疗后对PTEN进行药理抑制可显著重塑肿瘤微环境，将其从抑制性环境转变为炎性环境，肿瘤迅速消退。因此，肿瘤中的免疫抑制环境必须被积极维持，如果Treg中的PTEN通路被破坏，肿瘤就会变得易受免疫攻击。
