Radiation Therapy Induces Macrophages to Suppress T-Cell Responses Against Pancreatic Tumors in Mice.
Radiation Therapy Induces Macrophages to Suppress T-Cell Responses Against Pancreatic Tumors in Mice.
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DOI：
10.1053/j.gastro.2016.02.070
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发表时间：
2016-06
期刊：
影响因子：
29.4
通讯作者：
Miller G
中科院分区：
文献类型：
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作者：
Seifert L;Werba G;Tiwari S;Giao Ly NN;Nguy S;Alothman S;Alqunaibit D;Avanzi A;Daley D;Barilla R;Tippens D;Torres-Hernandez A;Hundeyin M;Mani VR;Hajdu C;Pellicciotta I;Oh P;Du K;Miller G
放射治疗在胰腺导管腺癌（PDA）治疗中的作用存在争议。随机对照试验研究了放射治疗在局部晚期不可切除PDA患者中的疗效，报告了混合结果，与对照治疗相比，效果从适度获益到更差结局不等。我们研究了放射是否会导致炎症细胞获得免疫抑制表型，从而限制放射对侵袭性PDA的治疗效果并加速侵袭前病灶的进展。我们研究了辐射对p48 Cre; LSL-KrasG 12 D（KC）和p48 Cre; LSLKrasG 12 D; LSL-Trp 53 R172 H（KPC）小鼠以及C57 BL/6小鼠的影响，这些小鼠的原位肿瘤生长自KPC小鼠的FC 1242细胞。一些小鼠被给予抗巨噬细胞集落刺激因子1（CSF 1或MCSF）或F4/80的中和抗体。将胰腺暴露于2-12戈伊的辐射剂量，并通过流式细胞术进行分析。KC小鼠胰腺暴露于辐射有更高的频率，先进的胰腺上皮内病变和更多的病灶浸润性癌比胰腺的未暴露的小鼠（对照组）;辐射减少生存时间超过6个月。与对照小鼠相比，侵袭性和侵袭前胰腺肿瘤中更大比例的巨噬细胞具有免疫抑制性M2样表型。来自暴露于辐射的小鼠的胰腺具有比对照更少的CD 8 + T细胞和更多数量的辅助性T细胞2和调节性T细胞表型的CD 4 + T细胞。将T细胞从辐照的PDA连续转移到对照小鼠的肿瘤中加速了肿瘤生长。辐射诱导PDA细胞产生MCSF。抗MCSF的抗体防止辐射改变肿瘤中巨噬细胞的表型，增加抗肿瘤T细胞反应并减缓肿瘤生长。辐射暴露导致小鼠PDA中的巨噬细胞获得免疫抑制表型并降低T细胞介导的抗肿瘤应答。阻断MCSF的药物可以防止这种效应，使放射在减缓肿瘤生长方面具有更高的功效。
The role of radiation therapy in the treatment of patients with pancreatic ductal adenocarcinoma (PDA) is controversial. Randomized controlled trials investigating the efficacy of radiation therapy in patients with locally advanced unresectable PDA have reported mixed results, with effects ranging from modest benefit to worse outcome, compared with control therapies. We investigated whether radiation causes inflammatory cells to acquire an immune-suppressive phenotype that limits the therapeutic effects of radiation on invasive PDAs and accelerates progression of pre-invasive foci. We investigated the effects of radiation in p48Cre;LSL-KrasG12D (KC) and p48Cre;LSLKrasG12D;LSL-Trp53R172H (KPC) mice, as well as in C57BL/6 mice with orthotopic tumors grown from FC1242 cells derived from KPC mice. Some mice were given neutralizing antibodies against macrophage colony stimulating factor 1 (CSF1 or MCSF) or F4/80. Pancreata were exposed to doses of radiation ranging from 2–12 Gy and analyzed by flow cytometry. Pancreata of KC mice exposed to radiation had a higher frequency of advanced pancreatic intraepithelial lesions and more foci of invasive cancer than pancreata of unexposed mice (controls); radiation reduced survival time by more than 6 months. A greater proportion of macrophages from invasive and pre-invasive pancreatic tumors had an immune-suppressive, M2-like phenotype, compared with control mice. Pancreata from mice exposed to radiation had fewer CD8+ T cells than controls and greater numbers of CD4+ T cells of T-helper 2 and T-regulatory cell phenotypes. Adoptive transfer of T cells from irradiated PDA to tumors of control mice accelerated tumor growth. Radiation induced production of MCSF by PDA cells. An antibody against MCSF prevented radiation from altering the phenotype of macrophages in tumors, increasing the anti-tumor T-cell response and slowing tumor growth. Radiation exposure causes macrophages in PDAs of mice to acquire an immune-suppressive phenotype and reduce T-cell mediated anti-tumor responses. Agents that block MCSF prevent this effect, allowing radiation to have increased efficacy in slowing tumor growth.