Tumor-Derived CCL2 Mediates Resistance to Radiotherapy in Pancreatic Ductal Adenocarcinoma.
Tumor-Derived CCL2 Mediates Resistance to Radiotherapy in Pancreatic Ductal Adenocarcinoma.
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DOI：
10.1158/1078-0432.ccr-16-0870
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发表时间：
2017-01-01
期刊：
影响因子：
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通讯作者：
Beatty GL
中科院分区：
文献类型：
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作者：
Kalbasi A;Komar C;Tooker GM;Liu M;Lee JW;Gladney WL;Ben-Josef E;Beatty GL
局部肿瘤生长是近30%胰腺导管腺癌（PDAC）患者发病和死亡的主要原因。放射治疗（RT）常用于PDAC的局部疾病控制，但疗效有限。我们研究了选择性干预RT诱导炎症的影响，作为一种克服PDAC对RT抵抗的方法。KrasLSL-G12D/+、Trp53LSL-R172H/+、Trp53LSL-R172H/+来源于原发性胰腺肿瘤的PDAC细胞系；将Pdx-1 Cre （KPC）小鼠植入同种小鼠体内，利用小动物辐射研究平台（SARRP）对肿瘤进行局部照射。我们确定了消耗T细胞和Ly6C+单核细胞以及抑制趋化因子CCL2对RT疗效的影响。采用流式细胞术和免疫组织化学检测肿瘤白细胞浸润、肿瘤活力和血管的变化。对肿瘤组织进行细胞因子和基因表达检测。单独消融RT对PDAC生长的影响很小，但导致肿瘤细胞CCL2的产生和Ly6C+CCR2+单核细胞的募集显著增加。一种中和性抗ccl2抗体选择性地抑制RT依赖性单核/巨噬细胞募集和延迟肿瘤生长，但仅与RT联合使用（p<0.001）。这种抗肿瘤作用与肿瘤增殖和血管的减少有关。PDAC细胞中CCL2基因缺失也能提高RT疗效。PDAC通过产生CCL2响应RT， CCL2招募Ly6C+CCR2+单核细胞支持RT后肿瘤增殖和新生血管。破坏CCL2-CCR2轴联合RT有望提高RT在PDAC中的疗效。
Local tumor growth is a major cause of morbidity and mortality in nearly 30% of patients with pancreatic ductal adenocarcinoma (PDAC). Radiotherapy (RT) is commonly used for local disease control in PDAC, but efficacy is limited. We studied the impact of selectively intervening on RT-induced inflammation as an approach to overcome resistance to RT in PDAC. PDAC cell lines derived from primary pancreatic tumors arising spontaneously in KrasLSL-G12D/+;Trp53LSL-R172H/+;Pdx-1 Cre (KPC) mice were implanted into syngeneic mice and tumors were focally irradiated using the Small Animal Radiation Research Platform (SARRP). We determined the impact of depleting T cells and Ly6C+ monocytes as well as inhibiting the chemokine CCL2 on RT efficacy. Tumors were analyzed by flow cytometry and immunohistochemistry to detect changes in leukocyte infiltration, tumor viability and vascularity. Assays were performed on tumor tissues to detect cytokines and gene expression. Ablative RT alone had minimal impact on PDAC growth but led to a significant increase in CCL2 production by tumor cells and recruitment of Ly6C+CCR2+ monocytes. A neutralizing anti-CCL2 antibody selectively inhibited RT-dependent recruitment of monocytes/macrophages and delayed tumor growth but only in combination with RT (p<0.001). This anti-tumor effect was associated with decreased tumor proliferation and vascularity. Genetic deletion of CCL2 in PDAC cells also improved RT efficacy. PDAC responds to RT by producing CCL2, which recruits Ly6C+CCR2+ monocytes to support tumor proliferation and neovascularization after RT. Disrupting the CCL2-CCR2 axis in combination with RT holds promise for improving RT efficacy in PDAC.