Inhibition of Mac-1 (CD11b/CD18) enhances tumor response to radiation by reducing myeloid cell recruitment
Inhibition of Mac-1 (CD11b/CD18) enhances tumor response to radiation by reducing myeloid cell recruitment
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DOI：
10.1073/pnas.0911378107
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发表时间：
2010-05-04
影响因子：
11.1
通讯作者：
Brown, J. Martin
中科院分区：
文献类型：
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作者：
Ahn, G-One;Tseng, Diane;Brown, J. Martin
尽管放射治疗最近取得了进展，但局部区域失败仍然是许多癌症患者死亡的主要原因。我们以前曾报道，骨髓来源的CD 11b（+）髓样细胞被招募到在辐射组织中生长的肿瘤中，从而恢复血管系统和肿瘤生长。在这项研究中，我们研究了中和性CD 11b单克隆抗体是否可以抑制骨髓细胞向辐射肿瘤的募集并抑制其再生长。我们观察到一个显着增强的抗肿瘤反应的放射性在小鼠鳞状细胞癌异种移植物时，CD 11b抗体全身给药。肿瘤的组织学检查显示，CD 11b抗体减少了表达S100 A8和基质金属蛋白酶-9的髓样细胞的浸润。CD 11b抗体进一步抑制骨髓来源的细胞粘附和迁移到C166内皮细胞单层和趋化刺激，分别与CD 11b敲除或CD 18低型小鼠的水平相当。鉴于人源化CD 18抗体的临床可用性，我们在CD 18亚型或CD 11b敲除小鼠中测试了两种鼠肿瘤模型，发现肿瘤在CD 18亚型小鼠中生长时对辐射更敏感，而在CD 11b敲除小鼠中则不然。当用野生型骨髓重建部分挽救CD 18亚型时，肿瘤对辐射的抵抗力恢复。因此，我们的研究支持使用临床可用的Mac-1（CD 11b/CD 18）抗体作为放疗辅助治疗的基本原理。
Despite recent advances in radiotherapy, loco-regional failures are still the leading cause of death in many cancer patients. We have previously reported that bone marrow-derived CD11b(+) myeloid cells are recruited to tumors grown in irradiated tissues, thereby restoring the vasculature and tumor growth. In this study, we examined whether neutralizing CD11b monoclonal antibodies could inhibit the recruitment of myeloid cells into irradiated tumors and inhibit their regrowth. We observed a significant enhancement of antitumor response to radiation in squamous cell carcinoma xenografts in mice when CD11b antibodies are administered systemically. Histological examination of tumors revealed that CD11b antibodies reduced infiltration of myeloid cells expressing S100A8 and matrix metalloproteinase-9. CD11b antibodies further inhibited bone marrow-derived cell adhesion and transmigration to C166 endothelial cell monolayers and chemotactic stimuli, respectively, to levels comparable to those from CD11b knockout or CD18 hypomorphic mice. Given the clinical availability of humanized CD18 antibodies, we tested two murine tumor models in CD18 hypomorphic or CD11b knockout mice and found that tumors were more sensitive to irradiation when grown in CD18 hypomorphic mice but not in CD11b knockout mice. When CD18 hypomorphism was partially rescued by reconstitution with the wild-type bone marrow, the resistance of the tumors to irradiation was restored. Our study thus supports the rationale of using clinically available Mac-1 (CD11b/CD18) antibodies as an adjuvant therapy to radiotherapy.