Tissues in Different Anatomical Sites Can Sculpt and Vary the Tumor Microenvironment to Affect Responses to Therapy
Tissues in Different Anatomical Sites Can Sculpt and Vary the Tumor Microenvironment to Affect Responses to Therapy
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DOI：
10.1038/mt.2013.219
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发表时间：
2014-01-01
影响因子：
12.4
通讯作者：
Kershaw, Michael H.
中科院分区：
文献类型：
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作者：
Devaud, Christel;Westwood, Jennifer A.;Kershaw, Michael H.
肿瘤微环境可促进肿瘤生长，降低治疗效果。肿瘤可以发生在体内的许多部位，但不同解剖部位的周围正常组织如何影响肿瘤微环境以及它们随后对治疗的反应尚不清楚。我们证明，来自原位肾、结肠或前列腺细胞系的肿瘤对由三种名为Tri-mAb的激动剂抗体组成的免疫治疗的反应比位于皮下的同一肿瘤类型的反应要小得多。通过体外分离皮下或原位肿瘤细胞与基质细胞，然后将肿瘤细胞重新注入对侧部位，证实了对Tri-mAb的组织特异性反应。与SC肿瘤相比，原位肿瘤具有与2型免疫反应相关的微环境，与免疫抑制相关，并参与肾脏模型中交替激活的巨噬细胞。原位肾肿瘤比SC肿瘤血运更为丰富。中和巨噬细胞和Th2相关分子趋化因子(C-C基序)配体2或白细胞介素13可显著提高治疗效果。这项研究强调了植入组织在塑造肿瘤微环境中的重要性。这些都是肿瘤生物学中的重要基本问题，也是设计实验模型和治疗策略时需要考虑的关键因素。
The tumor microenvironment can promote tumor growth and reduce treatment efficacy. Tumors can occur in many sites in the body, but how surrounding normal tissues at different anatomical sites affect tumor microenvironments and their subsequent response to therapy is not known.We demonstrated that tumors from renal, colon, or prostate cell lines in orthotopic locations responded to immunotherapy consisting of three agonist antibodies, termed Tri-mAb, to a much lesser extent than the same tumor type located subcutaneously. A tissue-specific response to Tri-mAb was confirmed by ex vivo separation of subcutaneous (SC) or orthotopic tumor cells from stromal cells, followed by reinjection of tumor cells into the opposite site. Compared with SC tumors, orthotopic tumors had a microenvironment associated with a type 2 immune response, related to immunosuppression, and an involvement of alternatively activated macrophages in the kidney model. Orthotopic kidney tumors were more highly vascularized than SC tumors. Neutralizing the macrophage-and Th2-associated molecules chemokine (C-C motif) ligand 2 or interleukin-13 led to a significantly improved therapeutic effect. This study highlights the importance of the tissue of implantation in sculpting the tumor microenvironment. These are important fundamental issues in tumor biology and crucial factors to consider in the design of experimental models and treatment strategies.