The HIF-1α Hypoxia Response in Tumor-Infiltrating T Lymphocytes Induces Functional CD137 (4-1BB) for Immunotherapy
The HIF-1α Hypoxia Response in Tumor-Infiltrating T Lymphocytes Induces Functional CD137 (4-1BB) for Immunotherapy
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DOI：
10.1158/2159-8290.cd-11-0314
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发表时间：
2012-07-01
期刊：
影响因子：
28.2
通讯作者：
Melero, Ignacio
中科院分区：
文献类型：
--
作者：
Palazon, Asis;Martinez-Forero, Ivan;Melero, Ignacio
正电子发射断层扫描(PET)证实，移植和自发性小鼠肿瘤的微环境严重缺乏氧气。移植性结肠癌、黑色素瘤和自发性乳腺癌的CD8和CD4肿瘤浸润性T淋巴细胞(TIL)CD137(4-1BB)阳性，而肿瘤引流淋巴结和脾CD137(4-1BB)阳性。活化的T淋巴细胞上CD137的表达在低氧和脯氨酸羟基酶抑制剂DMOG(DMOG)的作用下显著增强。重要的是，低氧不会上调低氧诱导因子(HIF)-1α基因敲除T细胞中CD137的表达，而且这种HIF-1α缺陷的T细胞即使成为TIL也仍然是CD137阴性的，这与共浸润和共转移的HIF-1α充足的T细胞形成了鲜明的对比。CD137在TIL上选择性表达的事实被用来限制激动型抗CD137单抗对肿瘤组织的免疫治疗效果。因此，低剂量的肿瘤内注射可以避免肝脏炎症，达到抗肿瘤的全身效应，并与PD-L1/B7-H1阻断具有协同治疗作用。HIF-1α系统检测到的肿瘤微环境中的缺氧增加了肿瘤浸润性淋巴细胞上CD137的表达，从而对正在进行的临床试验中使用的抗CD137激动剂单抗的免疫治疗效果产生选择性反应。癌症发现；2(7)；608-23。(C)2012年AACR。
The tumor microenvironment of transplanted and spontaneous mouse tumors is profoundly deprived of oxygenation as confirmed by positron emission tomographic (PET) imaging. CD8 and CD4 tumor-infiltrating T lymphocytes (TIL) of transplanted colon carcinomas, melanomas, and spontaneous breast adenocarcinomas are CD137 (4-1BB)-positive, as opposed to their counterparts in tumor-draining lymph nodes and spleen. Expression of CD137 on activated T lymphocytes is markedly enhanced by hypoxia and the prolyl-hydroxylase inhibitor dimethyloxalylglycine (DMOG). Importantly, hypoxia does not upregulate CD137 in hypoxia-inducible factor (HIF)-1 alpha-knockout T cells, and such HIF-1 alpha-deficient T cells remain CD137-negative even when becoming TILs, in clear contrast to co-infiltrating and co-transferred HIF-1 alpha-sufficient T lymphocytes. The fact that CD137 is selectively expressed on TILs was exploited to confine the effects of immunotherapy with agonist anti-CD137 monoclonal antibodies to the tumor tissue. As a result, low-dose intratumoral injections avoid liver inflammation, achieve antitumor systemic effects, and permit synergistic therapeutic effects with PD-L1/B7-H1 blockade.SIGNIFICANCE: CD137 (4-1BB) is an important molecular target to augment antitumor immunity. Hypoxia in the tumor microenvironment as sensed by the HIF-1 alpha system increases expression of CD137 on tumor-infiltrating lymphocytes that thereby become selectively responsive to the immunotherapeutic effects of anti-CD137 agonist monoclonal antibodies as those used in ongoing clinical trials. Cancer Discov; 2(7); 608-23. (C) 2012 AACR.