The response to hypoxia modulates the expression of multiple genes. The tumor microenvironment of transplanted and spontaneous mouse tumors is profoundly deprived of oxygenation as confirmed by PET imaging. CD8 and CD4 tumor-infiltrating T lymphocytes (TILs) 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-hydroxilase inhibitor DMOG. Importantly, hypoxia does not up-regulate CD137 in inducible HIF-1α knock-out T cells, and such HIF-1α-deficient T cells remain CD137-negative even when becoming TILs, in clear contrast to co-infiltrating HIF-1α-sufficient T cells. The fact that CD137 is selectively expressed on TILs was exploited to confine the effects of immunotherapy with agonist anti-CD137 monoclonal antibodies (mAb) to the tumor tissue, thereby avoiding liver inflammation, while still permitting synergistic therapeutic effects with PD-L1/B7-H1 blockade.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3538. doi:1538-7445.AM2012-3538