The HIF-1α hypoxia response in tumor-infi ltrating T lymphocytes induces functional CD137 (4-1BB) for immunotherapy

Abstract

The tumor microenvironment of transplanted and spontaneous mouse tumors is profoundly deprived of oxygenation as confi rmed by positron emission tomographic (PET) imaging. CD8 and CD4 tumor-infi ltrating 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)-1α- knockout T cells, and such HIF-1α-defi cient T cells remain CD137-negative even when becoming TILs, in clear contrast to co-infi ltrating and co-transferred HIF-1α-suffi cient T lymphocytes. The fact that CD137 is selectively expressed on TILs was exploited to confi ne the effects of immunotherapy with agonist anti-CD137 monoclonal antibodies to the tumor tissue. As a result, low-dose intratumoral injections avoid liver infl ammation, 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-1α system increases expression of CD137 on tumor-infi ltrating lymphocytes that thereby become selectively responsive to the immunotherapeutic effects of anti-CD137 agonist monoclonal antibodies as those used in ongoing clinical trials. © 2012 American Association for Cancer Research.