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UnlabelledThe 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)-1α-knockout T cells, and such HIF-1α-deficient T cells remain CD137-negative even when becoming TILs, in clear contrast to co-infiltrating and co-transferred HIF-1α-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.SignificanceCD137 (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-infiltrating lymphocytes that thereby become selectively responsive to the immunotherapeutic effects of anti-CD137 agonist monoclonal antibodies as those used in ongoing clinical trials.

Original publication




Journal article


Cancer discovery

Publication Date





608 - 623


CIMA and CUN University of Navarra, Pamplona, Navarra, Spain.


T-Lymphocytes, Lymphocytes, Tumor-Infiltrating, Animals, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Knockout, Mice, Neoplasms, Antibodies, Monoclonal, Microscopy, Fluorescence, Immunotherapy, Flow Cytometry, Lymphocyte Activation, Female, Male, Hypoxia-Inducible Factor 1, alpha Subunit, Tumor Microenvironment, Hypoxia, Tumor Necrosis Factor Receptor Superfamily, Member 9