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

A Palazón, I Martínez-Forero, A Teijeira… - Cancer discovery, 2012 - AACR
A Palazón, I Martínez-Forero, A Teijeira, A Morales-Kastresana, C Alfaro, MF Sanmamed…
Cancer discovery, 2012AACR
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 …
Abstract
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)-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.
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-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. ©2012 AACR.
Read the Commentary on this article by Melief, p. 586.
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