The HIF-1α Hypoxia Response in Tumor-Infiltrating T Lymphocytes Induces Functional CD137 (4-1BB) for Immunotherapy

Cancer Discovery - Tập 2 Số 7 - Trang 608-623 - 2012
Asís Palazón1, Iván Martínez‐Forero1, Álvaro Teijeira1, Aizea Morales‐Kastresana1, Carlos Alfaro1, Miguel F. Sanmamed1, José Luis Pérez‐Gracia1, Iván Peñuelas1, Sandra Hervás‐Stubbs1, Ana Rouzaut1, M O de Landázuri1, Anna Maria Di Giacomo1, Julián Aragonés1, Ignacio Melero1
1Authors' Affiliations: 1CIMA and CUN University of Navarra, Pamplona, Navarra; 2Servicio de Inmunología, Hospital la Princesa, Madrid, Spain; and 3Bristol-Myers Squibb, Research and Development, Princeton, New Jersey

Tóm tắt

AbstractThe 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.This article is highlighted in the In This Issue feature, p. 569.

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