PD-L1 is a novel direct target of HIF-1α, and its blockade under hypoxia enhanced MDSC-mediated T cell activation

Journal of Experimental Medicine - Tập 211 Số 5 - Trang 781-790 - 2014
Muhammad Zaeem Noman1, Giacomo Desantis, Bassam Janji2, Meriem Hasmim3, Saoussen Karray, Philippe Dessen4, Vincenzo Bronte, Salem Chouaı̈b5
1CPTP - Centre de Physiopathologie Toulouse Purpan (Hôpital de Purpan Place du Docteur Baylac 31024 TOULOUSE CEDEX 3 - France)
2IBCP - Institut de biologie et chimie des protéines [Lyon] (7 Passage du Vercors 69367 LYON CEDEX 07 - France)
3Division of Experimental Oncology (Epalinges - Switzerland)
4U1170 Inserm - Hématopoïèse normale et pathologique (Gustave Roussy - Pavillon de recherche 1 - 114, rue Édouard-Vaillant 94805 Villejuif Cedex -France - France)
5CBM - Centre de biophysique moléculaire (Rue Charles Sadron 45071 ORLEANS CEDEX 2 - France)

Tóm tắt

Tumor-infiltrating myeloid cells such as myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs) form an important component of the hypoxic tumor microenvironment. Here, we investigated the influence of hypoxia on immune checkpoint receptors (programmed death [PD]-1 and CTLA-4) and their respective ligands (PD-1 ligand 1 [PD-L1], PD-L2, CD80, and CD86) on MDSCs. We demonstrate that MDSCs at the tumor site show a differential expression of PD-L1 as compared with MDSCs from peripheral lymphoid organ (spleen). Hypoxia caused a rapid, dramatic, and selective up-regulation of PD-L1 on splenic MDSCs in tumor-bearing mice. This was not limited to MDSCs, as hypoxia also significantly increased the expression of PD-L1 on macrophages, dendritic cells, and tumor cells. Furthermore, PD-L1 up-regulation under hypoxia was dependent on hypoxia-inducible factor-1α (HIF-1α) but not HIF-2α. Chromatin immunoprecipitation and luciferase reporter assay revealed direct binding of HIF-1α to a transcriptionally active hypoxia-response element (HRE) in the PD-L1 proximal promoter. Blockade of PD-L1 under hypoxia enhanced MDSC-mediated T cell activation and was accompanied by the down-regulation of MDSCs IL-6 and IL-10. Finally, neutralizing antibodies against IL-10 under hypoxia significantly abrogated the suppressive activity of MDSCs. Simultaneous blockade of PD-L1 along with inhibition of HIF-1α may thus represent a novel approach for cancer immunotherapy.

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Journal of Experimental Medicine

Tập 211 Số 5

781-790

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