PD-L1 is a novel direct target of HIF-1α, and its blockade under hypoxia enhanced MDSC-mediated T cell activation.
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.
Unité Institut National de la Santé et de la Recherche Médicale U753, Institut de Cancérologie Gustave Roussy, 94805 Villejuif, France.
Muhammad Zaeem
MZ
Noman
Giacomo
G
Desantis
Bassam
B
Janji
Meriem
M
Hasmim
Saoussen
S
Karray
Philippe
P
Dessen
Vincenzo
V
Bronte
Salem
S
Chouaib
D000818:Animals; D060890:B7-H1 Antigen / Q000378:metabolism*; D052160:Benzothiazoles; D015687:Cell Hypoxia / Q000276:immunology*; D047369:Chromatin Immunoprecipitation; D003959:Diamines; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D005786:Gene Expression Regulation / Q000276:immunology*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D008156:Luciferases; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D022423:Myeloid Cells / Q000276:immunology*; D009930:Organic Chemicals; D011804:Quinolines; D034622:RNA Interference; D060888:Real-Time Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000276:immunology*; D059016:Tumor Microenvironment / Q000276:immunology*
D060890:B7-H1 Antigen; D052160:Benzothiazoles; C498919:Cd274 protein, mouse; D003959:Diamines; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009930:Organic Chemicals; D011804:Quinolines; C098022:SYBR Green I; D008156:Luciferases