Hypoxia and hypoxia-inducible factor (HIF) downregulate antigen-presenting MHC class I molecules limiting tumor cell recognition by T cells

• Published in: PloS one Vol. 12; no. 11; p. e0187314
• Main Authors: Sethumadhavan, Shalini, Silva, Murillo, Philbrook, Phaethon, Nguyen, Thao, Hatfield, Stephen M, Ohta, Akio, Sitkovsky, Michail V
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 20.11.2017; Public Library of Science (PLoS)
• Subjects: Antigen presentation; Antigen-Presenting Cells - immunology; Antigen-Presenting Cells - pathology; Antigens; ATP Binding Cassette Transporter, Subfamily B, Member 2 - genetics; ATP Binding Cassette Transporter, Subfamily B, Member 2 - immunology; Biology; Biology and Life Sciences; Biotechnology; Cancer; Cancer vaccines; Cell culture; Cell Hypoxia - immunology; Cell recognition; Epitopes; Gene expression; Gene Expression Regulation, Neoplastic; Genes, MHC Class I - immunology; Genetic aspects; Humans; Hyperoxia; Hypoxia; Hypoxia-Inducible Factor 1 - genetics; Hypoxia-Inducible Factor 1 - immunology; Hypoxia-inducible factors; Inflammation; Kidney cancer; Kidney Neoplasms - genetics; Kidney Neoplasms - immunology; Kidney Neoplasms - pathology; Kidneys; Lymphocytes; Lymphocytes T; Major histocompatibility complex; Medical research; Medicine and Health Sciences; Mutation; Neoplasia; Oxygen; Oxygen - metabolism; Oxygen tension; Peptides; Phaethon; Physical Sciences; Physiological aspects; Proteasome Endopeptidase Complex - genetics; Proteasome Endopeptidase Complex - immunology; Proteins; Recognition; Renal cell carcinoma; siRNA; T cells; T-Lymphocytes - immunology; Transcription; Transcription factors; Transcriptional Activation - genetics; Transcriptional Activation - immunology; Tumor cells; Tumor Microenvironment - genetics; Tumor Microenvironment - immunology; Tumors; Vaccines; VHL protein; Von Hippel-Lindau Tumor Suppressor Protein - genetics; Von Hippel-Lindau Tumor Suppressor Protein - immunology; United States; United States > US
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0187314

Human cancers are known to downregulate Major Histocompatibility Complex (MHC) class I expression thereby escaping recognition and rejection by anti-tumor T cells. Here we report that oxygen tension in the tumor microenvironment (TME) serves as an extrinsic cue that regulates antigen presentation by MHC class I molecules. In support of this view, hypoxia is shown to negatively regulate MHC expression in a HIF-dependent manner as evidenced by (i) lower MHC expression in the hypoxic TME in vivo and in hypoxic 3-dimensional (3D) but not 2-dimensional (2D) tumor cell cultures in vitro; (ii) decreased MHC in human renal cell carcinomas with constitutive expression of HIF due to genetic loss of von Hippel-Lindau (VHL) function as compared with isogenically paired cells with restored VHL function, and iii) increased MHC in tumor cells with siRNA-mediated knockdown of HIF. In addition, hypoxia downregulated antigen presenting proteins like TAP 1/2 and LMP7 that are known to have a dominant role in surface display of peptide-MHC complexes. Corroborating oxygen-dependent regulation of MHC antigen presentation, hyperoxia (60% oxygen) transcriptionally upregulated MHC expression and increased levels of TAP2, LMP2 and 7. In conclusion, this study reveals a novel mechanism by which intra-tumoral hypoxia and HIF can potentiate immune escape. It also suggests the use of hyperoxia to improve tumor cell-based cancer vaccines and for mining novel immune epitopes. Furthermore, this study highlights the advantage of 3D cell cultures in reproducing hypoxia-dependent changes observed in the TME.