Sethumadhavan et al. discovered that hypoxia in the tumor microenvironment, and in 3D cultures, leads to decreased surface expression of MHC class I molecules by downregulating transcription of MHC class I heavy chains via the hypoxia-inducible factor (HIF) and by decreasing the levels of TAP1, TAP2, and LMP7, critical components of the antigen processing pathway. These results suggest that cancer immunotherapy may be improved by the addition of oxygenation or HIF inhibition.

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.

Author Info: (1) New England Inflammation and Tissue Protection Institute, Northeastern University, Boston, MA, United States of America. (2) New England Inflammation and Tissue Protection Institute, Northeastern

Author Info: (1) New England Inflammation and Tissue Protection Institute, Northeastern University, Boston, MA, United States of America. (2) New England Inflammation and Tissue Protection Institute, Northeastern University, Boston, MA, United States of America. (3) New England Inflammation and Tissue Protection Institute, Northeastern University, Boston, MA, United States of America. (4) New England Inflammation and Tissue Protection Institute, Northeastern University, Boston, MA, United States of America. (5) New England Inflammation and Tissue Protection Institute, Northeastern University, Boston, MA, United States of America. (6) New England Inflammation and Tissue Protection Institute, Northeastern University, Boston, MA, United States of America. (7) New England Inflammation and Tissue Protection Institute, Northeastern University, Boston, MA, United States of America. Dana Farber Cancer Institute, Harvard Institutes of Medicine, Boston, MA, United States of America.

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