Abstract
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.
Highlights
The tumor microenvironment (TME) has been identified as a critical factor in controlling the progression and metastasis of cancer, along with dictating responses to conventional antitumor therapies [1,2,3]
Our previous findings show that Major Histocompatibility Complex (MHC) class I is heterogeneously expressed in the TME, with hypoxic regions having lower MHC expression as compared with normoxic regions of the same tumor [31]
Independent of anatomical location, both pulmonary tumors (Fig 1A and 1C) and subcutaneous solid tumors (Fig 1B and 1D) from hypoxia breathing mice had significantly downregulated expression of MHC class I molecules as compared with tumors from mice in normoxic conditions
Summary
The tumor microenvironment (TME) has been identified as a critical factor in controlling the progression and metastasis of cancer, along with dictating responses to conventional antitumor therapies [1,2,3]. Hypoxia downregulates MHC class I can be tumor-protective in many solid tumors and be a poor prognosis factor [4]. Despite significant advances in understanding of how hypoxia leads to an immunosuppressive TME by inhibiting effector functions of immune cells [5,6,7], little is known about the mechanisms by which hypoxia alters tumor immunogenicity [8,9,10]. Immunogenicity is critical in the establishment of an effective adaptive immune response [11, 12] and is largely dependent on tumor-associated antigen presentation by Major Histocompatibility Complex (MHC) class I molecules [13]. Cancers with downregulated MHC expression have been associated with greater metastatic potential and present a poor prognosis for patients [16, 17]. There is an acute medical need to improve tumor immunogenicity [20, 21] and prevent evasion of tumors from tumor-reactive T cells by increasing our understanding of the complex regulation of MHC class I expression and developing methods to manipulate it [22, 23]
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