Microenvironmental stresses induce HLA‐E/Qa‐1 surface expression and thereby reduce CD8⁺ T‐cell recognition of stressed cells

Abstract

Hypoxia and glucose deprivation are often observed in the microenvironment surrounding solid tumors in vivo. However, how they interfere with MHC class I antigen processing and CD8 + T-cell responses remains unclear. In this study, we analyzed the production of antigenic peptides presented by classical MHC class I in mice, and showed that it is quantitatively decreased in the cells exposed to either hypoxia or glucose deprivation. In addition, we unexpectedly found increased surface expression of HLA-E in human and Qa-1 in mouse tumor cells exposed to combined oxygen and glucose deprivation. The induced Qa-1 on the stressed tumor model interacted with an inhibitory NKG2/CD94 receptor on activated CD8 + T cells and attenuated their specific response to the antigen. Our results thus suggest that microenvironmental stresses modulate not only classical but also nonclassical MHC class I presentation, and confer the stressed cells the capability to escape from the CD8 + T-cell recognition.Keywords: Antigen presentation r Glucose deprivation hypoxia r HLA-E r MHC class I r Microenvironmental stress r Qa-1 Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionSolid tumors provide a special microenvironment that alters the biological aspects of the cells within [1]. Because of aberrant Correspondence: Dr. Takayuki Kanaseki e-mail: kanaseki@sapmed.ac.jp and disorganized vasculature, tumor cells inside a mass are often exposed to chronic hypoxia, which induces stress-related gene expression as well as resistance to apoptosis, radiation, and chemotherapy [2,3]. Moreover, tumor cells predominantly use the tricarboxylic acid cycle rather than oxidative phosphorylation for energy production (Warburg effect) and they are exposed to severe glucose deprivation [4,5]. The biological adaptation models of tumor cells to survive under such combined-stress condition C 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu 930Takanori Sasaki et al. Eur. J. Immunol. 2016. 46: 929-940 have been established [6][7][8][9], however the understanding of how the microenvironmental stresses interfere MHC class I antigen processing and CD8 + T-cell responses is incomplete. MHC class I molecules are expressed on most nucleated cells and determine the outcome of CD8 + T-cell mediated immune surveillance. They are classified into highly polymorphic classical MHC class I molecules and nonpolymorphic nonclassical MHC class I molecules. The classical MHC I molecules on the surface present short peptides originating from endogenous self or foreign proteins and form complexes with a diverse set of peptide (pMHC I) [10,11]. Such short peptides are generally 8-10-mer in length and conserve anchor residues that locate at discrete positions, allowing the peptide to be bound to MHC I molecules [12]. The peptides are produced by MHC I antigen processing that begins in the cytosol and continues in the ER where the precursor peptides are optimized for binding and finally load...

HLA-F*01:01 presents peptides with N-terminal flexibility and a preferred length of 16 residues

“…Before being presented by an HLA-Ib molecule, the selection criteria are understandably more severe due to the limited polymorphisms in HLA-Ib molecules (Braud et al 1997 ). While peptide/HLA-E expression levels are highly dependent on cellular stress (van Hall et al 2010 ; Sasaki et al 2016 ), HLA-G selects tissue-specific peptides (Celik et al 2018b ) that are independent of peptide anchor motifs (Celik et al 2018a ). The restricted interaction between peptide/HLA-F (pHLA-F) complexes and the NK cell receptor KIR3DS1 during HIV infection suggests that understanding HLA-F peptide selection and presentation is functionally important.…”

NKG2A Expression Is Not per se Detrimental for the Anti-Multiple Myeloma Activity of Activated Natural Killer Cells in an In Vitro System Mimicking the Tumor Microenvironment

“…Furthermore, we demonstrated in an earlier study that HLA-E levels on MM tumor cells are increased upon in vivo growth in the BM of immunodeficient mice as compared to in vitro passaged cells ( 15 ). Moreover, a recent paper has shown that under hypoxia and glucose deprivation, HLA-E can be upregulated in both human and mouse tumor cells as a result of microenvironmental stress ( 31 ). It would, therefore, be valuable to determine the effect of NKG2A on high dose IL-2-activated NK cells in an in vivo MM model or after longer exposure of hypoxia and or other TMEF.…”

Immunity, Hypoxia, and Metabolism–the Ménage à Trois of Cancer: Implications for Immunotherapy

“…Given the immunosuppressive function of HLA-G on cytotoxic T cells and NK cells, HLA-G expression in hypoxic cancer cells may drive immune evasion and, hence, represents a novel immune checkpoint molecule. Noteworthy, glucose deprivation in combination with hypoxic stress leads to increased surface expression of HLA-E cancer cells (623). Therefore, it will be interesting to investigate the impact of hypoxia on other MHC-I molecules in a cancer cell context.…”