The prognostic benefit of tumour-infiltrating Natural Killer cells in endometrial cancer is dependent on concurrent overexpression of Human Leucocyte Antigen-E in the tumour microenvironment

Published:October 20, 2017DOI:


      • Upregulation of HLA-E is associated with improved survival in endometrial cancer (EC).
      • The presence of NK cells predicts survival when HLA-E expression is upregulated.
      • The presence of NK cells is associated with a worse prognosis when HLA-E expression is normal.
      • The prognostic benefit of T cells is not modulated by HLA-E expression in EC.
      • HLA-E may have opposing actions on tumour-infiltrating immune cells in EC.



      Human Leucocyte Antigen- E (HLA-E) has been reported as both a positive and negative prognostic marker in cancer. This apparent discrepancy may be due to opposing actions of HLA-E on tumour-infiltrating immune cells. Therefore, we evaluated HLA-E expression and survival in relation to the presence of intratumoural natural killer (NK) cells and cytotoxic T cells (CTLs).


      Tissue microarrays (TMAs) of endometrial tumours were used for immunohistochemical staining of parameters of interest. The combined impact of clinical, pathological and immune parameters on survival was analysed using log rank testing and Cox regression analyses.


      Upregulation of HLA-E was associated with an improved disease-free and disease-specific survival in univariate analysis (HR 0.58 95% CI 0.37–0.89; HR 0.42 95% CI 0.25–0.73, respectively). In multivariate analysis, the presence of NK cells predicts survival with a hazard ratio (HR) 0.28 (95% confidence interval (CI) 0.09–0.91) when HLA-E expression is upregulated; but it is associated with a worse prognosis when HLA-E expression is normal (HR 13.43, 95% CI 1.70–106.14). By contrast, the prognostic benefit of T cells was not modulated by HLA-E expression.


      Taken together, we demonstrate that the prognostic benefit of NK cells, but not T-cells, is influenced by HLA-E expression in endometrial cancer (EC) and propose a model to explain our observations.


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        • Algarra I.
        • Garcia-Lora A.
        • Cabrera T.
        • Ruiz-Cabello F.
        • Garrido F.
        The selection of tumor variants with altered expression of classical and nonclassical MHC class I molecules: implications for tumor immune escape.
        Cancer Immunol Immunother. 2004; 53: 904-910
        • Benevolo M.
        • Mottolese M.
        • Tremante E.
        • Rollo F.
        • Diodoro M.G.
        • Ercolani C.
        • et al.
        High expression of HLA-E in colorectal carcinoma is associated with a favorable prognosis.
        J Transl Med. 2011; 9 (9-184): 184-5876
        • Bijen C.B.
        • Bantema-Joppe E.J.
        • de Jong R.A.
        • Leffers N.
        • Mourits M.J.
        • Eggink H.F.
        • et al.
        The prognostic role of classical and nonclassical MHC class I expression in endometrial cancer.
        Int J Cancer. 2010; 126: 1417-1427
        • Boeckh M.
        • Murphy W.J.
        • Peggs K.S.
        Recent advances in cytomegalovirus: an update on pharmacologic and cellular therapies.
        Biol Blood Marrow Transpl. 2015; 21: 24-29
        • Braud V.M.
        • Allan D.S.
        • O'Callaghan C.A.
        • Soderstrom K.
        • D'Andrea A.
        • Ogg G.S.
        • et al.
        HLA-E binds to natural killer cell receptors CD94/NKG2A, B and C.
        Nature. 1998; 391: 795-799
        • de Jong R.A.
        • Boerma A.
        • Boezen H.M.
        • Mourits M.J.
        • Hollema H.
        • Nijman H.W.
        Loss of HLA class I and mismatch repair protein expression in sporadic endometrioid endometrial carcinomas.
        Int J Cancer. 2012; 131: 1828-1836
        • de Jong R.A.
        • Leffers N.
        • Boezen H.M.
        • ten Hoor K.A.
        • van der Zee A.G.
        • Hollema H.
        • et al.
        Presence of tumor-infiltrating lymphocytes is an independent prognostic factor in type I and II endometrial cancer.
        Gynecol Oncol. 2009; 114: 105-110
        • de Kruijf E.M.
        • Sajet A.
        • van Nes J.G.
        • Natanov R.
        • Putter H.
        • Smit V.T.
        • et al.
        HLA-E and HLA-G expression in classical HLA class I-negative tumors is of prognostic value for clinical outcome of early breast cancer patients.
        J Immunol. 2010; 185: 7452-7459
        • Elboim M.
        • Gazit R.
        • Gur C.
        • Ghadially H.
        • Betser-Cohen G.
        • Mandelboim O.
        Tumor immunoediting by NKp46.
        J Immunol. 2010; 184: 5637-5644
        • Ferlay J.
        • Soerjomataram I.
        • Dikshit R.
        • Eser S.
        • Mathers C.
        • Rebelo M.
        • et al.
        Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012.
        Int J Cancer. 2015; 136: E359-E386
        • Gooden M.
        • Lampen M.
        • Jordanova E.S.
        • Leffers N.
        • Trimbos J.B.
        • van der Burg S.H.
        • et al.
        HLA-E expression by gynecological cancers restrains tumor-infiltrating CD8(+) T lymphocytes.
        Proc Natl Acad Sci U S A. 2011; 108: 10656-10661
        • Hoare H.L.
        • Sullivan L.C.
        • Clements C.S.
        • Ely L.K.
        • Beddoe T.
        • Henderson K.N.
        • et al.
        Subtle changes in peptide conformation profoundly affect recognition of the non-classical MHC class I molecule HLA-E by the CD94-NKG2 natural killer cell receptors.
        J Mol Biol. 2008; 377: 1297-1303
        • Kaiser B.K.
        • Pizarro J.C.
        • Kerns J.
        • Strong R.K.
        Structural basis for NKG2A/CD94 recognition of HLA-E.
        Proc Natl Acad Sci U S A. 2008; 105: 6696-6701
        • Kirkwood R.K.S.J.
        Chapter 29: regression modelling.
        in: Medical statistics, anonymous. Blackwell Science Ltd, 2003: 315-342
        • Kochan G.
        • Escors D.
        • Breckpot K.
        • Guerrero-Setas D.
        Role of non-classical MHC class I molecules in cancer immunosuppression.
        Oncoimmunology. 2013; 2: e26491
        • Lampen M.H.
        • Hassan C.
        • Sluijter M.
        • Geluk A.
        • Dijkman K.
        • Tjon J.M.
        • et al.
        Alternative peptide repertoire of HLA-E reveals a binding motif that is strikingly similar to HLA-A2.
        Mol Immunol. 2013; 53: 126-131
        • Lauterbach N.
        • Wieten L.
        • Popeijus H.E.
        • Voorter C.E.
        • Tilanus M.G.
        HLA-E regulates NKG2C+ natural killer cell function through presentation of a restricted peptide repertoire.
        Hum Immunol. 2015; 76: 578-586
        • Le D.T.
        • Uram J.N.
        • Wang H.
        • Bartlett B.R.
        • Kemberling H.
        • Eyring A.D.
        • et al.
        PD-1 blockade in tumors with mismatch-repair deficiency.
        N Engl J Med. 2015; 372: 2509-2520
        • Levy E.M.
        • Bianchini M.
        • Von Euw E.M.
        • Barrio M.M.
        • Bravo A.I.
        • Furman D.
        • et al.
        Human leukocyte antigen-E protein is overexpressed in primary human colorectal cancer.
        Int J Oncol. 2008; 32: 633-641
        • Michaelsson J.
        • Teixeira de Matos C.
        • Achour A.
        • Lanier L.L.
        • Karre K.
        • Soderstrom K.
        A signal peptide derived from hsp60 binds HLA-E and interferes with CD94/NKG2A recognition.
        J Exp Med. 2002; 196: 1403-1414
        • Moretta A.
        • Bottino C.
        • Vitale M.
        • Pende D.
        • Cantoni C.
        • Mingari M.C.
        • et al.
        Activating receptors and coreceptors involved in human natural killer cell-mediated cytolysis.
        Annu Rev Immunol. 2001; 19 (19/1/197): 197-223
        • Morice P.
        • Leary A.
        • Creutzberg C.
        • Abu-Rustum N.
        • Darai E.
        Endometrial cancer.
        Lancet. 2015; (S0140-6736(15)00130-0)
        • Oncoline guidelines
        Dutch guideline on endometrial cancer.
        • Orr M.T.
        • Lanier L.L.
        Natural killer cell education and tolerance.
        Cell. 2010; 142: 847-856
        • Pahl J.
        • Cerwenka A.
        Tricking the balance: NK cells in anti-cancer immunity.
        Immunobiology. 2015; (S0171-2985(15)30031-0)
        • Pietra G.
        • Romagnani C.
        • Manzini C.
        • Moretta L.
        • Mingari M.C.
        The emerging role of HLA-E-restricted CD8+ T lymphocytes in the adaptive immune response to pathogens and tumors.
        J Biomed Biotechnol. 2010; 2010: 907092
        • Ruiter D.J.
        • Ferrier C.M.
        • van Muijen G.N.
        • Henzen-Logmans S.C.
        • Kennedy S.
        • Kramer M.D.
        • et al.
        Quality control of immunohistochemical evaluation of tumour-associated plasminogen activators and related components. European BIOMED-1 concerted action on clinical relevance of proteases in tumour invasion and metastasis.
        Eur J Cancer. 1998; 34: 1334-1340
        • Spaans V.M.
        • Peters A.A.
        • Fleuren G.J.
        • Jordanova E.S.
        HLA-E expression in cervical adenocarcinomas: association with improved long-term survival.
        J Transl Med. 2012; 10 (184-5876-10-184)
        • Strong R.K.
        • Holmes M.A.
        • Li P.
        • Braun L.
        • Lee N.
        • Geraghty D.E.
        HLA-E allelic variants. Correlating differential expression, peptide affinities, crystal structures, and thermal stabilities.
        J Biol Chem. 2003; 278: 5082-5090
        • Talebian Yazdi M.
        • van Riet S.
        • van Schadewijk A.
        • Fiocco M.
        • van Hall T.
        • Taube C.
        • et al.
        The positive prognostic effect of stromal CD8+ tumor-infiltrating T cells is restrained by the expression of HLA-E in non-small cell lung carcinoma.
        Oncotarget. 2016; 7: 3477-3488
        • Uhlen M.
        • Fagerberg L.
        • Hallstrom B.M.
        • Lindskog C.
        • Oksvold P.
        • Mardinoglu A.
        • et al.
        Proteomics. Tissue-based map of the human proteome.
        Science. 2015; 347: 1260419,
        • Vales-Gomez M.
        • Reyburn H.T.
        • Erskine R.A.
        • Lopez-Botet M.
        • Strominger J.L.
        Kinetics and peptide dependency of the binding of the inhibitory NK receptor CD94/NKG2-A and the activating receptor CD94/NKG2-C to HLA-E.
        EMBO J. 1999; 18: 4250-4260
        • van Hall T.
        • Oliveira C.C.
        • Joosten S.A.
        • Ottenhoff T.H.
        The other Janus face of Qa-1 and HLA-E: diverse peptide repertoires in times of stress.
        Microbes Infect. 2010; 12: 910-918
        • Vanderstraeten A.
        • Tuyaerts S.
        • Amant F.
        The immune system in the normal endometrium and implications for endometrial cancer development.
        J Reprod Immunol. 2015; 109: 7-16
        • Versluis M.A.
        • de Jong R.A.
        • Plat A.
        • Bosse T.
        • Smit V.T.
        • Mackay H.
        • et al.
        Prediction model for regional or distant recurrence in endometrial cancer based on classical pathological and immunological parameters.
        Br J Cancer. 2015; 113: 786-793
        • Vesely M.D.
        • Kershaw M.H.
        • Schreiber R.D.
        • Smyth M.J.
        Natural innate and adaptive immunity to cancer.
        Annu Rev Immunol. 2011; 29: 235-271
        • Waldhauer I.
        • Steinle A.
        NK cells and cancer immunosurveillance.
        Oncogene. 2008; 27: 5932-5943
        • Wischhusen J.
        • Friese M.A.
        • Mittelbronn M.
        • Meyermann R.
        • Weller M.
        HLA-E protects glioma cells from NKG2D-mediated immune responses in vitro: implications for immune escape in vivo.
        J Neuropathol Exp Neurol. 2005; 64: 523-528
        • Zeestraten E.C.
        • Reimers M.S.
        • Saadatmand S.
        • Dekker J.W.
        • Liefers G.J.
        • van den Elsen P.J.
        • et al.
        Combined analysis of HLA class I, HLA-E and HLA-G predicts prognosis in colon cancer patients.
        Br J Cancer. 2014; 110: 459-468
        • Zhen Z.J.
        • Ling J.Y.
        • Cai Y.
        • Luo W.B.
        • He Y.J.
        Impact of HLA-E gene polymorphism on HLA-E expression in tumor cells and prognosis in patients with stage III colorectal cancer.
        Med Oncol. 2013; 30 (482-013-0482-2. Epub 2013 Feb 3)