title: HLA-E expression by gynecological cancers restrains tumor-infiltrating CD8⁺ T lymphocytes.
abstract: HLA-E is a nonclassical HLA class I molecule, which differs from classical HLA molecules by its nonpolymorphic, conserved nature. Expression and function of HLA-E in normal tissues and solid tumors is not fully understood. We investigated HLA-E protein expression on tissue sections of 420 ovarian and cervical cancers and found equal or higher levels than normal counterpart epithelia in 80% of the tumors. Expression was strongly associated with components of the antigen presentation pathway, e.g., transporter associated with antigen processing (TAP), endoplasmic reticulum aminopeptide (ERAP), β2 microglobulin (β2m), HLA classes I and II, and for ovarian cancer with tumor infiltrating CD8(+) T lymphocytes (CTLs). This association argues against the idea that HLA-E would compensate for the loss of classical HLA in tumors. In situ detection of HLA-E interacting receptors revealed a very low infiltrate of natural killer (NK) cells, but up to 50% of intraepithelial CTLs expressed the inhibiting CD94/NKG2A receptor. In cervical cancer, HLA-E expression did not alter the prognostic effect of CTLs, most likely due to very high infiltrating CTL numbers in this virus-induced tumor. Overall survival of ovarian cancer patients, however, was strongly influenced by HLA-E, because the beneficial effect of high CTL infiltration was completely neutralized in the subpopulation with strong HLA-E expression. Interestingly, these results indicate that CTL infiltration in ovarian cancer is associated with better survival only when HLA-E expression is low and that intratumoral CTLs are inhibited by CD94/NKG2A receptors on CTLs in the tumor microenvironment.
authors.affiliation: Department of Obstetrics and Gynecology, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, The Netherlands.
authors.forename: Marloes
authors.initials: M
authors.lastname: Gooden
authors.forename: Margit
authors.initials: M
authors.lastname: Lampen
authors.forename: Ekaterina S
authors.initials: ES
authors.lastname: Jordanova
authors.forename: Ninke
authors.initials: N
authors.lastname: Leffers
authors.forename: J Baptist
authors.initials: JB
authors.lastname: Trimbos
authors.forename: Sjoerd H
authors.initials: SH
authors.lastname: van der Burg
authors.forename: Hans
authors.initials: H
authors.lastname: Nijman
authors.forename: Thorbald
authors.initials: T
authors.lastname: van Hall
mesh_terms: D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D015331:Cohort Studies; D005260:Female; D005434:Flow Cytometry; D006680:HLA Antigens / Q000276:immunology*; D015395:Histocompatibility Antigens Class I / Q000276:immunology*; D006801:Humans; D007150:Immunohistochemistry; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology*; D010051:Ovarian Neoplasms / Q000276:immunology* / Q000473:pathology; D002583:Uterine Cervical Neoplasms / Q000276:immunology* / Q000473:pathology; D000097625:HLA-E Antigens
chemical_list: D006680:HLA Antigens; D015395:Histocompatibility Antigens Class I; D000097625:HLA-E Antigens