title: The prognostic impact of soluble and vesicular HLA-G and its relationship to circulating tumor cells in neoadjuvant treated breast cancer patients.
abstract: The non-classical human leukocyte antigen G (HLA-G) molecule and its soluble forms exert multiple immune suppressive regulatory functions in malignancy and in stem cells contributing to immune escape mechanisms. HLA-G can be secreted as free soluble HLA-G molecules or via extracellular vesicles (EVs). Here we evaluated these soluble HLA-G forms as prognostic marker for prediction of the clinical outcome of neoadjuvant chemotherapy (NACT) treated breast cancer (BC) patients. Plasma samples of BC patients procured before (n=142) and after (n=154) NACT were quantified for total soluble HLA-G (sHLA-Gtot) and HLA-G levels in ExoQuick™ derived EV fractions (sHLA-GEV) by ELISA. The corresponding increments were specified as free sHLA-G (sHLA-Gfree). Total and free sHLA-G were significantly increased in NACT treated BC patients compared to healthy controls (n=16). High sHLA-Gfree levels were exclusively associated to estrogen receptor expression before NACT. Importantly, high sHLA-GEV levels before NACT were related to disease progression and the detection of stem cell-like circulating tumor cells, but high sHLA-Gfree levels indicated an improved clinical outcome. Thus, this study demonstrates for the first time that the different sHLA-G subcomponents represent dissimilar qualitative prognostic impacts on the clinical outcome of NACT treated BC patients, whereas the total sHLA-G levels without separating into subcomponents are not related to clinical outcome.
authors.affiliation: Institute for Transfusion Medicine, University Hospital Essen, University of Duisburg-Essen, Virchowstr. 179, 45147 Essen, Germany; Department of Gynecology and Obstetrics, University Hospital Essen, University of Duisburg-Essen, Hufelandstraße 55, 45122 Essen, Germany. Electronic address: Lisa.koenig@uk-essen.de.
authors.forename: Lisa
authors.initials: L
authors.lastname: König
authors.affiliation: Department of Gynecology and Obstetrics, University Hospital Essen, University of Duisburg-Essen, Hufelandstraße 55, 45122 Essen, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Kasimir-Bauer
authors.affiliation: Department of Gynecology and Obstetrics, University Hospital Essen, University of Duisburg-Essen, Hufelandstraße 55, 45122 Essen, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Hoffmann
authors.affiliation: Department of Gynecology and Obstetrics, University Hospital Essen, University of Duisburg-Essen, Hufelandstraße 55, 45122 Essen, Germany.
authors.forename: Ann-Kathrin
authors.initials: AK
authors.lastname: Bittner
authors.affiliation: Institute for Transfusion Medicine, University Hospital Essen, University of Duisburg-Essen, Virchowstr. 179, 45147 Essen, Germany.
authors.forename: Bettina
authors.initials: B
authors.lastname: Wagner
authors.affiliation: Institute for Transfusion Medicine, University Hospital Essen, University of Duisburg-Essen, Virchowstr. 179, 45147 Essen, Germany; The Capes Foundation, Ministry of Education of Brazil, Cx. Postal 250, Brasília DF 70.040-020, Brazil.
authors.forename: Luis Felipe Santos
authors.initials: LF
authors.lastname: Manvailer
authors.affiliation: Institute for Transfusion Medicine, University Hospital Essen, University of Duisburg-Essen, Virchowstr. 179, 45147 Essen, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Schramm
authors.affiliation: Institute for Pathology, University Hospital Essen, University of Duisburg-Essen, Hufelandstraße 55, 45122 Essen, Germany.
authors.forename: Agnes
authors.initials: A
authors.lastname: Bankfalvi
authors.affiliation: Institute for Transfusion Medicine, University Hospital Essen, University of Duisburg-Essen, Virchowstr. 179, 45147 Essen, Germany.
authors.forename: Bernd
authors.initials: B
authors.lastname: Giebel
authors.affiliation: Department of Gynecology and Obstetrics, University Hospital Essen, University of Duisburg-Essen, Hufelandstraße 55, 45122 Essen, Germany.
authors.forename: Rainer
authors.initials: R
authors.lastname: Kimmig
authors.affiliation: Institute for Transfusion Medicine, University Hospital Essen, University of Duisburg-Essen, Virchowstr. 179, 45147 Essen, Germany.
authors.forename: Peter A
authors.initials: PA
authors.lastname: Horn
authors.affiliation: Institute for Transfusion Medicine, University Hospital Essen, University of Duisburg-Essen, Virchowstr. 179, 45147 Essen, Germany.
authors.forename: Vera
authors.initials: V
authors.lastname: Rebmann
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001798:Blood Proteins / Q000378:metabolism*; D001943:Breast Neoplasms / Q000175:diagnosis* / Q000188:drug therapy; D044584:Carcinoma, Ductal / Q000175:diagnosis* / Q000188:drug therapy; D055252:Cell-Derived Microparticles / Q000378:metabolism*; D018450:Disease Progression; D005260:Female; D059951:HLA-G Antigens / Q000378:metabolism*; D006801:Humans; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D009360:Neoplastic Cells, Circulating / Q000473:pathology*; D014411:Neoplastic Stem Cells / Q000473:pathology*; D011379:Prognosis; D016896:Treatment Outcome; D019139:Tumor Escape; D055815:Young Adult
chemical_list: D001798:Blood Proteins; D059951:HLA-G Antigens
keywords: Breast cancer; Extracellular vesicles; Neoadjuvant chemotherapy; Prognostic impact; sHLA-G