Subscribe to RSS
DOI: 10.1055/a-1678-0867
Das Nicht-Pseudogen HLA‑J ist ein neuer prognostischer Marker für das Ansprechen auf Therapie und das Überleben bei Brustkrebs
HLA‑J, a Non-Pseudogene as a New Prognostic Marker for Therapy Response and Survival in Breast Cancer
Zusammenfassung
Humane Leukozyten-Antigene (HLA) sind Proteine auf der Zelloberfläche, die essenziell für die Immunzellinteraktion sind. HLA‑G ist für seine hohe immunosuppressive Wirkung sowie als potenzieller prädikativer Marker für Brustkrebs bekannt. Dagegen ist kaum etwas über HLA‑J und seine immunosuppressiven, prognostischen und prädiktiven Eigenschaften bekannt, da es basierend auf In-silico-Sequenzanalysen als „Pseudogen“ interpretiert wurde. Die Expression von HLA‑J, ESR1, ERBB2, KRT5 und KRT20 mRNA wurde in 29 frisch gefrorenen Brustkrebsbiopsien analysiert und mit den klinisch-pathologischen Daten von Patientinnen, welche mit neoadjuvanter Chemotherapie behandelt wurden, verglichen. Die mRNA-Expression wurde mit genspezifischen TaqMan-basierten Primer/Probe-Sets analysiert und auf Calmodulin 2 normalisiert. Alle Gewebeproben von Patientinnen mit Brustkrebs exprimierten HLA‑J, und der HLA‑J-mRNA-Spiegel war nach NACT oft erhöht. In den Brustkrebsstanzbiopsien war die HLA-J-mRNA-Expression signifikant mit der Überexpression von ESR1-mRNA (Spearmans ρ 0,5679; p = 0,0090) und KRT5-mRNA (Spearmans ρ 0,6121; p = 0,0041) assoziiert und dominierte im Luminal-B-Subtyp. Die Kaplan-Meier-Analyse zeigte, dass ein Anstieg der HLA-J-mRNA-Expression nach NACT mit einem schlechteren progressionsfreien Überleben einhergeht (p = 0,0096), womöglich als Gegenreaktion des Tumorgewebes, um eine Eliminierung durch tumorinfiltrierende Lymphozyten, welche durch eine NACT induziert wurden, zu verhindern. Diese Gegenreaktion ist mit einer schlechteren Prognose assoziiert. Soweit uns bekannt, handelt es sich hierbei um die erste Studie, die HLA-J als neuen prädiktiven Marker im Brustkrebs identifiziert hat und möglicherweise zur Immunevasion beiträgt.
Abstract
The human leukocyte antigen (HLA) genes are cell-surface proteins, essential for immune cell interaction. HLA‑G is known for their high immunosuppressive effect and its potential as predictive marker in breast cancer. However, nothing is known about the HLA‑J and its immunosuppressive, prognostic and predictive features, as it is assumed to be a “pseudogene” by in silico sequence interpretation. HLA‑J, ESR1, ERBB2, KRT5 and KRT20 mRNA expression were analysed in 29 fresh frozen breast cancer biopsies and their corresponding resectates obtained from patients treated with neoadjuvant chemotherapy (NACT). mRNA was analysed with gene specific TaqMan-based Primer/Probe sets and normalized to Calmodulin 2. All breast cancer samples did express HLA‑J and frequently increased HLA-J mRNA levels after NACT. HLA‑J mRNA was significantly associated with overexpression of the ESR1 mRNA status (Spearman ρ 0,5679; p = 0.0090) and KRT5 mRNA (Spearman ρ 0,6121; p = 0.0041) in breast cancer core biopsies and dominated in luminal B subtype. Kaplan Meier analysis revealed that an increase of HLA‑J mRNA expression after NACT had worse progression free survival (p = 0,0096), indicating a counterreaction of tumor tissues presumably to prevent elimination by enhanced immune infiltration induced by NACT. This counterreaction is associated with worse prognosis. To our knowledge this is the first study identifying HLA‑J as a new predictive marker in breast cancer being involved in immune evasion mechanisms.
Publication History
Article published online:
14 December 2021
© 2020. This article was originally published by Thieme as Franziska M. Würfel et al., HLA‑J, a Non-Pseudogene as a New Prognostic Marker for Therapy Response and Survival in Breast Cancer. Geburtsh Frauenheilk 2020; 80: 1123–1133 as an open access article under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial-License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/)
Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany
-
Literatur
- 1 Neefjes J, Jongsma ML, Paul P. et al. Towards a systems understanding of MHC class I and MHC class II antigen presentation. Nat Rev Immunol 2011; 11: 823-836 DOI: 10.1038/nri3084.
- 2 Wieczorek M, Abualrous ET, Sticht J. et al. Major Histocompatibility Complex (MHC) Class I and MHC Class II Proteins: Conformational Plasticity in Antigen Presentation. Front Immunol 2017; 8: 292 DOI: 10.3389/fimmu.2017.00292.
- 3 Abraham JP, Barker DJ, Robinson J. et al. The IPD Databases: Cataloguing and Understanding Allele Variants. Methods Mol Biol 2018; 1802: 31-48 DOI: 10.1007/978-1-4939-8546-3_3.
- 4 Würfel FM, Winterhalter C, Trenkwalder P. et al. European Patent in Immunoncology: From Immunological Principles of Implantation to Cancer Treatment. Int J Mol Sci 2019; 20: 1830 DOI: 10.3390/ijms20081830.
- 5 Hughes AL. Origin and evolution of HLA class I pseudogenes. Mol Biol Evol 1995; 12: 247-258 DOI: 10.1093/oxfordjournals.molbev.a040201.
- 6 Kovalenko TF, Patrushev LI. Pseudogenes as Functionally Significant Elements of the Genome. Biochemistry (Mosc) 2018; 83: 1332-1349 DOI: 10.1134/s0006297918110044.
- 7 Roberts TC, Morris KV. Not so pseudo anymore: pseudogenes as therapeutic targets. Pharmacogenomics 2013; 14: 2023-2034 DOI: 10.2217/pgs.13.172.
- 8 Messer G, Zemmour J, Orr HT. et al. HLA‑J, a second inactivated class I HLA gene related to HLA‑G and HLA‑A. Implications for the evolution of the HLA‑A-related genes. J Immunol 1992; 148: 4043-4053
- 9 Lin A, Yan WH. Heterogeneity of HLA‑G Expression in Cancers: Facing the Challenges. Front Immunol 2018; 9: 2164 DOI: 10.3389/fimmu.2018.02164.
- 10 Sheu J, Shih IeM. HLA‑G and immune evasion in cancer cells. J Formos Med Assoc 2010; 109: 248-257 DOI: 10.1016/s0929-6646(10)60050-2.
- 11 Lin A, Yan WH. Human Leukocyte Antigen-G (HLA‑G) Expression in Cancers: Roles in Immune Evasion, Metastasis and Target for Therapy. Mol Med 2015; 21: 782-791 DOI: 10.2119/molmed.2015.00083.
- 12 Konig L, Kasimir-Bauer S, Hoffmann O. et al. The prognostic impact of soluble and vesicular HLA‑G and its relationship to circulating tumor cells in neoadjuvant treated breast cancer patients. Hum Immunol 2016; 77: 791-799 DOI: 10.1016/j.humimm.2016.01.002.
- 13 von Minckwitz G, Untch M, Blohmer JU. et al. Definition and impact of pathologic complete response on prognosis after neoadjuvant chemotherapy in various intrinsic breast cancer subtypes. J Clin Oncol 2012; 30: 1796-1804 DOI: 10.1200/jco.2011.38.8595.
- 14 Cortazar P, Zhang L, Untch M. et al. Pathological complete response and long-termclinical benefit in breast cancer: the CTNeoBC pooled analysis. Lancet 2014; 384: 164-172 DOI: 10.1016/s0140-6736(13)62422-8.
- 15 Würfel F, Erber R, Huebner H. et al. TILGen: A Program to Investigate Immune Targets in Breast Cancer Patients – First Results on the Influence of Tumor-Infiltrating Lymphocytes. Breast Care (Basel) 2018; 13: 8-14 DOI: 10.1159/000486949.
- 16 Denkert C, Loibl S, Noske A. et al. Tumor-associated lymphocytes as an independent predictor of response to neoadjuvant chemotherapy in breast cancer. J Clin Oncol 2010; 28: 105-113 DOI: 10.1200/jco.2009. 23.7370.
- 17 Kozak M. An analysis of vertebrate mRNA sequences: intimations of translational control. J Cell Biol 1991; 115: 887-903 DOI: 10.1083/jcb. 115.4.887.
- 18 Kozak M. Regulation of translation via mRNA structure in prokaryotes and eukaryotes. Gene 2005; 361: 13-37 DOI: 10.1016/j.gene.2005. 06.037.
- 19 Noske A, Loibl S, Darb-Esfahani S. et al. Comparison of different approaches for assessment of HER2 expression on protein and mRNA level: prediction of chemotherapy response in the neoadjuvant GeparTrio trial (NCT00544765). Breast Cancer Res Treat 2011; 126: 109-117 DOI: 10.1007/s10549-010-1316-y.
- 20 Kotoula V, Kalogeras KT, Kouvatseas G. et al. Sample parameters affecting the clinical relevance of RNA biomarkers in translational breast cancer research. Virchows Arch 2013; 462: 141-154 DOI: 10.1007/s00428-012-1357-1.
- 21 Wirtz RM, Sihto H, Isola J. et al. Biological subtyping of early breast cancer: a study comparing RT-qPCR with immunohistochemistry. Breast Cancer Res Treat 2016; 157: 437-446 DOI: 10.1007/s10549-016-3835-7.
- 22 Ogston KN, Miller ID, Payne S. et al. A new histological grading system to assess response of breast cancers to primary chemotherapy: prognostic significance and survival. Breast 2003; 12: 320-327 DOI: 10.1016/s0960-9776(03)00106-1.
- 23 Goldhirsch A, Wood WC, Coates AS. et al. Strategies for subtypes-dealing with the diversity of breast cancer: highlights of the St. Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2011. Ann Oncol 2011; 22: 1736-1747 DOI: 10.1093/annonc/mdr304.
- 24 Denkert C, Loibl S, Kronenwett R. et al. RNA-based determination of ESR1 and HER2 expression and response to neoadjuvant chemotherapy. Ann Oncol 2013; 24: 632-639 DOI: 10.1093/annonc/mds339.
- 25 König L, Kasimir-Bauer S, Hoffmann O. et al. The prognostic impact of soluble and vesicular HLA‑G and its relationship to circulating tumor cells in neoadjuvant treated breast cancer patients. Human Immunology 2016; 77: 791-799 DOI: 10.1016/j.humimm.2016.01.002.
- 26 Kirana C, Ruszkiewicz A, Stubbs RS. et al. Soluble HLA‑G is a differential prognostic marker in sequential colorectal cancer disease stages. Int J Cancer 2017; 140: 2577-2586 DOI: 10.1002/ijc.30667.
- 27 Zhang RL, Zhang X, Dong SS. et al. Predictive value of different proportion of lesion HLA‑G expression in colorectal cancer. Oncotarget 2017; 8: 107441-107451 DOI: 10.18632/oncotarget.22487.
- 28 De Martino M, Forzati F, Arra C. et al. HMGA1-pseudogenes and cancer. Oncotarget 2016; 7: 28724-28735 DOI: 10.18632/oncotarget.7427.
- 29 Tutar Y. Pseudogenes. Comp Funct Genomics 2012; 2012: 424526 DOI: 10.1155/2012/424526.
- 30 Moreau P, Faure O, Lefebvre S. et al. Glucocorticoid hormones upregulate levels of HLA‑G transcripts in trophoblasts. Transplant Proc 2001; 33: 2277-2280 DOI: 10.1016/s0041-1345(01)01990-x.
- 31 He X, Dong DD, Yie SM. et al. HLA‑G expression in human breast cancer: implications for diagnosis and prognosis, and effect on allocytotoxic lymphocyte response after hormone treatment in vitro. Ann Surg Oncol 2010; 17: 1459-1469 DOI: 10.1245/s10434-009-0891-9.
- 32 Horwitz KB, Dye WW, Harrell JC. et al. Rare steroid receptor-negative basal-like tumorigenic cells in luminal subtype human breast cancer xenografts. Proc Natl Acad Sci U S A 2008; 105: 5774-5779 DOI: 10.1073/pnas.0706216105.
- 33 Goodman CR, Sato T, Peck AR. et al. Steroid induction of therapy-resistant cytokeratin-5-positive cells in estrogen receptor-positive breast cancer through a BCL6-dependent mechanism. Oncogene 2016; 35: 1373-1385 DOI: 10.1038/onc.2015.193.
- 34 Dong DD, Yie SM, Li K. et al. Importance of HLA‑G expression and tumor infiltrating lymphocytes in molecular subtypes of breast cancer. Hum Immunol 2012; 73: 998-1004 DOI: 10.1016/j.humimm.2012.07.321.
- 35 Kabos P, Haughian JM, Wang X. et al. Cytokeratin 5 positive cells represent a steroid receptor negative and therapy resistant subpopulation in luminal breast cancers. Breast Cancer Res Treat 2011; 128: 45-55 DOI: 10.1007/s10549-010-1078-6.
- 36 Nicolini A, Ferrari P, Duffy MJ. Prognostic and predictive biomarkers in breast cancer: Past, present and future. Semin Cancer Biol 2018; 52: 56-73 DOI: 10.1016/j.semcancer.2017.08.010.
- 37 OʼDonnell T, Christie EL, Ahuja A. et al. Chemotherapy weakly contributes to predicted neoantigen expression in ovarian cancer. BMC Cancer 2018; 18: 87 DOI: 10.1186/s12885-017-3825-0.
- 38 Lu YC, Robbins PF. Cancer immunotherapy targeting neoantigens. Semin Immunol 2016; 28: 22-27 DOI: 10.1016/j.smim.2015.11.002.
- 39 Wu D, Kuiaste I, Moreau P. et al. Rescuing lymphocytes from HLA‑G immunosuppressive effects mediated by the tumor microenvironment. Oncotarget 2015; 6: 37385-37397 DOI: 10.18632/oncotarget.6044.
- 40 Sinn HP, Schmid H, Junkermann H. et al. Histologische Regression des Mammakarzinoms nach primärer (neoadjuvanter) Chemotherapie. Geburtshilfe Frauenheilkd 1994; 54: 552-558 DOI: 10.1055/s-2007-1022338.