SpringerLink
Log in

Retained or altered expression of major histocompatibility complex class I in patient-derived xenograft models in breast cancer

  • Original Article
  • Published:
Immunologic Research Aims and scope Submit manuscript

Abstract

The expression of major histocompatibility complex class I (MHC I) in tumor cells is regulated by interferon signaling, and it is an important factor in the efficacy of cytotoxic T cell–dependent immunotherapy. To determine the impact of immune cells in MHC I expression on tumor cells, we compared the expression of MHC I in tumor cells derived from primary breast cancers and patient-derived xenograft (PDX) models. MHC I and myxovirus resistance gene A (MxA) expression were analyzed using immunohistochemistry in 23 cases of tumor tissue and corresponding primary and secondary PDXs. The median H score of MHC I was 210 (0–300) in patient tumor tissues, 197.5 (0–300) in primary PDX tumors, and 157.5 (5–300) in secondary PDX tumors. Cases were divided into four groups based on the difference in MHC I expression between the patient tumor tissues and secondary PDXs. Eleven cases constituted the high MHC I group, four constituted the low MHC I group, six comprised the decreased MHC I group, and two comprised the increased MHC I group. MHC I and MxA expressions in each tumor were weakly correlated within patients’ tumors, while strongly correlated within PDX models. Retained or altered expression of MHC I in breast cancer PDXs reveals the presence of intrinsic and extrinsic interferon signaling pathways in tumor cells. Thus, considering MHC I expression in PDX is important when using PDX models to evaluate the efficacy of cancer immunotherapy in a preclinical setting.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price includes VAT (Germany)

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Zheng PP, Kros JM, Li J. Approved CAR T cell therapies: ice bucket challenges on glaring safety risks and long-term impacts. Drug Discov Today. 2018. https://doi.org/10.1016/j.drudis.2018.02.012.

    Article  PubMed  Google Scholar 

  2. Gong J, Chehrazi-Raffle A, Reddi S, Salgia R. Development of PD-1 and PD-L1 inhibitors as a form of cancer immunotherapy: a comprehensive review of registration trials and future considerations. J Immunother Cancer. 2018;6(1):8. https://doi.org/10.1186/s40425-018-0316-z.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Chae YK, Oh MS, Giles FJ. Molecular biomarkers of primary and acquired resistance to T-cell-mediated immunotherapy in cancer: landscape, clinical implications, and future directions. Oncologist. 2018;23(4):410–21. https://doi.org/10.1634/theoncologist.2017-0354.

    Article  PubMed  Google Scholar 

  4. Agrawal S, Kishore MC. MHC class I gene expression and regulation. J Hematother Stem Cell Res. 2000;9(6):795–812. https://doi.org/10.1089/152581600750062237.

    Article  CAS  PubMed  Google Scholar 

  5. Silginer M, Nagy S, Happold C, Schneider H, Weller M, Roth P. Autocrine activation of the IFN signaling pathway may promote immune escape in glioblastoma. Neuro-Oncology. 2017;19(10):1338–49. https://doi.org/10.1093/neuonc/nox051.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Hu JL, Hua YJ, Chen Y, Yu B, Gao S. Structural analysis of tumor-related single amino acid mutations in human MxA protein. Chin J Cancer. 2015;34(12):583–93. https://doi.org/10.1186/s40880-015-0055-1.

    Article  CAS  PubMed  Google Scholar 

  7. Lee HJ, Song IH, Park IA, Heo SH, Kim YA, Ahn JH, et al. Differential expression of major histocompatibility complex class I in subtypes of breast cancer is associated with estrogen receptor and interferon signaling. Oncotarget. 2016;7(21):30119–32. https://doi.org/10.18632/oncotarget.8798.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Kim YA, Lee HJ, Heo SH, Park HS, Park SY, Bang W, et al. MxA expression is associated with tumor-infiltrating lymphocytes and is a prognostic factor in triple-negative breast cancer. Breast Cancer Res Treat. 2016;156(3):597–606. https://doi.org/10.1007/s10549-016-3786-z.

    Article  CAS  PubMed  Google Scholar 

  9. Whittle JR, Lewis MT, Lindeman GJ, Visvader JE. Patient-derived xenograft models of breast cancer and their predictive power. Breast Cancer Res. 2015;17:17. https://doi.org/10.1186/s13058-015-0523-1.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Salgado R, Denkert C, Demaria S, Sirtaine N, Klauschen F, Pruneri G, et al. The evaluation of tumor-infiltrating lymphocytes (TILs) in breast cancer: recommendations by an International TILs Working Group 2014. Ann Oncol. 2015;26(2):259–71. https://doi.org/10.1093/annonc/mdu450.

    Article  CAS  PubMed  Google Scholar 

  11. Harvey JM, Clark GM, Osborne CK, Allred DC. Estrogen receptor status by immunohistochemistry is superior to the ligand-binding assay for predicting response to adjuvant endocrine therapy in breast cancer. J Clin Oncol. 1999;17(5):1474–81. https://doi.org/10.1200/JCO.1999.17.5.1474.

    Article  CAS  PubMed  Google Scholar 

  12. Wolff AC, Hammond ME, Hicks DG, Dowsett M, McShane LM, Allison KH, Allred DC, Bartlett JM, Bilous M, Fitzgibbons P, Hanna W, Jenkins RB, Mangu PB, Paik S, Perez EA, Press MF, Spears PA, Vance GH, Viale G, Hayes DF, American Society of Clinical O, College of American P (2014) Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline update. Arch Pathol Lab Med 138 (2):241–256. doi:https://doi.org/10.5858/arpa.2013-0953-SA.

    Article  Google Scholar 

  13. WHO classification of tumours of the breast (2012). 4th. International Agency for Research on Cancer

  14. Cerami E, Gao J, Dogrusoz U, Gross BE, Sumer SO, Aksoy BA, et al. The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov. 2012;2(5):401–4. https://doi.org/10.1158/2159-8290.CD-12-0095.

    Article  PubMed  Google Scholar 

  15. Gao J, Aksoy BA, Dogrusoz U, Dresdner G, Gross B, Sumer SO, et al. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci signal. 2013;6(269):pl1-pl1. https://doi.org/10.1126/scisignal.2004088.

    Article  CAS  Google Scholar 

  16. Fleming JM, Miller TC, Meyer MJ, Ginsburg E, Vonderhaar BK. Local regulation of human breast xenograft models. J Cell Physiol. 2010;224(3):795–806. https://doi.org/10.1002/jcp.22190.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Ben-David U, Ha G, Tseng YY, Greenwald NF, Oh C, Shih J, et al. Patient-derived xenografts undergo mouse-specific tumor evolution. Nat Genet. 2017;49(11):1567–75. https://doi.org/10.1038/ng.3967.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Eirew P, Steif A, Khattra J, Ha G, Yap D, Farahani H, et al. Dynamics of genomic clones in breast cancer patient xenografts at single-cell resolution. Nature. 2015;518(7539):422–6. https://doi.org/10.1038/nature13952.

    Article  CAS  PubMed  Google Scholar 

  19. Izumchenko E, Paz K, Ciznadija D, Sloma I, Katz A, Vasquez-Dunddel D, et al. Patient-derived xenografts effectively capture responses to oncology therapy in a heterogeneous cohort of patients with solid tumors. Ann Oncol. 2017;28(10):2595–605. https://doi.org/10.1093/annonc/mdx416.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Everson RG, Antonios JP, Lisiero DN, Soto H, Scharnweber R, Garrett MC, et al. Efficacy of systemic adoptive transfer immunotherapy targeting NY-ESO-1 for glioblastoma. Neuro-Oncology. 2016;18(3):368–78. https://doi.org/10.1093/neuonc/nov153.

    Article  CAS  PubMed  Google Scholar 

  21. Jespersen H, Lindberg MF, Donia M, Soderberg EMV, Andersen R, Keller U, et al. Clinical responses to adoptive T-cell transfer can be modeled in an autologous immune-humanized mouse model. Nat Commun. 2017;8(1):707. https://doi.org/10.1038/s41467-017-00786-z.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. De La Rochere P, Guil-Luna S, Decaudin D, Azar G, Sidhu SS, Piaggio E. Humanized mice for the study of immuno-oncology. Trends Immunol. 2018;39(9):748–63. https://doi.org/10.1016/j.it.2018.07.001.

    Article  CAS  Google Scholar 

  23. Capasso A, Lang J, Pitts TM, Jordan KR, Lieu CH, Davis SL, et al. Characterization of immune responses to anti-PD-1 mono and combination immunotherapy in hematopoietic humanized mice implanted with tumor xenografts. Journal for ImmunoTherapy of Cancer. 2019;7(1):37. https://doi.org/10.1186/s40425-019-0518-z.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Li H, Zhu Y, Tang X, Li J, Li Y, Zhong Z, et al. Integrated analysis of transcriptome in cancer patient-derived xenografts. PLoS One. 2015;10(5):e0124780. https://doi.org/10.1371/journal.pone.0124780.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Wang D, Li JR, Zhang YH, Chen L, Huang T, Cai YD. Identification of differentially expressed genes between original breast cancer and xenograft using machine learning algorithms. Genes (Basel). 2018;9(3). https://doi.org/10.3390/genes9030155.

    Article  PubMed Central  Google Scholar 

  26. Kaur G, Batra S. Emerging role of immunoproteasomes in pathophysiology. Immunol Cell Biol. 2016;94(9):812–20. https://doi.org/10.1038/icb.2016.50.

    Article  CAS  PubMed  Google Scholar 

  27. Gresser I, Maury C, Brouty-Boye D. Mechanism of the antitumour effect of interferon in mice. Nature. 1972;239(5368):167–8.

    Article  CAS  PubMed  Google Scholar 

  28. Brockwell NK, Parker BS. Tumor inherent interferons: impact on immune reactivity and immunotherapy. Cytokine. 2018. https://doi.org/10.1016/j.cyto.2018.04.006.

    Article  CAS  PubMed  Google Scholar 

  29. Weiss JM, Subleski JJ, Back T, Chen X, Watkins SK, Yagita H, et al. Regulatory T cells and myeloid-derived suppressor cells in the tumor microenvironment undergo Fas-dependent cell death during IL-2/αCD40 therapy. Journal of immunology (Baltimore, Md : 1950). 2014;192(12):5821–9. https://doi.org/10.4049/jimmunol.1400404.

    Article  CAS  Google Scholar 

  30. Sisirak V, Faget J, Gobert M, Goutagny N, Vey N, Treilleux I, et al. Impaired IFN-α production by plasmacytoid dendritic cells favors regulatory T-cell expansion that may contribute to breast cancer progression. Cancer Res. 2012;72(20):5188–97. https://doi.org/10.1158/0008-5472.CAN-11-3468.

    Article  CAS  PubMed  Google Scholar 

  31. Sistigu A, Yamazaki T, Vacchelli E, Chaba K, Enot DP, Adam J, et al. Cancer cell-autonomous contribution of type I interferon signaling to the efficacy of chemotherapy. Nat Med. 2014;20(11):1301–9. https://doi.org/10.1038/nm.3708.

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

This work was supported by the Korean Health Technology R&D Project, Ministry of Health & Welfare (HI15C0708 and HI17C0337); Basic Science Research Programs through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT & Future Planning, Republic of Korea (NRF-2016R1D1A1B03935367 and NRF-2018R1D1A1B07040612); and the Asan Institute for Life Sciences, Asan Medical Center, Seoul, Korea (2016-169).

Author information

Author notes

  1. In Hye Song and Young-Ae Kim contributed equally to this work.

Authors and Affiliations

  1. Department of Pathology, University of Ulsan College of Medicine Asan Medical Center, 88 Olympic-ro 43-gil, Songpa-gu, Seoul, 138-736, South Korea

    In Hye Song, Young-Ae Kim, Hyeon** Lee, Hye Seon Park, In Ah Park, Gyungyub Gong & Hee ** Lee

  2. Asan Center for Cancer Genome Discovery Asan Institute for Life Sciences, University of Ulsan College of Medicine Asan Medical Center, Seoul, South Korea

    Young-Ae Kim, Hyeon** Lee & Hye Seon Park

  3. Lab of Molecular Immunology and Medicine Department of Biomedical Sciences, University of Ulsan College of Medicine, Seoul, South Korea

    Chan Kyu Sim & Myeong Sup Lee

Authors
  1. In Hye Song
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Young-Ae Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hyeon** Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hye Seon Park
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. In Ah Park
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Chan Kyu Sim
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Myeong Sup Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Gyungyub Gong
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Hee ** Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Gyungyub Gong or Hee ** Lee.

Ethics declarations

Conflict of interest

The authors declare that that they have no conflict of interest.

Ethical approval

This study was performed in accordance with the Declaration of Helsinki and was approved by the Institutional Review Board of Asan Medical Center (IRB#2015-0438) and the International Animal Care and Use Committee (IACUC) of the Laboratory of Animal Research at the Asan Medical Center, Seoul, Republic of Korea.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Précis

Tumor cells derived from PDX models showed retainment or alteration of MHC I expression. Thus, considering MHC I expression in PDX is important when using PDX models to evaluate the efficacy of cancer immunotherapy in a preclinical setting.

Electronic supplementary material

ESM 1

(PDF 447 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Song, I.H., Kim, YA., Lee, H. et al. Retained or altered expression of major histocompatibility complex class I in patient-derived xenograft models in breast cancer. Immunol Res 67, 469–477 (2019). https://doi.org/10.1007/s12026-019-09109-4

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12026-019-09109-4

Keywords

Search

Navigation