Skip to main content

Advertisement

SpringerLink
Log in

A signature of immune function genes associated with recurrence-free survival in breast cancer patients

  • Preclinical study
  • Published:
Breast Cancer Research and Treatment Aims and scope Submit manuscript

Abstract

The clinical significance of tumor-infiltrating immune cells has been reported in a variety of human carcinomas including breast cancer. However, molecular signature of tumor-infiltrating immune cells and their prognostic value in breast cancer patients remain elusive. We hypothesized that a distinct network of immune function genes at the tumor site can predict a low risk versus high risk of distant relapse in breast cancer patients regardless of the status of ER, PR, or HER-2/neu in their tumors. We conducted retrospective studies in a diverse cohort of breast cancer patients with a 1–5 year tumor relapse versus those with up to 7 years relapse-free survival. The RNAs were extracted from the frozen tumor specimens at the time of diagnosis and subjected to microarray analysis and real-time RT-PCR. Paraffin-embedded tissues were also subjected to immunohistochemistry staining. We determined that a network of immune function genes involved in B cell development, interferon signaling associated with allograft rejection and autoimmune reaction, antigen presentation pathway, and cross talk between adaptive and innate immune responses were exclusively upregulated in patients with relapse-free survival. Among the 299 genes, five genes which included B cell response genes were found to predict with >85% accuracy relapse-free survival. Real-time RT-PCR confirmed the 5-gene prognostic signature that was distinct from an FDA-cleared 70-gene signature of MammaPrint panel and from the Oncotype DX recurrence score assay panel. These data suggest that neoadjuvant immunotherapy in patients with high risk of relapse may reduce tumor recurrence by inducing the immune function genes.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Onitilo AA, Engel JM, Greenlee RT, Mukesh BN (2009) Breast cancer subtypes based on ER/PR and Her2 expression: comparison of clinicopathologic features and survival. Clin Med Res 7:4–13

    Article  PubMed  CAS  Google Scholar 

  2. van ‘t Veer LJ, Dai H, van de Vijver MJ, He YD, Hart AA, Mao M, Peterse HL, van der Kooy K, Marton MJ, Witteveen AT, Schreiber GJ, Kerkhoven RM, Roberts C, Linsley PS, Bernards R, Friend SH (2002) Gene expression profiling predicts clinical outcome of breast cancer. Nature 415:530–536

    Article  PubMed  Google Scholar 

  3. van de Vijver MJ, He YD, van’t Veer LJ, Dai H, Hart AA, Voskuil DW, Schreiber GJ, Peterse JL, Roberts C, Marton MJ, Parrish M, Atsma D, Witteveen A, Glas A, Delahaye L, van der Velde T, Bartelink H, Rodenhuis S, Rutgers ET, Friend SH, Bernards R (2002) A gene-expression signature as a predictor of survival in breast cancer. N Engl J Med 347:1999–2009

    Article  PubMed  Google Scholar 

  4. Wang Y, Klijn JG, Zhang Y, Sieuwerts AM, Look MP, Yang F, Talantov D, Timmermans M, Meijer-van Gelder ME, Yu J, Jatkoe T, Berns EM, Atkins D, Foekens JA (2005) Gene-expression profiles to predict distant metastasis of lymph-node-negative primary breast cancer. Lancet 365:671–679

    PubMed  CAS  Google Scholar 

  5. Sørlie T, Perou CM, Tibshirani R, Aas T, Geisler S, Johnsen H, Hastie T, Eisen MB, van de Rijn M, Jeffrey SS, Thorsen T, Quist H, Matese JC, Brown PO, Botstein D, Eystein Lønning P, Børresen-Dale AL (2001) Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci U S A 98:10869–10874

    Article  PubMed  Google Scholar 

  6. Knauer M, Mook S, Rutgers EJ, Bender RA, Hauptmann M, van de Vijver MJ, Koornstra RH, Bueno-de-Mesquita JM, Linn SC, van ‘t Veer LJ (2010) The predictive value of the 70-gene signature for adjuvant chemotherapy in early breast cancer. Breast Cancer Res Treat 120:655–661

    Article  PubMed  CAS  Google Scholar 

  7. Cronin M, Sangli C, Liu ML, Pho M, Dutta D, Nguyen A, Jeong J, Wu J, Langone KC, Watson D (2007) Analytical validation of the Oncotype DX genomic diagnostic test for recurrence prognosis and therapeutic response prediction in node-negative, estrogen receptor-positive breast cancer. Clin Chem 53:1084–1091

    Article  PubMed  CAS  Google Scholar 

  8. Finak G, Bertos N, Pepin F, Sadekova S, Souleimanova M, Zhao H, Chen H, Omeroglu G, Meterissian S, Omeroglu A, Hallett M, Park M (2008) Stromal gene expression predicts clinical outcome in breast cancer. Nat Med 14:518–527

    Article  PubMed  CAS  Google Scholar 

  9. Pagès F, Berger A, Camus M, Sanchez-Cabo F, Costes A, Molidor R, Mlecnik B, Kirilovsky A, Nilsson M, Damotte D, Meatchi T, Bruneval P, Cugnenc PH, Trajanoski Z, Fridman WH, Galon J (2005) Effector memory T cells, early metastasis, and survival in colorectal cancer. N Engl J Med 353:2654–2666

    Article  PubMed  Google Scholar 

  10. Naito Y, Saito K, Shiiba K, Ohuchi A, Saigenji K, Nagura H, Ohtani H (1998) CD8+T cells infiltrated within cancer cell nests as a prognostic factor in human colorectal cancer. Cancer Res 58:3491–3494

    PubMed  CAS  Google Scholar 

  11. Ueno T, Toi M, Saji H, Muta M, Bando H, Kuroi K, Koike M, Inadera H, Matsushima K (2000) Significance of macrophage chemoattractant protein-1 in macrophage recruitment, angiogenesis, and survival in human breast cancer. Clin Cancer Res 6:3282–3289

    PubMed  CAS  Google Scholar 

  12. Rody A, Holtrich U, Pusztai L, Liedtke C, Gaetje R, Ruckhaeberle E, Solbach C, Hanker L, Ahr A, Metzler D, Engels K, Karn T, Kaufmann M (2009) T-cell metagene predicts a favorable prognosis in estrogen receptor-negative and HER2-positive breast cancers. Breast Cancer Res 11(2):R15

    Article  PubMed  Google Scholar 

  13. Worschech A, Kmieciak M, Knutson KL, Bear HD, Szalay AA, Wang E, Marincola FM, Manjili MH (2008) Signatures associated with rejection or recurrence in HER-2/neu-positive mammary tumors. Cancer Res 68:2436–2446

    Article  PubMed  CAS  Google Scholar 

  14. Wang E, Miller LD, Ohnmacht GA, Liu ET, Marincola FM (2000) High fidelity mRNA amplification. Nat Biotechnol 18:457–459

    Article  PubMed  CAS  Google Scholar 

  15. Wang E (2005) RNA amplification for successful gene profiling analysis. J Transl Med 3:28

    Article  PubMed  Google Scholar 

  16. Jin P, Zhao Y, Ngalame Y, Panelli MC, Nagorsen D, Monsurró V, Smith K, Hu N, Su H, Taylor PR, Marincola FM, Wang E (2004) Selection and validation of endogenous endogenous reference genes using a high throughput approach. BMC Genomics 5:55

    Article  PubMed  Google Scholar 

  17. Wang E, Miller LD, Ohnmacht GA, Mocellin S, Perez-Diez A, Petersen D, Zhao Y, Simon R, Powell JI, Asaki E, Alexander HR, Duray PH, Herlyn M, Restifo NP, Liu ET, Rosenberg SA, Marincola FM (2002) Prospective molecular profiling of subcutaneous melanoma metastases suggests classifiers of immune responsiveness. Cancer Res 62:3581–3586

    PubMed  CAS  Google Scholar 

  18. Simon R, Lam A, Li MC, Ngan M, Menenzes S, Zhao Y (2007) Analysis of gene expression data using BRB-array tools. Cancer Inform 3:11–17

    PubMed  Google Scholar 

  19. Boyman O, Hefti HP, Conrad C, Nickoloff BJ, Suter M, Nestle FO (2004) Spontaneous development of psoriasis in a new animal model shows an essential role for resident T cells and tumor necrosis factor. J Exp Med 199:731–736

    Article  PubMed  CAS  Google Scholar 

  20. Dominguez F, Martínez S, Quiñonero A, Loro F, Horcajadas JA, Pellicer A, Simón C (2008) CXCL10 and IL-6 induce chemotaxis in human trophoblast cell lines. Mol Hum Reprod 14:423–430

    Article  PubMed  CAS  Google Scholar 

  21. Sun W, Xu W, Snyder M, He W, Ho H, Ivashkiv LB, Zhang JJ (2005) The conserved leu-724 residue is required for both serine phosphorylation and co-activator recruitment for stat1-mediated transcription activation in response to interferon-γ. J Biol Chem 280:41844–41851

    Article  PubMed  CAS  Google Scholar 

  22. Lundmark F, Duvefelt K, Iacobaeus E, Kockum I, Wallström E, Khademi M, Oturai A, Ryder LP, Saarela J, Harbo HF, Celius EG, Salter H, Olsson T, Hillert J (2007) Variation in interleukin 7 receptor alpha chain (IL7R) influences risk of multiple sclerosis. Nat Genet 39:1108–1113

    Article  PubMed  CAS  Google Scholar 

  23. Morales JK, Kmieciak M, Graham L, Feldmesser M, Bear HD, Manjili MH (2009) Adoptive transfer of HER2/neu-specific T cells expanded with alternating gamma chain cytokines mediate tumor regression when combined with the depletion of myeloid-derived suppressor cells. Cancer Immunol Immunother 58:941–953

    Article  PubMed  CAS  Google Scholar 

  24. Morales JK, Kmieciak M, Knutson KL, Bear HD, Manjili MH (2010) GM-CSF is one of the main breast tumor-derived soluble factors involved in the differentiation of CD11b-Gr1- bone marrow progenitor cells into myeloid-derived suppressor cells. Breast Cancer Res Treat 123:39–49

    Article  PubMed  CAS  Google Scholar 

  25. Le HK, Graham L, Cha E, Morales JK, Manjili MH, Bear HD (2009) Gemcitabine directly inhibits myeloid derived suppressor cells in BALB/c mice bearing 4T1 mammary carcinoma and augments expansion of T cells from tumor-bearing mice. Int Immunopharmacol 9:900–909

    Article  PubMed  CAS  Google Scholar 

  26. Vincent J, Mignot G, Chalmin F, Ladoire S, Bruchard M, Chevriaux A, Martin F, Apetoh L, Rébé C, Ghiringhelli F (2010) 5-Fluorouracil selectively kills tumor-associated myeloid-derived suppressor cells resulting in enhanced T cell-dependent antitumor immunity. Cancer Res 70:3052–3061

    Article  PubMed  CAS  Google Scholar 

  27. Lechner MG, Liebertz DJ, Epstein AL (2010) Characterization of cytokine-induced myeloid-derived suppressor cells from normal human peripheral blood mononuclear cells. J Immunol 185:2273–2284

    Article  PubMed  CAS  Google Scholar 

  28. Krathwohl MD, Anderson JL (2006) Chemokine CXCL10 (IP-10) is sufficient to trigger an immune response to injected antigens in a mouse model. Vaccine 24:2987–2993

    Article  PubMed  CAS  Google Scholar 

  29. Naschberger E, Croner RS, Merkel S, Dimmler A, Tripal P, Amann KU, Kremmer E, Brueckl WM, Papadopoulos T, Hohenadl C, Hohenberger W, Stürzl M (2008) Angiostatic immune reaction in colorectal carcinoma: impact on survival and perspectives for antiangiogenic therapy. Int J Cancer 123:2120–2129

    Article  PubMed  CAS  Google Scholar 

  30. Thomas M, Finnegan CE, Rogers KM, Purcell JW, Trimble A, Johnston PG, Boland MP (2004) STAT1: a modulator of chemotherapy-induced apoptosis. Cancer Res 64:8357–8364

    Article  PubMed  CAS  Google Scholar 

  31. Khodarev NN, Roach P, Pitroda SP, Golden DW, Bhayani M, Shao MY, Darga TE, Beveridge MG, Sood RF, Sutton HG, Beckett MA, Mauceri HJ, Posner MC, Weichselbaum RR (2009) STAT1 pathway mediates amplification of metastatic potential and resistance to therapy. PLoS One 4:e5821

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

This study was supported by NIH R01 CA104757 Grant (M. H. Manjili), Massey Cancer Center Pilot Project Program 2006FPP-04 (M. H. Manjili), and VCU Technology Transfer Fund. We gratefully acknowledge the support of VCU Massey Cancer Center and the Commonwealth Foundation for Cancer Research. We thank Dr. K. Najarian for his review of the statistical analysis.

Author information

Authors and Affiliations

  1. Infectious Disease and Immunogenetics Section (IDIS), Department of Transfusion Medicine and Center for Human Immunology, National Institutes of Health, Bethesda, MD, 20892, USA

    Maria Libera Ascierto, Ena Wang & Francesco M. Marincola

  2. Department of Microbiology & Immunology, Virginia Commonwealth University Massey Cancer Center, Richmond, VA, 23298, USA

    Maciej Kmieciak, Rose Manjili & Masoud H. Manjili

  3. Department of Pathology, Virginia Commonwealth University Massey Cancer Center, Richmond, VA, 23298, USA

    Michael O. Idowu, Margaret Grimes & Catherine Dumur

  4. Division of Cancer Treatment and Diagnosis, National Institutes of Health, Bethesda, MD, 20892, USA

    Yingdong Zhao

  5. Department of Biostatistics, Virginia Commonwealth University Massey Cancer Center, Richmond, VA, 23298, USA

    Viswanathan Ramakrishnan

  6. Department of Human and Molecular Genetics, Virginia Commonwealth University Massey Cancer Center, Richmond, VA, 23298, USA

    Xiang-Yang Wang

  7. Department of Surgery, Virginia Commonwealth University Massey Cancer Center, Richmond, VA, 23298, USA

    Harry D. Bear

Authors
  1. Maria Libera Ascierto
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Maciej Kmieciak
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Michael O. Idowu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Rose Manjili
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yingdong Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Margaret Grimes
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Catherine Dumur
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Ena Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Viswanathan Ramakrishnan
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Xiang-Yang Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Harry D. Bear
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Francesco M. Marincola
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Masoud H. Manjili
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Masoud H. Manjili.

Additional information

Maria Libera Ascierto and Maciej Kmieciak equally contributed to this study.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOC 43 kb)

Supplementary material 2 (DOCX 23 kb)

Supplementary material 3 (DOCX 12 kb)

10549_2011_1470_MOESM4_ESM.ppt

Supplementary Fig. 1. Significant pathways at the nominal 0.001 level of the unpaired Student’s t test. a B cell development, b antigen presentation, c GVHD signaling, d interferon signaling, and e primary immunodeficiency signaling. (PPT 532 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ascierto, M.L., Kmieciak, M., Idowu, M.O. et al. A signature of immune function genes associated with recurrence-free survival in breast cancer patients. Breast Cancer Res Treat 131, 871–880 (2012). https://doi.org/10.1007/s10549-011-1470-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10549-011-1470-x

Keywords

Search

Navigation