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Loss of Anti-HER-3 CD4+ T-Helper Type 1 Immunity Occurs in Breast Tumorigenesis and is Negatively Associated with Outcomes

  • Breast Oncology
  • Published:
Annals of Surgical Oncology Aims and scope Submit manuscript

Abstract

Background

We previously demonstrated a progressive loss of the anti-human epidermal growth factor receptor 2 (HER2) CD4+ T-helper type 1 (Th1) response during HER2pos breast tumorigenesis. This loss is associated with residual disease following neoadjuvant therapy and increased risk of recurrence. In this study, we assessed the fate of anti-HER3 Th1 immunity during breast tumorigenesis.

Methods

Peripheral blood from 131 subjects, including healthy donors (HDs), patients with benign breast disease (BD), ductal carcinoma in situ (DCIS) and invasive breast cancer (IBC), was collected. Interferon (IFN)-γpos immune responses to four HER3-derived major histocompatibility complex (MHC) class II promiscuous peptides were tested via enzyme-linked immunosorbent (ELISPOT) assays, and three immune response parameters were compared: anti-HER3 (i) responsivity, or proportion of subjects responding to at least one peptide; (ii) repertoire, or number of responding peptides; and (iii) cumulative response, or summed peptide response.

Results

A significant decline in anti-HER3 Th1 response was observed going from HDs to IBC patients; patients with triple-negative breast cancer (TNBC) demonstrated the lowest responses. HDs had significantly higher Th1 responses versus estrogen receptor (ER)pos IBC and TNBC patients across all three immune parameters; HER2pos IBC patients displayed responses similar to HDs and BDs. Patients with recurrent breast cancer and residual disease following neoadjuvant therapy demonstrated significantly lower anti-HER3 Th1 immunity compared with patients without recurrence or with a pathologic complete response to neoadjuvant therapy.

Conclusions

Anti-HER3 CD4+ Th1 responses decline during breast tumorigenesis, particularly in TNBC. Attempts to immunologically restore depressed responses in vulnerable subgroups may help mitigate recurrence.

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References

  1. Smigal C, Jemal A, Ward E, Cokkinides V, Smith R, Howe H, et al. Trends in breast cancer by race and ethnicity: update 2006. CA Cancer J Clin. 2006;56(3):168–83.

    Article  PubMed  Google Scholar 

  2. Wang GS, Zhu H, Bi SJ. Pathological features and prognosis of different molecular subtypes of breast cancer. Mol Med Rep. 2012;6(4);779–82.

    PubMed  Google Scholar 

  3. Giordano SH, Temin S, Kirshner JJ, et al. Systemic therapy for patients with advanced human epidermal growth factor receptor 2-positive breast cancer: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol. 2014;32(19):2078–99.

    Article  CAS  PubMed  Google Scholar 

  4. Datta J, Rosemblit C, Berk E, et al. Progressive loss of anti-HER2 CD4+ T-helper type 1 response in breast tumorigenesis and the potential for immune restoration. Oncoimmunology. 2015;4(10):e1022301. Ecollection 2015 Oct

    Article  PubMed  PubMed Central  Google Scholar 

  5. Datta J, Berk E, Xu S, Fitzpatrick E, Rosemblit C, Lowenfeld L, et al. Anti-HER2 CD4+ T-helper type 1 response is a novel immune correlate to pathologic response following neoadjuvant therapy in HER2-positive breast cancer. Breast Cancer Res. 2015; 17:71.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Datta J, Fracol M, McMillan MT, Berk E, Xu S, Goodman N, et al. Association of depressed anti-HER2 T-helper type 1 response with recurrence in patients with completely treated HER2-positive breast cancer: role for immune monitoring. JAMA Oncol. 2016; 2(2):242–6.

    Article  PubMed  Google Scholar 

  7. Sharma A, Koldovsky U, Xu S, et al. HER-2 pulsed dendritic cell vaccine can eliminate HER-2 expression and impact DCIS. Cancer. 2012;118(17):4354–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Koski GK, Koldovsky U, Xu S, Mick R, Sharma A, Fitzpatrick E, et al. A novel dendritic cell-based immunization approach for the induction of durable Th1-polarized anti-HER-2/neu responses in women with early breast cancer. J Immunother. 2012;35(1):54–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Czopek J, Pawlega J, Fijorek K, Puskulluoglu M, Rozanowski P, Okori K. HER-3 expression in HER-2-amplified breast carcinoma. Contemp Oncol. 2013;17(5):446–9.

    CAS  Google Scholar 

  10. Bae SY, La Choi Y, Kim S, et al. HER-3 status by immunohistochemistry is correlated with poor prognosis in hormone receptor-negative breast cancer patients. Breast Cancer Res Treat. 2013;139(3):741–50.

    Article  CAS  PubMed  Google Scholar 

  11. Jhaveri K, Esteva FJ. Pertuzumab in the treatment of HER-2+ breast cancer. J Natl Compr Canc Netw. 2014;12(4):591–8.

    CAS  PubMed  Google Scholar 

  12. Harbeck N, Beckmann MW, Rody A, et al. HER-2 dimerization inhibitor pertuzumab- mode of action and clinical data in breast cancer. Breast Care. 2013;8(1):49–55.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Giltnane JM, Moeder C, Camp RL, Rimm D. Quantitative multiplexed analysis of ErbB family coexpression for primary breast cancer prognosis in a large retrospective cohort. Cancer. 2009:115(11):2400–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Bae SY, Choi YL, Kim S, Kim M, Kim J, Yung SP, et al. Her-3 status by immunohistochemistry is correlated with poor-prognosis in hormone receptor-negative breast cancer patients. Breast Cancer Res Treat. 2013;139:741–750.

    Article  CAS  PubMed  Google Scholar 

  15. Karamouzis M, Dalagiorgou G, Georgopoulou U, Nonni A, Kontos M, Papvassiliou A. HER-3 targeting alters the dimerization pattern of ErbB protein family members in breast carcinomas. Oncotarget. 2015;7(5):5576–97.

    PubMed Central  Google Scholar 

  16. Moi L, Flageng M, Gjerde J, Madsen A, Rost T, Gudbrandsen O, et al. Steroid receptor coactivators, HER-2 and HER-3 expression is stimulated by tamoxifen treatment in DMBA-induced breast cancer. BMC Cancer. 2012;12:247.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Datta J, Xu S, Terhune JH, Rosemblit C, Berk E, Fitzpatrick E, et al. Novel strategy to identify MHC class II-promiscuous CD4+ peptides from tumor antigens for utilization in vaccination [abstract]. J Immunother Cancer. 2014;2 Suppl 3:P47.

    Article  PubMed Central  Google Scholar 

  18. Boshoff C, Weiss R. AIDS-related malignancies. Nature Rev Cancer. 2002:2;373–82.

    Google Scholar 

  19. Sheil AG. Cancer after transplantation. World J Surg. 1986;10:389–96.

    Article  CAS  PubMed  Google Scholar 

  20. Penn I. Malignant melanoma in organ allograft recipients.Transplantation. 1996;61:274–8.

    Article  CAS  PubMed  Google Scholar 

  21. Penn, I. Sarcomas in organ allograft recipients. Transplantation. 1995;60:1485–91.

    Article  CAS  PubMed  Google Scholar 

  22. Alokail MS, Al-Daghri NM, Mohammed AK, Vanhoutte P, Alenad A. Increased TNF alpha, IL-6 and ErbB2 mRNA expression in peripheral blood leukocytes from breast cancer patients. Med Oncol. 2014;31:38.

    Article  PubMed  Google Scholar 

  23. Jia Y, Xu L, Lin Q, Zhu M, Ding L, Wu K, et al.. Levels of lymphocyte subsets in peripheral blood prior to treatment are associated with aggressive breast cancer phenotypes or subtypes. Med Oncol. 2014;31:981.

    Article  PubMed  Google Scholar 

  24. Matsumoto H, Koo S, Dent R, Tan PH, Iqbal J. Role of inflammatory infiltrates in triple negative breast cancer. J Clin Pathol. 2015;68(7):506–10.

    Article  CAS  PubMed  Google Scholar 

  25. Schmidt G, Meyberg-Solomayer G, Gerlinger C, Juhasz-Boss I, Herr D, Rody A, et al. Identification of prognostic different subgroups in triple negative breast cancer by HER2-neu protein expression. Arch Gynecol Obstet. 2014;290:1221–9.

    Article  CAS  PubMed  Google Scholar 

  26. Li Q, Yuan Z, Cao B. The function of human epidermal growth factor receptor-3 and its role in tumors. Oncol Rep. 2013;30:2563–70.

    CAS  PubMed  Google Scholar 

  27. Smirnova T, Zhou ZN, Flinn RJ, et al. Phosphoinositide 3-kinase signaling is critical for ErbB3-driven breast cancer cell motility and metastasis. Oncogene. 2012;31: 706–15.

    Article  CAS  PubMed  Google Scholar 

  28. Ocana A, Vera-Badillo F, Seruga B, Templeton A, Pandiella A, Amir E. HER3 overexpression and survival in solid tumors: a meta-analysis. J Natl Cancer Inst. 2013;105(4):266–73.

    Article  CAS  PubMed  Google Scholar 

  29. Dunn GP, Bruce AT, Ikeda H, Old LJ, Schreiber RD. Cancer immunoediting: from immune-surveillance to tumor escape. Nat Immunol. 2002;3(11):991–8.

    Article  CAS  PubMed  Google Scholar 

  30. Idirisinghe PKA, Thike AA, Cheok PY, Tse GM, Lui PC, Fook-Chong S, et al. Hormone receptor and c-ERBB2 status in distant metastatic and locally recurrent breast cancer. Am J Clin Pathol. 2010;133:416–29.

    Article  PubMed  Google Scholar 

  31. Broom RJ, Tang PA, Simmons C, Bordeleau L, Mulligan AM, O’Malley FP, et al. Changes in estrogen receptor, progesterone receptor and HER-2/neu status with time: discordance rates between primary and metastatic breast cancer. Anticancer Res. 2009;29:1557–62.

    PubMed  Google Scholar 

  32. Liedtke C, Broglio K, Moulder S, Hsu L, Kau SW, Symmans WF, et al. Prognostic impact of discordance between triple-receptor measurements in primary and recurrent breast cancer. Ann Oncol. 2009;20:1953–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Sergina NV, Rausch M, Wang D, et al. Escape from HER-family tyrosine kinase inhibitor therapy by the kinase-inactive HER3. Nature. 2007;445:437–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Frogne T, Benjaminsen RV, Sonne-Hansen K, et al. Activation of ErbB3, EGFR and Erk is essential for growth of human breast cancer cell lines with acquired resistance to fulvestrant. Breast Cancer Res Treat. 2009;114:263–75.

    Article  CAS  PubMed  Google Scholar 

  35. Press MF, Cordon-Cardo C, Slamon DJ. Expression of the HER-2/neu proto- oncogene in normal human adult and fetal tissues. Oncogene. 1990;5:953–62.

    CAS  PubMed  Google Scholar 

  36. Clendenen TV, Kim S, Moy L, Wan L, Rusinek H, Stanczyk FZ, et al. Magnetic resonance imaging (MRI) of hormone-induced breast changes in young premenopausal women. Magn Reson Imaging. 2013;31:1–9.

    Article  CAS  PubMed  Google Scholar 

  37. Howlader N, Altekruse SF, Li CI, Chen VW, Clarke CA, Ries L, et al. US incidence of breast cancer subtypes defined by joint hormone receptor and HER2 status. J Natl Cancer Inst. 2014;106(5):1–8.

    Article  Google Scholar 

  38. Aapro M, Wildiers H. Triple negative breast cancer in the older population. Ann Oncol. 2012;23(6):vi52–5.

    PubMed  Google Scholar 

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Acknowledgment

Financial support for this project was made possible by a Bertha Dagan Berman FOCUS Fellowship grant and Pennies-in-Action® (www.pennies-in-action.org).

Conflict of interest

Megan Fracol, Jashodeep Datta, Lea Lowenfeld, Shuwen Xu, Paul J. Zhang, Carla S. Fisher, and Brian J. Czerniecki have no conflict of interest to declare.

Author information

Authors and Affiliations

  1. Harrison Department of Surgical Research, Hospital of the University of Pennsylvania, Philadelphia, PA, USA

    Megan Fracol MD, Jashodeep Datta MD, Lea Lowenfeld MD, Shuwen Xu MD, Carla S. Fisher MD & Brian J. Czerniecki MD, PhD

  2. Department of Pathology, Hospital of the University of Pennsylvania, Philadelphia, PA, USA

    Paul J. Zhang MD

  3. Rena Rowen Breast Center, Hospital of the University of Pennsylvania, Philadelphia, PA, USA

    Carla S. Fisher MD & Brian J. Czerniecki MD, PhD

  4. Department of Breast Oncology, Moffitt Cancer Center, Tampa, FL, USA

    Brian J. Czerniecki MD, PhD

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  1. Megan Fracol MD
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  4. Shuwen Xu MD
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  7. Brian J. Czerniecki MD, PhD
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Correspondence to Brian J. Czerniecki MD, PhD.

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Fracol, M., Datta, J., Lowenfeld, L. et al. Loss of Anti-HER-3 CD4+ T-Helper Type 1 Immunity Occurs in Breast Tumorigenesis and is Negatively Associated with Outcomes. Ann Surg Oncol 24, 407–417 (2017). https://doi.org/10.1245/s10434-016-5584-6

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  • DOI: https://doi.org/10.1245/s10434-016-5584-6

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