Skip to main content

Advertisement

SpringerLink
Log in

Indicators of a pro-tumor immune response are evident at early stages of breast cancer

  • Review Article
  • Published:
Clinical and Translational Oncology Aims and scope Submit manuscript

Abstract

With advances in checkpoint inhibitor and CAR T-cell therapies, among other advances in immunotherapy, this is an exciting time to be a tumor immunologist. We are witnessing the transition of decades of work at the bench leading to substantial success in the clinic. While work continues developing new and improving existing immunotherapies, there remains a great deal of basic tumor immunology still to learn, information that can only lead to greater success in the clinic. One area in need of more attention is understanding the immune response at early stages of breast cancer. While there is no question that early diagnosis and treatment save lives, a greater understanding about the immune response during early stages of breast cancer may reveal information that could assist in monitoring individuals at risk of breast cancer, and could have implications for patients diagnosed at early stages of disease, and may provide important information about the origins of an immune-suppressive environment. Here, we review studies that have looked at the very early immune response to breast cancer focusing on patients with DCIS, before invasion in spontaneous transgenic murine mammary carcinoma models, and before transplantable or orthotopic murine mammary carcinoma models become palpable. The findings revealed that indicators of a pro-tumor immune response are already present at early stages of disease.

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

Similar content being viewed by others

References

  1. Gwak JM, Jang MH, Kim DI, Seo AN, Park SY. Prognostic value of tumor-associated macrophages according to histologic locations and hormone receptor status in breast cancer. PLoS ONE. 2015;10:4. https://doi.org/10.1371/journal.pone.0125728.

    Article  CAS  Google Scholar 

  2. Yuan ZY, Luo RZ, Peng RJ, Wang SS, Xue C. High infiltration of tumor-associated macrophages in triple negative breast cancer is associated with a higher risk of distant metastasis. Onco Targets Ther. 2014;7:1475–80. https://doi.org/10.2147/OTT.S61838.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Illemann M, Laerum OD, Hasselby JP, Thurison T, Hoyer-Hansen G, et al. Urokinase-type plasminogen activator receptor (uPAR) on tumor-associated macrophages is a marker of poor prognosis in colorectal cancer. Cancer Med. 2014;3:855–64. https://doi.org/10.1002/cam4.242.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Gollapudi K, Galet C, Grogan T, Zhang H, Said JW, et al. Association between tumor-associated macrophage infiltration, high grade prostate cancer, and biochemical recurrence after radical prostatectomy. Am J Cancer Res. 2013;3:523–9.

    PubMed  PubMed Central  Google Scholar 

  5. Zhao X, Qu J, Sun Y, Wang J, Liu X, et al. Prognostic significance of tumor-associated macrophages in breast cancer: a meta-analysis of the literature. Oncotarget. 2017;8:30576–86. https://doi.org/10.18632/oncotarget.15736.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Santoni M, Romagnoli E, Saladino T, Foghini L, Guarino S, et al. Triple negative breast cancer: key role of tumor-associated macrophages in regulating the activity of anti-PD-1/PD-L1 agents. Biochim Biophys Acta. 2018;1869:78–84. https://doi.org/10.1016/j.bbcan.2017.10.007.

    Article  CAS  Google Scholar 

  7. Arlauckas SP, Garris CS, Kohler RH, Kitaoka M, Cuccarese MF, et al. In vivo imaging reveals a tumor-associated macrophage-mediated resistance pathway in anti-PD-1 therapy. Sci Transl Med. 2017. https://doi.org/10.1126/scitranslmed.aal3604.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Cassetta L, Kitamura T. Targeting tumor-associated macrophages as a potential strategy to enhance the response to immune checkpoint inhibitors. Front Cell Dev Biol. 2018. https://doi.org/10.3389/fcell.2018.00038.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Gudewicz PW, Saba TM. Inhibition of phagocytosis and glucose metabolism of alveolar macrophages during pulmonary tumour growth. Br J Cancer. 1977;36:670–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Carron EC, Homra S, Rosenberg J, Coffelt SB, Kittrell F, et al. Macrophages promote the progression of premalignant mammary lesions to invasive cancer. Oncotarget. 2017;8:50731–46.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Zhang C, Adusei M, Baranovic A, DeBenedetto M, Lauricella A, et al. Analysis of macrophages and neutrophils infiltrating murine mammary carcinoma sites within hours of tumor delivery. Cell Immunol. 2019. https://doi.org/10.1016/j.cellimm.2019.103929.

    Article  PubMed  Google Scholar 

  12. McKee GT, Tildsley G, Hammond S. Cytologic diagnosis and grading of ductal carcinoma in situ. Cancer. 1999;87:203–9.

    Article  CAS  PubMed  Google Scholar 

  13. Lee AH, Happerfield LC, Bobrow LG, Millis RR. Angiogenesis and inflammation in ductal carcinoma in situ of the breast. J Pathol. 1997;181:200–6.

    Article  CAS  PubMed  Google Scholar 

  14. Sharma M, Beck AH, Webster JA, Espinosa I, Montgomery K, Varma S, van de Rijn M, Jensen KC, West RB. Analysis of stromal signatures in the tumor microenvironment of ductal carcinoma in situ. Breast Cancer Res Treat. 2010;123:397–404. https://doi.org/10.1007/s10549-009-0654-0.

    Article  CAS  PubMed  Google Scholar 

  15. Stanley ER, Chitu V. CSF-1 receptor signaling in myeloid cells. Cold Spring Harb Perspect Biol. 2014. https://doi.org/10.1101/cshperspect.a021857.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Campbell MJ, Baehner F, O'Meara T, Ojukwu E, Han B, Mukhtar R, Tandon V, Endicott M, Zhu Z, Wong J, Krings G, Au A, Gray JW, Esserman L. Characterizing the immune microenvironment in high-risk ductal carcinoma in situ of the breast. Breast Cancer Res Treat. 2017;161:17–28. https://doi.org/10.1007/s10549-016-4036-0.

    Article  CAS  PubMed  Google Scholar 

  17. Thompson E, Taube JM, Elwood H, Sharma R, Meeker A, Warzecha HN, Argani P, Cimino-Mathews A, Emens LA. The immune microenvironment of breast ductal carcinoma in situ. Mod Pathol. 2016;29:249–58. https://doi.org/10.1038/modpathol.2015.158.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Degnim AC, Hoskin TL, Arshad M, Frost MH, Winham SJ, Brahmbhatt RA, Pena A, Carter JM, Stallings-Mann ML, Murphy LM, Miller EE, Denison LA, Vachon CM, Knutson KL, Radisky DC, Visscher DW. Alterations in the immune cell composition in premalignant breast tissue that precede breast cancer development. Clin Cancer Res. 2017;23:3945–52. https://doi.org/10.1158/1078-0432.CCR-16-2026.

    Article  CAS  PubMed  Google Scholar 

  19. Hussein MR, Hassan HI. Analysis of the mononuclear inflammatory cell infiltrate in the normal breast, benign proliferative breast disease, in situ and infiltrating ductal breast carcinomas: preliminary observations. J Clin Pathol. 2006;59:972–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Gyorki DE, Asselin-Labat ML, van Rooijen N, Lindeman GJ, Visvader JE. Resident macrophages influence stem cell activity in the mammary gland. Breast Cancer Res. 2009. https://doi.org/10.1186/bcr2353.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Gouon-Evans V, Lin EY, Pollard JW. Requirement of macrophages and eosinophils and their cytokines/chemokines for mammary gland development. Breast Cancer Res. 2002;4:155–64. https://doi.org/10.1186/bcr441.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Schwertfeger KL, Rosen JM, Cohen DA. Mammary gland macrophages: pleiotropic functions in mammary development. J Mammary Gland Biol Neoplasia. 2006;11:229–38. https://doi.org/10.1007/s10911-006-9028-y.

    Article  PubMed  Google Scholar 

  23. Lin EY, Jones JG, Li P, Zhu L, Whitney KD, Muller WJ, Pollard JW. Progression to malignancy in the polyoma middle T oncoprotein mouse breast cancer model provides a reliable model for human diseases. Am J Pathol. 2003;163:2113–266.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Lin EY, Nguyen AV, Russell RG, Pollard JW. Colony-stimulating factor 1 promotes progression of mammary tumors to malignancy. J Exp Med. 2001;193:727–39.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Wang S, Yuan Y, Liao L, Kuang SQ, Tien JC, O'Malley BW, Xu J. Disruption of the SRC-1 gene in mice suppresses breast cancer metastasis without affecting primary tumor formation. Proc Natl Acad Sci USA. 2009;106:151–6. https://doi.org/10.1073/pnas.0808703105.

    Article  PubMed  Google Scholar 

  26. Strachan DC, Ruffell B, Oei Y, Bissell MJ, Coussens LM, Pryer N, Daniel D. CSF1R inhibition delays cervical and mammary tumor growth in murine models by attenuating the turnover of tumor-associated macrophages and enhancing infiltration by CD8+ T cells. Oncoimmunology. 2013. https://doi.org/10.4161/onci.26968.

    Article  PubMed  PubMed Central  Google Scholar 

  27. DeNardo DG, Barreto JB, Andreu P, Vasquez L, Tawfik D, Kolhatkar N, Coussens LM. CD4(+) T cells regulate pulmonary metastasis of mammary carcinomas by enhancing protumor properties of macrophages. Cancer Cell. 2009;16:91–102. https://doi.org/10.1016/j.ccr.2009.06.018.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Kirma N, Luthra R, Jones J, Liu YG, Nair HB, Mandava U, Tekmal RR. Overexpression of the colony-stimulating factor (CSF-1) and/or its receptor c-fms in mammary glands of transgenic mice results in hyperplasia and tumor formation. Cancer Res. 2004;64:4162–70.

    Article  CAS  PubMed  Google Scholar 

  29. Schwertfeger KL, Xian W, Kaplan AM, Burnett SH, Cohen DA, Rosen JM. A critical role for the inflammatory response in a mouse model of preneoplastic progression. Cancer Res. 2006;66:5676–85. https://doi.org/10.1158/0008-5472.

    Article  PubMed  Google Scholar 

  30. Bohrer LR, Schwertfeger KL. Macrophages promote fibroblast growth factor receptor-driven tumor cell migration and invasion in a CXCR2-dependent manner. Mol Cancer Res. 2012;10:1294–305. https://doi.org/10.1158/15417786.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Campbell KM, O'Leary KA, Rugowski DE, Mulligan WA, Barnell EK, Skidmore ZL, Krysiak K, Griffith M, Schuler LA, Griffith OL. A spontaneous aggressive ERα+ mammary tumor model is driven by Kras activation. Cell Rep. 2019;28:1526–37. https://doi.org/10.1016/j.celrep.2019.06.098.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Balogh KN, Templeton DJ, Cross JV. Macrophage migration inhibitory factor protects cancer cells from immunogenic cell death and impairs anti-tumor immune responses. PLoS ONE. 2018;13(6):e0197702. https://doi.org/10.1371/journal.pone.0197702.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Luo Y, Zhou H, Krueger J, Kaplan C, Lee SH, Dolman C, Markowitz D, Wu W, Liu C, Reisfeld RA, Xiang R. Targeting tumor-associated macrophages as a novel strategy against breast cancer. J Clin Invest. 2006;116:2132–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Steenbrugge J, Breyne K, Demeyere K, De Wever O, Sanders NN, Van Den Broeck W, Colpaert C, Vermeulen P, Van Laere S, Meyer E. Anti-inflammatory signaling by mammary tumor cells mediates prometastatic macrophage polarization in an innovative intraductal mouse model for triple-negative breast cancer. J Exp Clin Cancer Res. 2018;37(1):191. https://doi.org/10.1186/s13046-018-0860-x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Bunt SK, Yang L, Sinha P, Clements VK, Leips J, Ostrand-Rosenberg S. Reduced inflammation in the tumor microenvironment delays the accumulation of myeloid-derived suppressor cells and limits tumor progression. Cancer Res. 2007;67:10019–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Matory YL, Dorfman DM, Chen M, Wu L, Spanjaard RA, Goedegebuure PS, Eberlein TJ. T cells mediate treatment of six-day-old cytokine-gene-transfected mouse mammary tumor. Pathobiology. 1999;67:3–11.

    Article  CAS  PubMed  Google Scholar 

  37. Stewart CC, Beetham KL. Cytocidal activity and proliferative ability of macrophages infiltrating the EMT6 tumor. Int J Cancer. 1978;22:152–9.

    Article  CAS  PubMed  Google Scholar 

  38. Akporiaye ET, Stewart SJ, Stevenson AP, Stewart CC. A gelatin sponge model for studying tumor growth: flow cytometric analysis and quantitation of leukocytes and tumor cells in the EMT6 mouse tumor. Cancer Res. 1985;45:6457–62.

    CAS  PubMed  Google Scholar 

  39. Stevenson AP, Martin JC, Stewart CC. Simultaneous measurements of macrophage-induced cytostasis and cytotoxicity of EMT6 cells by flow cytometry. Cancer Res. 1986;46:99–105.

    Article  CAS  PubMed  Google Scholar 

  40. Robinson SC, Scott KA, Wilson JL, Thompson RG, Proudfoot AE, Balkwill FR. A chemokine receptor antagonist inhibits experimental breast tumor growth. Cancer Res. 2003;63:8360–5.

    CAS  PubMed  Google Scholar 

  41. Musiani P, Allione A, Modica A, Lollini PL, Giovarelli M, Cavallo F, Belardelli F, Forni G, Modesti A. Role of neutrophils and lymphocytes in inhibition of a mouse mammary adenocarcinoma engineered to release IL-2, IL-4, IL-7, IL-10, IFN-alpha, IFN-gamma, and TNF-alpha. Lab Invest. 1996;74:146–57.

    CAS  PubMed  Google Scholar 

  42. Lu H, Clauser KR, Tam WL, Fröse J, Ye X, Eaton EN, Reinhardt F, Donnenberg VS, Bhargava R, Carr SA, Weinberg RA. A breast cancer stem cell niche supported by juxtacrine signaling from monocytes and macrophages. Nat Cell Biol. 2014;16:1105–17. https://doi.org/10.1038/ncb3041.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Ohl K, Tenbrock K. Reactive oxygen species as regulators of MDSC-mediated immune suppression. Front Immunol. 2018;9:2499. https://doi.org/10.3389/fimmu.2018.02499.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Roux C, Jafari SM, Shinde R, Duncan G, Cescon DW, Silvester J, Chu MF, Hodgson K, Berger T, Wakeham A, Palomero L, Garcia-Valero M, Pujana MA, Mak TW, McGaha TL, Cappello P, Gorrini C. Reactive oxygen species modulate macrophage immunosuppressive phenotype through the up-regulation of PD-L1. Proc Natl Acad Sci USA. 2019;116:4326–35. https://doi.org/10.1073/pnas.1819473116.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Cruceriu D, Baldasici O, Balacescu O, Berindan-Neagoe I. The dual role of tumor necrosis factor-alpha (TNF-α) in breast cancer: molecular insights and therapeutic approaches. Cell Oncol (Dordr). 2020;43:1–18. https://doi.org/10.1007/s13402-019-00489-1.

    Article  CAS  PubMed  Google Scholar 

  46. Gao Y, Yang Y, Yuan F, Huang J, Xu W, Mao B, Yuan Z, Bi W. TNFα-YAP/p65- HK2 axis mediates breast cancer cell migration. Oncogenesis. 2017;6(9):e383. https://doi.org/10.1038/oncsis.2017.83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors thank the librarians at the Skillman Library for assistance in obtaining the articles discussed in this review. Pulling together literature specifically focused the very early immune response to breast cancer proved challenging and we apologize to those whose manuscripts we have inadvertently overlooked in this review.

Author information

Authors and Affiliations

  1. Department of Molecular and Cellular Biology, University of California Berkeley, Berkeley, CA, 94720, USA

    C. Zhang

  2. Department Biology, Rockwell Integrated Science Center, Lafayette College, Easton, PA, 18042, USA

    R. A. Kurt

Authors
  1. C. Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. R. A. Kurt
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to R. A. Kurt.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

This article does not contain any studies with human participants or animals performed by the authors.

Informed consent

For this retrospective review formal consent is not required.

Additional information

Publisher's Note

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

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhang, C., Kurt, R.A. Indicators of a pro-tumor immune response are evident at early stages of breast cancer. Clin Transl Oncol 22, 2153–2161 (2020). https://doi.org/10.1007/s12094-020-02368-w

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12094-020-02368-w

Keywords

Search

Navigation