Tumor stromal type is associated with stromal PD-L1 expression and predicts outcomes in breast cancer

Autoři: Qinglian Zhai aff001;  Jiawen Fan aff002;  Qiulian Lin aff001;  Xia Liu aff001;  Jinting Li aff002;  Ruoxi Hong aff001;  Shusen Wang aff001
Působiště autorů: Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China aff001;  Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Molecular Oncology, Peking University Cancer Hospital & Institute, Beijing, China aff002
Vyšlo v časopise: PLoS ONE 14(10)
Kategorie: Research Article
doi: 10.1371/journal.pone.0223325



The aim of this study is to determine the relationship between stromal types, PD-L1 status and clinicopathological characteristics in patients with different molecular subtypes of breast cancer.

Materials and methods

Protein expression levels of PD-L1 were determined by immunohistochemistry assay. Stromal type was classified based on the maturity of the tumor stroma.


Different subtypes of breast cancer had distinct stromal types. Tumors from patients with mature stroma had lower pathological N stage and AJCC stage, more frequent high p53 expression and positive stromal PD-L1 staining. Hormone receptor negative patients had higher frequency of positive stromal PD-L1 staining. Stromal PD-L1 status was also associated with different breast cancer subtypes and EGFR expression level. Importantly, our data revealed that stromal types and stromal PD-L1 status were independent prognostic factors.


This study highlighted the importance of stromal types and stromal PD-L1 status in determining clinical outcomes in patients with breast cancer, and suggested that stromal type classification might be readily incorporated into routine clinical risk assessment following curative resection or optimal therapeutic design.

Klíčová slova:

Breast cancer – Cancer treatment – Collagens – Immune response – Immunohistochemistry techniques – Survival analysis – Clinical pathology – Fluorescent in situ hybridization


1. Shimoda M, Mellody KT, Orimo A. Carcinoma-associated fibroblasts are a rate-limiting determinant for tumour progression. Semin Cell Dev Biol. 2010;21(1):19–25. doi: 10.1016/j.semcdb.2009.10.002 19857592

2. Ahn S, Cho J, Sung J, Lee JE, Nam SJ, Kim KM, et al. The prognostic significance of tumor-associated stroma in invasive breast carcinoma. Tumour Biol. 2012;33(5):1573–80. doi: 10.1007/s13277-012-0411-6 22581521

3. Beck AH, Sangoi AR, Leung S, Marinelli RJ, Nielsen TO, van de Vijver MJ, et al. Systematic analysis of breast cancer morphology uncovers stromal features associated with survival. Sci Transl Med. 2011;3(108):108ra13.

4. Ueno H, Jones AM, Wilkinson KH, Jass JR, Talbot IC. Histological categorisation of fibrotic cancer stroma in advanced rectal cancer. Gut. 2004;53(4):581–6. doi: 10.1136/gut.2003.028365 15016755

5. Kauppila S, Stenback F, Risteli J, Jukkola A, Risteli L. Aberrant type I and type III collagen gene expression in human breast cancer in vivo. J Pathol. 1998;186(3):262–8. doi: 10.1002/(SICI)1096-9896(1998110)186:3<262::AID-PATH191>3.0.CO;2-3 10211114

6. Santa-Maria CA, Nanda R. Immune Checkpoint Inhibitor Therapy in Breast Cancer. J Natl Compr Canc Netw. 2018;16(10):1259–68. doi: 10.6004/jnccn.2018.7046 30323094

7. Emens LA. Breast cancer immunobiology driving immunotherapy: vaccines and immune checkpoint blockade. Expert Rev Anticancer Ther. 2012;12(12):1597–611. doi: 10.1586/era.12.147 23253225

8. Cimino-Mathews A, Foote JB, Emens LA. Immune targeting in breast cancer. Oncology (Williston Park). 2015;29(5):375–85. 25979549

9. Dong H, Zhu G, Tamada K, Chen L. B7-H1, a third member of the B7 family, co-stimulates T-cell proliferation and interleukin-10 secretion. Nat Med. 1999;5(12):1365–9. doi: 10.1038/70932 10581077

10. Dill EA, Gru AA, Atkins KA, Friedman LA, Moore ME, Bullock TN, et al. PD-L1 Expression and Intratumoral Heterogeneity Across Breast Cancer Subtypes and Stages: An Assessment of 245 Primary and 40 Metastatic Tumors. Am J Surg Pathol. 2017;41(3):334–42. doi: 10.1097/PAS.0000000000000780 28195880

11. Stovgaard ES, Dyhl-Polk A, Roslind A, Balslev E, Nielsen D. PD-L1 expression in breast cancer: expression in subtypes and prognostic significance: a systematic review. Breast Cancer Res Treat. 2019.

12. Zhang M, Sun H, Zhao S, Wang Y, Pu H, Wang Y, et al. Expression of PD-L1 and prognosis in breast cancer: a meta-analysis. Oncotarget. 2017;8(19):31347–54. doi: 10.18632/oncotarget.15532 28430626

13. Tawfik O, Kimler BF, Karnik T, Shehata P. Clinicopathological correlation of PD-L1 expression in primary and metastatic breast cancer and infiltrating immune cells. Hum Pathol. 2018;80:170–8. doi: 10.1016/j.humpath.2018.06.008 29936058

14. Gao Z, Wang C, Cui Y, Shen Z, Jiang K, Shen D, et al. Efficacy and Safety of Complete Mesocolic Excision in Patients With Colon Cancer: Three-year Results From a Prospective, Nonrandomized, Double-blind, Controlled Trial. Ann Surg. 2018.

15. Zhang W, Hong R, Xue L, Ou Y, Liu X, Zhao Z, et al. Piccolo mediates EGFR signaling and acts as a prognostic biomarker in esophageal squamous cell carcinoma. Oncogene. 2017;36(27):3890–902. doi: 10.1038/onc.2017.15 28263981

16. Press MF, Sauter G, Buyse M, Fourmanoir H, Quinaux E, Tsao-Wei DD, et al. HER2 Gene Amplification Testing by Fluorescent In Situ Hybridization (FISH): Comparison of the ASCO-College of American Pathologists Guidelines With FISH Scores Used for Enrollment in Breast Cancer International Research Group Clinical Trials. J Clin Oncol. 2016;34(29):3518–+. doi: 10.1200/JCO.2016.66.6693 27573653

17. Guiu S, Michiels S, Andre F, Cortes J, Denkert C, Di Leo A, et al. Molecular subclasses of breast cancer: how do we define them? The IMPAKT 2012 Working Group Statement. Ann Oncol. 2012;23(12):2997–3006. doi: 10.1093/annonc/mds586 23166150

18. de Kruijf EM, Bastiaannet E, Ruberta F, de Craen AJM, Kuppen PJK, Smit VTHBM, et al. Comparison of frequencies and prognostic effect of molecular subtypes between young and elderly breast cancer patients. Mol Oncol. 2014;8(5):1014–25. doi: 10.1016/j.molonc.2014.03.022 24767310

19. Huijbers IJ, Iravani M, Popov S, Robertson D, Al-Sarraj S, Jones C, et al. A role for fibrillar collagen deposition and the collagen internalization receptor endo180 in glioma invasion. PLoS One. 2010;5(3):e9808. doi: 10.1371/journal.pone.0009808 20339555

20. Mohammed ZM, Going JJ, Edwards J, Elsberger B, Doughty JC, McMillan DC. The relationship between components of tumour inflammatory cell infiltrate and clinicopathological factors and survival in patients with primary operable invasive ductal breast cancer. Br J Cancer. 2012;107(5):864–73. doi: 10.1038/bjc.2012.347 22878371

21. Dekker TJ, van de Velde CJ, van Pelt GW, Kroep JR, Julien JP, Smit VT, et al. Prognostic significance of the tumor-stroma ratio: validation study in node-negative premenopausal breast cancer patients from the EORTC perioperative chemotherapy (POP) trial (10854). Breast Cancer Res Treat. 2013;139(2):371–9. doi: 10.1007/s10549-013-2571-5 23709090

22. Tlsty TD, Hein PW. Know thy neighbor: stromal cells can contribute oncogenic signals. Curr Opin Genet Dev. 2001;11(1):54–9. doi: 10.1016/s0959-437x(00)00156-8 11163151

23. Lukashev ME, Werb Z. ECM signalling: orchestrating cell behaviour and misbehaviour. Trends Cell Biol. 1998;8(11):437–41. 9854310

24. Kim JB, Stein R, O'Hare MJ. Tumour-stromal interactions in breast cancer: the role of stroma in tumourigenesis. Tumour Biol. 2005;26(4):173–85. doi: 10.1159/000086950 16006771

25. Hu M, Polyak K. Microenvironmental regulation of cancer development. Curr Opin Genet Dev. 2008;18(1):27–34. doi: 10.1016/j.gde.2007.12.006 18282701

26. Cirri P, Chiarugi P. Cancer-associated-fibroblasts and tumour cells: a diabolic liaison driving cancer progression. Cancer Metastasis Rev. 2012;31(1–2):195–208. doi: 10.1007/s10555-011-9340-x 22101652

27. Chen IX, Chauhan VP, Posada J, Ng MR, Wu MW, Adstamongkonkul P, et al. Blocking CXCR4 alleviates desmoplasia, increases T-lymphocyte infiltration, and improves immunotherapy in metastatic breast cancer. Proc Natl Acad Sci U S A. 2019.

28. Mesker WE, Junggeburt JM, Szuhai K, de Heer P, Morreau H, Tanke HJ, et al. The carcinoma-stromal ratio of colon carcinoma is an independent factor for survival compared to lymph node status and tumor stage. Cell Oncol. 2007;29(5):387–98. doi: 10.1155/2007/175276 17726261

29. Park JH, Richards CH, McMillan DC, Horgan PG, Roxburgh CS. The relationship between tumour stroma percentage, the tumour microenvironment and survival in patients with primary operable colorectal cancer. Ann Oncol. 2014;25(3):644–51. doi: 10.1093/annonc/mdt593 24458470

30. Wang K, Ma W, Wang J, Yu L, Zhang X, Wang Z, et al. Tumor-stroma ratio is an independent predictor for survival in esophageal squamous cell carcinoma. J Thorac Oncol. 2012;7(9):1457–61. doi: 10.1097/JTO.0b013e318260dfe8 22843085

31. Walker RA. The complexities of breast cancer desmoplasia. Breast Cancer Res. 2001;3(3):143–5. doi: 10.1186/bcr287 11305947

32. Shi J, Xiao H, Li J, Zhang J, Li Y, Zhang J, et al. Wild-type p53-modulated autophagy and autophagic fibroblast apoptosis inhibit hypertrophic scar formation. Lab Invest. 2018;98(11):1423–37. doi: 10.1038/s41374-018-0099-3 30089855

33. Vennin C, Melenec P, Rouet R, Nobis M, Cazet AS, Murphy KJ, et al. CAF hierarchy driven by pancreatic cancer cell p53-status creates a pro-metastatic and chemoresistant environment via perlecan. Nat Commun. 2019;10(1):3637. doi: 10.1038/s41467-019-10968-6 31406163

34. Wormann SM, Song L, Ai J, Diakopoulos KN, Kurkowski MU, Gorgulu K, et al. Loss of P53 Function Activates JAK2-STAT3 Signaling to Promote Pancreatic Tumor Growth, Stroma Modification, and Gemcitabine Resistance in Mice and Is Associated With Patient Survival. Gastroenterology. 2016;151(1):180–93 e12. doi: 10.1053/j.gastro.2016.03.010 27003603

35. Stein Y, Aloni-Grinstein R, Rotter V. Mutant p53—a potential player in shaping the tumor-stroma crosstalk. J Mol Cell Biol. 2019.

36. Fu R, Han CF, Ni T, Di L, Liu LJ, Lv WC, et al. A ZEB1/p53 signaling axis in stromal fibroblasts promotes mammary epithelial tumours. Nat Commun. 2019;10(1):3210. doi: 10.1038/s41467-019-11278-7 31324807

37. Matikas A, Zerdes I, Lovrot J, Richard F, Sotiriou C, Bergh J, et al. Prognostic Implications of PD-L1 Expression in Breast Cancer: Systematic Review and Meta-analysis of Immunohistochemistry and Pooled Analysis of Transcriptomic Data. Clin Cancer Res. 2019.

38. Thompson E, Taube JM, Elwood H, Sharma R, Meeker A, Warzecha HN, et al. The immune microenvironment of breast ductal carcinoma in situ. Mod Pathol. 2016;29(3):249–58. doi: 10.1038/modpathol.2015.158 26769139

39. Lee HH, Wang YN, Xia W, Chen CH, Rau KM, Ye L, et al. Removal of N-Linked Glycosylation Enhances PD-L1 Detection and Predicts Anti-PD-1/PD-L1 Therapeutic Efficacy. Cancer Cell. 2019;36(2):168–78 e4. doi: 10.1016/j.ccell.2019.06.008 31327656

40. Yasunaga M, Manabe S, Tarin D, Matsumura Y. Tailored immunoconjugate therapy depending on a quantity of tumor stroma. Cancer Sci. 2013;104(2):231–7. doi: 10.1111/cas.12062 23121194

41. Sau S, Petrovici A, Alsaab HO, Bhise K, Iyer AK. PDL-1 Antibody Drug Conjugate for Selective Chemo-Guided Immune Modulation of Cancer. Cancers (Basel). 2019;11(2).

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2019 Číslo 10