Multimedialna platforma wiedzy medycznej Internetowa Księgarnia Medyczna Kalendarium Konferencji
Folia Histochemica et Cytobiologica
MENU
Shortcuts Submit an article Author Guidelines Ahead of Print Reviewers 2023 Editorial Board

open access

Vol 61, No 4 (2023)
Original paper
Submitted: 2023-10-16
Accepted: 2023-12-04
Published online: 2023-12-11
View PDF Download PDF file
Get Citation

Correlation between stromal Th and Tc lymphocytes and PD-L1 expression in early breast cancer tumors

Jelena Vučinić12, Ljiljana Vučković12, Janja Raonić12
DOI: 10.5603/fhc.97855
·
Pubmed: 38073318
·
Folia Histochem Cytobiol 2023;61(4):193-204.
Affiliations
  1. Center for Pathology, Clinical Center of Montenegro, Podgorica, Montenegro
  2. Department of Histology and Embryology, Medical Faculty, University of Montenegro, Podgorica, Montenegro

open access

Vol 61, No 4 (2023)
ORIGINAL PAPERS
Submitted: 2023-10-16
Accepted: 2023-12-04
Published online: 2023-12-11

Abstract

Introduction. Prognostic and predictive value of PD-L1 as a biomarker in breast cancer remains controversial. While
some studies suggest its association with negative prognostic parameters, others reported a highly significant association
between PD-L1 expression and tumor-infiltrating lymphocytes, which are known to be an independent favorable
prognostic factor. The aim of present study is to examine the relationship between immune response markers and PD-L1
expression in early breast cancer.
Material and methods. Immunohistochemical expression of PD-L1, along with density and composition of stromal
lymphocytic infiltrate and peritumoral lymphoid aggregates was analyzed in 95 samples of invasive breast cancer.
Results. A strong positive correlation between PD-L1 expression and the density of stromal lymphocytic infiltrate and
peritumoral lymphoid aggregates was identified and a cut-off value of 53% coverage of tumor stroma by lymphocytes,
with which PD-L1 positivity can be predicted with excellent diagnostic accuracy, was determined for the first time
using statistical methods. Additionally, PD-L1 positivity was observed significantly more often in tumors with higher
absolute number of both CD4 and CD8 T-lymphocytes in the stromal infiltrate. No significant correlation with molecular
subtype of breast cancer was found.
Conclusions. Our results indicate that the density of stromal lymphocytic infiltrate might be a better predictor of PD-L1
positivity in early breast cancer than the molecular subtype and that the key to the optimization of PD-L1 as a biomarker
in breast cancer lies in its interpretation in the context of other immune response markers.

Abstract

Introduction. Prognostic and predictive value of PD-L1 as a biomarker in breast cancer remains controversial. While
some studies suggest its association with negative prognostic parameters, others reported a highly significant association
between PD-L1 expression and tumor-infiltrating lymphocytes, which are known to be an independent favorable
prognostic factor. The aim of present study is to examine the relationship between immune response markers and PD-L1
expression in early breast cancer.
Material and methods. Immunohistochemical expression of PD-L1, along with density and composition of stromal
lymphocytic infiltrate and peritumoral lymphoid aggregates was analyzed in 95 samples of invasive breast cancer.
Results. A strong positive correlation between PD-L1 expression and the density of stromal lymphocytic infiltrate and
peritumoral lymphoid aggregates was identified and a cut-off value of 53% coverage of tumor stroma by lymphocytes,
with which PD-L1 positivity can be predicted with excellent diagnostic accuracy, was determined for the first time
using statistical methods. Additionally, PD-L1 positivity was observed significantly more often in tumors with higher
absolute number of both CD4 and CD8 T-lymphocytes in the stromal infiltrate. No significant correlation with molecular
subtype of breast cancer was found.
Conclusions. Our results indicate that the density of stromal lymphocytic infiltrate might be a better predictor of PD-L1
positivity in early breast cancer than the molecular subtype and that the key to the optimization of PD-L1 as a biomarker
in breast cancer lies in its interpretation in the context of other immune response markers.

Full Text:

View PDF Download PDF file
Get Citation

Keywords

PD-L1; early breast cancer; tumor-infiltrating lymphocytes; CD4 lymphocytes; CD8 lymphocyte; peritumoral lymphoid aggregates

About this article
Title

Correlation between stromal Th and Tc lymphocytes and PD-L1 expression in early breast cancer tumors

Journal

Folia Histochemica et Cytobiologica

Issue

Vol 61, No 4 (2023)

Article type

Original paper

Pages

193-204

Published online

2023-12-11

Page views

520

Article views/downloads

195

DOI

10.5603/fhc.97855

Pubmed

38073318

Bibliographic record

Folia Histochem Cytobiol 2023;61(4):193-204.

Keywords

PD-L1
early breast cancer
tumor-infiltrating lymphocytes
CD4 lymphocytes
CD8 lymphocyte
peritumoral lymphoid aggregates

Authors

Jelena Vučinić
Ljiljana Vučković
Janja Raonić

References (56)
  1. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011; 144(5): 646–674.
    CrossRefPubMed
  2. Zitvogel L, Tesniere A, Kroemer G. Cancer despite immunosurveillance: immunoselection and immunosubversion. Nat Rev Immunol. 2006; 6(10): 715–727.
    CrossRefPubMed
  3. Nicholson LB. The immune system. Essays Biochem. 2016; 60(3): 275–301.
    CrossRefPubMed
  4. Salgado R, Denkert C, Demaria S, et al. International TILs Working Group 2014. The evaluation of tumor-infiltrating lymphocytes (TILs) in breast cancer: recommendations by an International TILs Working Group 2014. Ann Oncol. 2015; 26(2): 259–271.
    CrossRefPubMed
  5. Ostroumov D, Fekete-Drimusz N, Saborowski M, et al. CD4 and CD8 T lymphocyte interplay in controlling tumor growth. Cell Mol Life Sci. 2018; 75(4): 689–713.
    CrossRefPubMed
  6. Parry RV, Chemnitz JM, Frauwirth KA, et al. CTLA-4 and PD-1 receptors inhibit T-cell activation by distinct mechanisms. Mol Cell Biol. 2005; 25(21): 9543–9553.
    CrossRefPubMed
  7. Appleman LJ, Boussiotis VA. T cell anergy and costimulation. Immunol Rev. 2003; 192: 161–180.
    CrossRefPubMed
  8. Kinter AL, Godbout EJ, McNally JP, et al. The common gamma-chain cytokines IL-2, IL-7, IL-15, and IL-21 induce the expression of programmed death-1 and its ligands. J Immunol. 2008; 181(10): 6738–6746.
    CrossRefPubMed
  9. Sharpe AH, Freeman GJ. The B7-CD28 superfamily. Nat Rev Immunol. 2002; 2(2): 116–126.
    CrossRefPubMed
  10. Eroglu Z, Zaretsky JM, Hu-Lieskovan S, et al. What does PD-L1 positive or negative mean? J Exp Med. 2016; 213(13): 2835–2840.
    CrossRefPubMed
  11. Bardhan K, Anagnostou T, Boussiotis VA. The PD1:PD-L1/2 Pathway from Discovery to Clinical Implementation. Front Immunol. 2016; 7: 550.
    CrossRefPubMed
  12. Mandai M, Hamanishi J, Abiko K, et al. Dual faces of ifnγ in cancer progression: a role of PD-L1 induction in the determination of pro- and antitumor immunity. Clin Cancer Res. 2016; 22(10): 2329–2334.
    CrossRefPubMed
  13. Nakanishi J, Wada Y, Matsumoto K, et al. Overexpression of B7-H1 (PD-L1) significantly associates with tumor grade and postoperative prognosis in human urothelial cancers. Cancer Immunol Immunother. 2007; 56(8): 1173–1182.
    CrossRefPubMed
  14. Hino R, Kabashima K, Kato Yu, et al. Tumor cell expression of programmed cell death-1 ligand 1 is a prognostic factor for malignant melanoma. Cancer. 2010; 116(7): 1757–1766.
    CrossRefPubMed
  15. Anagnostou VK, Brahmer JR. Cancer immunotherapy: a future paradigm shift in the treatment of non-small cell lung cancer. Clin Cancer Res. 2015; 21(5): 976–984.
    CrossRefPubMed
  16. Doroshow DB, Sanmamed MF, Hastings K, et al. Immunotherapy in non-small cell lung cancer: facts and hopes. Clin Cancer Res. 2019; 25(15): 4592–4602.
    CrossRefPubMed
  17. Planes-Laine G, Rochigneux P, Bertucci F, et al. PD-1/PD-L1 targeting in breast cancer: the first clinical evidences are emerging. A literature review. Cancers (Basel). 2019; 11(7).
    CrossRefPubMed
  18. Iwai Y, Ishida M, Tanaka Y, et al. Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade. Proc Natl Acad Sci U S A. 2002; 99(19): 12293–12297.
    CrossRefPubMed
  19. Sung H, Ferlay J, Siegel RL, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021; 71(3): 209–249.
    CrossRefPubMed
  20. Thomas R, Al-Khadairi G, Decock J. Immune checkpoint inhibitors in triple negative breast cancer treatment: promising future prospects. Front Oncol. 2020; 10: 600573.
    CrossRefPubMed
  21. Saleh R, Taha RZ, Sasidharan Nair V, et al. PD-L1 blockade by atezolizumab downregulates signaling pathways associated with tumor growth, metastasis, and hypoxia in human triple negative breast cancer. Cancers (Basel). 2019; 11(8).
    CrossRefPubMed
  22. Cimino-Mathews A, Thompson E, Taube JM, et al. PD-L1 (B7-H1) expression and the immune tumor microenvironment in primary and metastatic breast carcinomas. Hum Pathol. 2016; 47(1): 52–63.
    CrossRefPubMed
  23. Denkert C, Loibl S, Noske A, et al. Tumor-associated lymphocytes as an independent predictor of response to neoadjuvant chemotherapy in breast cancer. J Clin Oncol. 2010; 28(1): 105–113.
    CrossRefPubMed
  24. Gao G, Wang Z, Qu X, et al. Prognostic value of tumor-infiltrating lymphocytes in patients with triple-negative breast cancer: a systematic review and meta-analysis. BMC Cancer. 2020; 20(1): 179.
    CrossRefPubMed
  25. Kitano A, Ono M, Yoshida M, et al. Tumour-infiltrating lymphocytes are correlated with higher expression levels of PD-1 and PD-L1 in early breast cancer. ESMO Open. 2017; 2(2): e000150.
    CrossRefPubMed
  26. Stovgaard ES, Dyhl-Polk A, Roslind A, et al. PD-L1 expression in breast cancer: expression in subtypes and prognostic significance: a systematic review. Breast Cancer Res Treat. 2019; 174(3): 571–584.
    CrossRefPubMed
  27. Ghebeh H, Mohammed S, Al-Omair A, et al. The B7-H1 (PD-L1) T lymphocyte-inhibitory molecule is expressed in breast cancer patients with infiltrating ductal carcinoma: correlation with important high-risk prognostic factors. Neoplasia. 2006; 8(3): 190–198.
    CrossRefPubMed
  28. Muenst S, Schaerli AR, Gao F, et al. Expression of programmed death ligand 1 (PD-L1) is associated with poor prognosis in human breast cancer. Breast Cancer Res Treat. 2014; 146(1): 15–24.
    CrossRefPubMed
  29. Sabatier R, Finetti P, Mamessier E, et al. Prognostic and predictive value of PDL1 expression in breast cancer. Oncotarget. 2015; 6(7): 5449–5464.
    CrossRefPubMed
  30. Guo Y, Yu P, Liu Z, et al. Prognostic and clinicopathological value of programmed death ligand-1 in breast cancer: a meta-analysis. PLoS One. 2016; 11(5): e0156323.
    CrossRefPubMed
  31. Ali HR, Glont SE, Blows FM, et al. PD-L1 protein expression in breast cancer is rare, enriched in basal-like tumours and associated with infiltrating lymphocytes. Ann Oncol. 2015; 26(7): 1488–1493.
    CrossRefPubMed
  32. Wang ZQ, Milne K, Derocher H, et al. PD-L1 and intratumoral immune response in breast cancer. Oncotarget. 2017; 8(31): 51641–51651.
    CrossRef
  33. Miles D, Gligorov J, André F, et al. IMpassion131 investigators. Primary results from IMpassion131, a double-blind, placebo-controlled, randomised phase III trial of first-line paclitaxel with or without atezolizumab for unresectable locally advanced/metastatic triple-negative breast cancer. Ann Oncol. 2021; 32(8): 994–1004.
    CrossRefPubMed
  34. Litvin IE, Paganella MP, Wendland EM, et al. Prognosis of PD-L1 in human breast cancer: protocol for a systematic review and meta-analysis. Syst Rev. 2020; 9(1): 66.
    CrossRefPubMed
  35. Erber R, Hartmann A. Understanding PD-L1 testing in breast cancer: a practical approach. Breast Care (Basel). 2020; 15(5): 481–490.
    CrossRefPubMed
  36. Savas P, Salgado R, Denkert C, et al. Clinical relevance of host immunity in breast cancer: from TILs to the clinic. Nat Rev Clin Oncol. 2016; 13(4): 228–241.
    CrossRefPubMed
  37. Salgado R, Denkert C, Demaria S, et al. International TILs Working Group 2014. The evaluation of tumor-infiltrating lymphocytes (TILs) in breast cancer: recommendations by an International TILs Working Group 2014. Ann Oncol. 2015; 26(2): 259–271.
    CrossRefPubMed
  38. Brierley JD, Gosodarowicz MK, Wittekind C. TNM classification of malignant tumours. 8th ed. John Wiley & Sons, Nashville, TN 2016: 151–158.
  39. Cardoso F, Kyriakides S, Ohno S, et al. ESMO Guidelines Committee. Electronic address: clinicalguidelines@esmo.org. Early breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up†. Ann Oncol. 2019; 30(8): 1194–1220.
    CrossRefPubMed
  40. Wolff AC, Hammond ME, Schwartz JN, et al. American Society of Clinical Oncology, College of American Pathologists. American Society of Clinical Oncology/College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer. J Clin Oncol. 2007; 25(1): 118–145.
    CrossRefPubMed
  41. Rugo HS, Loi S, Adams S, et al. IMpassion130 Trial Investigators. Atezolizumab and nab-paclitaxel in advanced triple-negative breast cancer. N Engl J Med. 2018; 379(22): 2108–2121.
    CrossRefPubMed
  42. Takahashi M, Cortés J, Dent R, et al. KEYNOTE-522 Investigators, KEYNOTE-522 Investigators. Pembrolizumab for early triple-negative breast cancer. N Engl J Med. 2020; 382(9): 810–821.
    CrossRefPubMed
  43. Escors D, Gato-Cañas M, Zuazo M, et al. The intracellular signalosome of PD-L1 in cancer cells. Signal Transduct Target Ther. 2018; 3: 26.
    CrossRefPubMed
  44. VENTANA PD-L1 (SP142) Assay for Triple-Negative Breast Carcinoma. Roche.com. Ventana Medical Systems, Inc. and Roche Diagnostics International, Inc. 2020. https://diagnostics.roche.com/content/dam/diagnostics/us/en/products/v/ventana-pd-l1-sp142-assay/VENTANA-PD-L1-SP142-Assay-TNBC-IG.pdf (3.12.2023).
  45. Schalper KA, Velcheti V, Carvajal D, et al. In situ tumor PD-L1 mRNA expression is associated with increased TILs and better outcome in breast carcinomas. Clin Cancer Res. 2014; 20(10): 2773–2782.
    CrossRefPubMed
  46. Huang Yi, Ma C, Zhang Q, et al. CD4+ and CD8+ T cells have opposing roles in breast cancer progression and outcome. Oncotarget. 2015; 6(19): 17462–17478.
    CrossRefPubMed
  47. Wang K, Shen T, Siegal GP, et al. The CD4/CD8 ratio of tumor-infiltrating lymphocytes at the tumor-host interface has prognostic value in triple-negative breast cancer. Hum Pathol. 2017; 69: 110–117.
    CrossRefPubMed
  48. Mittendorf EA, Philips AV, Meric-Bernstam F, et al. PD-L1 expression in triple-negative breast cancer. Cancer Immunol Res. 2014; 2(4): 361–370.
    CrossRefPubMed
  49. Fridman WH, Petitprez F, Meylan M, et al. B cells and cancer: To B or not to B? J Exp Med. 2021; 218(1).
    CrossRefPubMed
  50. Mahmoud SMA, Lee AHS, Paish EC, et al. The prognostic significance of B lymphocytes in invasive carcinoma of the breast. Breast Cancer Res Treat. 2012; 132(2): 545–553.
    CrossRefPubMed
  51. Shen M, Wang J, Ren X. New insights into tumor-infiltrating B lymphocytes in breast cancer: clinical impacts and regulatory mechanisms. Front Immunol. 2018; 9: 470.
    CrossRefPubMed
  52. Lam BM, Verrill C. Clinical Significance of Tumour-Infiltrating B Lymphocytes (TIL-Bs) in Breast Cancer: A Systematic Literature Review. Cancers (Basel). 2023; 15(4).
    CrossRefPubMed
  53. Vranic S, Cyprian FS, Gatalica Z, et al. PD-L1 status in breast cancer: Current view and perspectives. Semin Cancer Biol. 2021; 72: 146–154.
    CrossRefPubMed
  54. Barrett MT, Anderson KS, Lenkiewicz E, et al. Genomic amplification of 9p24.1 targeting JAK2, PD-L1, and PD-L2 is enriched in high-risk triple negative breast cancer. Oncotarget. 2015; 6(28): 26483–26493.
    CrossRefPubMed
  55. Franzoi MA, Romano E, Piccart M. Immunotherapy for early breast cancer: too soon, too superficial, or just right? Ann Oncol. 2021; 32(3): 323–336.
    CrossRefPubMed
  56. Valenza C, Taurelli Salimbeni B, Santoro C, et al. Tumor infiltrating lymphocytes across breast cancer subtypes: current issues for biomarker assessment. Cancers (Basel). 2023; 15(3).
    CrossRefPubMed

Regulations

Important: This website uses cookies. More >>

The cookies allow us to identify your computer and find out details about your last visit. They remembering whether you've visited the site before, so that you remain logged in - or to help us work out how many new website visitors we get each month. Most internet browsers accept cookies automatically, but you can change the settings of your browser to erase cookies or prevent automatic acceptance if you prefer.

By VM Media Group sp z o.o., ul. Świętokrzyska 73, 80–180 Gdańsk

tel.:+48 58 320 94 94, faks:+48 58 320 94 60, e-mail:  viamedica@viamedica.pl