Correlation between stromal Th and Tc lymphocytes and PD-L1 expression in early breast cancer tumors
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.
Keywords: PD-L1early breast cancertumor-infiltrating lymphocytesCD4 lymphocytesCD8 lymphocyteperitumoral lymphoid aggregates
References
- Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011; 144(5): 646–674.
- Zitvogel L, Tesniere A, Kroemer G. Cancer despite immunosurveillance: immunoselection and immunosubversion. Nat Rev Immunol. 2006; 6(10): 715–727.
- Nicholson LB. The immune system. Essays Biochem. 2016; 60(3): 275–301.
- 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.
- 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.
- 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.
- Appleman LJ, Boussiotis VA. T cell anergy and costimulation. Immunol Rev. 2003; 192: 161–180.
- 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.
- Sharpe AH, Freeman GJ. The B7-CD28 superfamily. Nat Rev Immunol. 2002; 2(2): 116–126.
- 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.
- Bardhan K, Anagnostou T, Boussiotis VA. The PD1:PD-L1/2 Pathway from Discovery to Clinical Implementation. Front Immunol. 2016; 7: 550.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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).
- 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.
- 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.
- Thomas R, Al-Khadairi G, Decock J. Immune checkpoint inhibitors in triple negative breast cancer treatment: promising future prospects. Front Oncol. 2020; 10: 600573.
- 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).
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- Sabatier R, Finetti P, Mamessier E, et al. Prognostic and predictive value of PDL1 expression in breast cancer. Oncotarget. 2015; 6(7): 5449–5464.
- 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.
- 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.
- Wang ZQ, Milne K, Derocher H, et al. PD-L1 and intratumoral immune response in breast cancer. Oncotarget. 2017; 8(31): 51641–51651.
- 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.
- 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.
- Erber R, Hartmann A. Understanding PD-L1 testing in breast cancer: a practical approach. Breast Care (Basel). 2020; 15(5): 481–490.
- 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.
- 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.
- Brierley JD, Gosodarowicz MK, Wittekind C. TNM classification of malignant tumours. 8th ed. John Wiley & Sons, Nashville, TN 2016: 151–158.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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).
- 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.
- 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.
- 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.
- 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.
- Fridman WH, Petitprez F, Meylan M, et al. B cells and cancer: To B or not to B? J Exp Med. 2021; 218(1).
- 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.
- 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.
- 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).
- 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.
- 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.
- 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.
- 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).