Differential Effects of Anthracycline-based Neoadjuvant Chemotherapy on Stromal and Intratumoral FOXP3+ Tumor-Infiltrating Lymphocytes in Invasive Breast Cancer of No Special Type

Primariadewi Rustamadji, Elvan Wiyarta, Meike Pramono, Sinta Chaira Maulanisa

Abstract


BACKGROUND: Neoadjuvant chemotherapy (NAC) plays a crucial role in the management of invasive breast cancer with no special type (IBC-NST), with the immune system's response to cancer heavily relying on the dynamics between tumor-infiltrating lymphocytes (TILs) and cancer cells. In this study, the differential effects of anthracycline-based NAC on stromal and intratumoral foxhead box P3 (FOXP3+) TILs expressions were specifically examined.

METHODS: In this cross-sectional study, 32 IBC-NST samples were evaluated for pre- and post-NAC FOXP3+ TIL expression as well as the changes of FOXP3+ TIL expression. Comprehensive data collection regarding subjects' age, tumor size, grade, lymphovascular invasion, regional lymph node metastasis, and receptor status were conducted. Immunohistochemistry was utilized to quantify FOXP3+ TILs. The stromal, intratumoral and total FOXP3+ TILs expression were then analyzed.

RESULTS: Significant reductions in FOXP3+ TIL expression post-NAC were observed, with stromal FOXP3+ TILs showing a median decrease of 3.6 units in subjetcs aged ≥50 years (p=0.013) and a median decrease of 13.2 units in subjects with tumors ≥5 cm after NAC (p=0.006). In contrast, intratumoral FOXP3+ TILs remained relatively stable, with minor changes. The total FOXP3+ TIL expression, combining stromal and intratumoral components, was significantly decreased with a median of 13.0 units decreased to 5.3 units (p<0.001).

CONCLUSION: This study highlights the significant reduction in stromal FOXP3+ TIL expression after NAC treatment in IBC-NST subjects, in contrast to the relatively stable intratumoral FOXP3+ TILs. Understanding these differences may guide future therapeutic strategies and improve treatment outcomes for IBC-NST.

KEYWORDS: biomarkers, chemotherapy, FOXP3, prognostic, response, lymphocyte

 


Full Text:

PDF

References


Arnold M, Morgan E, Rumgay H, Mafra A, Singh D, Laversanne M, et al. Current and future burden of breast cancer: Global statistics for 2020 and 2040. Breast. 2022; 66: 15-23, CrossRef.

Nadia YF, Syahrani RA, Arumsari S, Sadikin M, Wanandi SI. Effect of cell culture medium on the proliferation and stemness of CD24-/CD44+ human breast cancer stem cells. Indones Biomed J. 2021; 13(4): 355-63, CrossRef.

Rustamadji P, Wiyarta E, Bethania KA. CD44 variant exon 6 isoform expression as a potential predictor of lymph node metastasis in invasive breast carcinoma of no special type. Int J Breast Cancer. 2021; 2021: 1586367, CrossRef.

Abdihalim TS, Idris AAA. Mucin level as a potential biomarker for breast cancer diagnosis. Mol Cell Biomed Sci. 2022; 6(3): 117-20, CrossRef.

Widowati W, Jasaputra DK, Sumitro SB, Widodo MA, Afifah E, Rizal R, et al. Direct and indirect effect of TNFα and IFNγ toward apoptosis in breast cancer cells. Mol Cell Biomed Sci. 2018; 2(2): 60-9, CrossRef.

Mohamed MM, Al-Raawi D, Sabet SF, El-Shinawi M. Inflammatory breast cancer: New factors contribute to disease etiology: A review. J Adv Res. 2014; 5(5): 525-36, CrossRef.

Rustamadji P, Wiyarta E, Bethania KA. Exploring the integrated role of AKT2, CD44v6, and MT1-MMP as predictors of axillary lymph node metastasis in invasive breast carcinoma of no special type. Iran J Pathol. 2022; 17(4): 480-90, CrossRef.

Wanandi SI, Syahrani RA, Suraduhita A, Yunita E, Louisa M. Andrographolide reverses doxorubicin resistance in human breast cancer stem cells by regulating apoptotic gene expressions. Indones Biomed J. 2023; 15(5): 288-96, CrossRef.

Jamiyan T, Kuroda H, Yamaguchi R, Nakazato Y, Noda S, Onozaki M, et al. Prognostic impact of a tumor-infiltrating lymphocyte subtype in triple negative cancer of the breast. Breast Cancer. 2020; 27(5): 880-92, CrossRef.

Qiu Y, Ke S, Chen J, Qin Z, Zhang W, Yuan Y, et al. FOXP3+ regulatory T cells and the immune escape in solid tumours. Front Immunol. 2022; 13: 982986, CrossRef.

Chainitikun S, Saleem S, Lim B, Valero V, Ueno NT. Update on systemic treatment for newly diagnosed inflammatory breast cancer. J Adv Res. 2021; 29: 1-12, CrossRef.

Masood S. Neoadjuvant chemotherapy in breast cancers. Womens Health. 2016; 12(5): 480-91, CrossRef.

Gonzalez H, Hagerling C, Werb Z. Roles of the immune system in cancer: From tumor initiation to metastatic progression. Genes Dev. 2018; 32(19-20): 1267-84, CrossRef.

Salgado R, Denkert C, Campbell C, Savas P, Nuciforo P, Aura C, et al. Tumor-infiltrating lymphocytes and associations with pathological complete response and event-free survival in HER2-positive early-stage breast cancer treated with lapatinib and trastuzumab: A secondary analysis of the NeoALTTO trial. JAMA Oncol. 2015; 1(4): 448-54, CrossRef.

Wang J, Tian S, Sun J, Zhang J, Lin L, Hu C. The presence of tumour-infiltrating lymphocytes (TILs) and the ratios between different subsets serve as prognostic factors in advanced hypopharyngeal squamous cell carcinoma. BMC Cancer. 2020; 20(1): 731, CrossRef.

Workman CJ, Szymczak-Workman AL, Collison LW, Pillai MR, Vignali DA. The development and function of regulatory T cells. Cell Mol Life Sci. 2009; 66(16): 2603-22, CrossRef.

Whiteside TL. What are regulatory T cells (Treg) regulating in cancer and why? Semin Cancer Biol. 2012; 22(4): 327-34, CrossRef.

Salgado R, Denkert C, Demaria S, Sirtaine N, Klauschen F, Pruneri G, et al. The evaluation of tumor-infiltrating lymphocytes (TILs) in breast cancer: Recommendations by an International TILs Working Group 2014. Ann Oncol. 2015; 26(2): 259-71, CrossRef.

Wu R, Oshi M, Asaoka M, Yan L, Benesch MGK, Khoury T, et al. Intratumoral tumor infiltrating lymphocytes (TILs) are associated with cell proliferation and better survival but not always with chemotherapy response in breast cancer. Ann Surg. 2023; 278(4): 587-97, CrossRef.

Miyashita M, Sasano H, Tamaki K, Hirakawa H, Takahashi Y, Nakagawa S, et al. Prognostic significance of tumor-infiltrating CD8+ and FOXP3+ lymphocytes in residual tumors and alterations in these parameters after neoadjuvant chemotherapy in triple-negative breast cancer: A retrospective multicenter study. Breast Cancer Res. 2015; 17(1): 124, CrossRef.

Rashed HE, Muhammad SS, Sameh R, Elsebai E, Nawar N, Abdelhamid MI, et al. Predictive value of tumor-infiltrating lymphocytes (TILs) and programmed cell death-ligand 1 (PDL1) expression in breast cancer patients treated with neoadjuvant chemotherapy. Rev Senol Patolog Mamar. 2021; 34(4): 200-7, CrossRef.

Mao Y, Qu Q, Zhang Y, Liu J, Chen X, Shen K. The value of tumor infiltrating lymphocytes (TILs) for predicting response to neoadjuvant chemotherapy in breast cancer: A systematic review and meta-analysis. PLoS One. 2014; 9(12): e115103, CrossRef.

World Medical Association Declaration of Helsinki: Ethical principles for medical research involving human subjects. JAMA. 2013; 310(20): 2191-4, CrossRef.

Rustamadji P, Wiyarta E, Anggreani I. Correlation of before and after invasive breast cancer neoadjuvant chemotherapy for NFkB, cyclin D1, and survivin expression. Iran J Pathol. 2023; 18(2): 156-64, CrossRef.

Rustamadji P, Wiyarta E, Anggreani I. The potential of expression of cyclin-D1 on neoadjuvant chemotherapy in invasive breast carcinoma. Asian Pac J Cancer Prev. 2023; 24(4): 1131-6, CrossRef.

Wiyarta E, Kusmardi K, Midoen YH. Effect of omega-3-rich fish oil on TNF-α expression in mice's colonic tissue induced with azoxymethane (AOM) and dextran sodium sulphate (DSS). Res J Pharm Technol 2022; 15(7): 3179-84, CrossRef.

Kusmardi K, Wiyarta E, Estuningtyas A, Sahar N, Midoen YH, Tedjo A. Potential of Phaleria macrocarpa leaves ethanol extract to upregulate the expression of caspase-3 in mouse distal colon after dextran sodium sulphate induction. Pharmacogn J. 2021; 13(1): 23-9, CrossRef.

Rustamadji P, Wiyarta E, Bethania KA, Kusmardi K. Potential of AKT2 expression as a predictor of lymph-node metastasis in invasive breast carcinoma of no special type. J Pathol Transl Med. 2021; 51(3): 271-8, CrossRef.

Moamin MR, Allen R, Woods SL, Brown JE, Nunns H, Juncker-Jensen A, et al. Changes in the immune landscape of TNBC after neoadjuvant chemotherapy: Correlation with relapse. Front Immunol. 2023; 14: 1291643, CrossRef.

Chaudhary B, Elkord E. Regulatory T cells in the tumor microenvironment and cancer progression: Role and therapeutic targeting. Vaccines. 2016; 4(3): 28, CrossRef.

Wu MY, Kuo TY, Ho HN. Tumor-infiltrating lymphocytes contain a higher proportion of FOXP3+ T lymphocytes in cervical cancer. J Formos Med Assoc. 2011; 110(9): 580-6, CrossRef.

Chen G, Wu K, Li H, Xia D, He T. Role of hypoxia in the tumor microenvironment and targeted therapy. Front Oncol. 2022 12: 961637, CrossRef.

Martinenaite E, Munir Ahmad S, Hansen M, Met Ö, Westergaard MW, Larsen SK, et al. CCL22-specific T cells: Modulating the immunosuppressive tumor microenvironment. Oncoimmunology. 2016; 5(11): e1238541, CrossRef.

Liu J, Wang X, Deng Y, Yu X, Wang H, Li Z. Research progress on the role of regulatory T cell in tumor microenvironment in the treatment of breast cancer. Front Oncol. 2021; 11: 766248, CrossRef.

Tavares MC, Sampaio CD, Lima GE, Andrade VP, Gonçalves DG, Macedo MP, et al. A high CD8 to FOXP3 ratio in the tumor stroma and expression of PTEN in tumor cells are associated with improved survival in non-metastatic triple-negative breast carcinoma. BMC Cancer. 2021; 21(1): 901, CrossRef.

Lambrechts Y, Hatse S, Richard F, Boeckx B, Floris G, Desmedt C, et al. Differences in the tumor molecular and microenvironmental landscape between early (non-metastatic) and de novo metastatic primary luminal breast tumors. Cancers. 2023; 15(17): 4341, CrossRef.

McCoy MJ, Hemmings C, Miller TJ, Austin SJ, Bulsara MK, Zeps N, et al. Low stromal Foxp3+ regulatory T-cell density is associated with complete response to neoadjuvant chemoradiotherapy in rectal cancer. Br J Cancer. 2015; 113(12): 1677-86, CrossRef.

Xing X, Shi J, Jia Y, Dou Y, Li Z, Dong B, et al. Effect of neoadjuvant chemotherapy on the immune microenvironment in gastric cancer as determined by multiplex immunofluorescence and T cell receptor repertoire analysis. J Immunother Cancer. 2022; 10(3): e003984, CrossRef.




DOI: https://doi.org/10.18585/inabj.v16i2.2828

Copyright (c) 2024 The Prodia Education and Research Institute

Creative Commons License
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.

 

Indexed by:

                  

               

                   

 

 

The Prodia Education and Research Institute