Expression of CD8+ T Lymphocyte and Foxp3+ T Lymphocyte as Risk Factor for Response to Neoadjuvant Chemotherapy in Stage III Breast Cancer
Abstract
BACKGROUND: Neoadjuvant chemotherapy (NAC) in breast cancer is usually utilized to eradicate micro-metastasis, induce apoptosis in tumor cells, and reduce the primary tumor size, enabling surgical intervention. Recent studies have shown that tumor-infiltrating lymphocytes (TILs), especially cytotoxic CD8+ T cells and immunosuppressive Foxp3+ regulatory T cells, influence tumor response to treatment. However, their role as predictive markers for NAC response remains unclear. Therefore, this study was performed to investigate whether high expression of CD8+ and low expression of Foxp3+ T lymphocytes are associated with better response to NAC in stage III breast cancer patients.
METHODS: Total of 60 biopsy samples from stage III breast cancer patients were included, comprising 30 subjects in the response group (+) and 30 subjects in the non-response group (−). The expression levels of CD8+ and Foxp3+ T lymphocytes in tumor tissue were assessed semi-quantitatively by immunohistochemistry (IHC), using a scoring system based on the proportion and intensity of positively stained cells (Black’s grading criteria).
RESULTS: Stage III breast cancer with high expression of CD8+ T lymphocytes was significantly associated with a better response to NAC (p=0.004; OR=6.882). Meanwhile, low expression of Foxp3+ T lymphocytes was not significantly associated with chemotherapy response (p=0.067; OR=3.250). A higher tumor grade was also associated with an improved response to treatment. The probability of achieving a positive response to NAC in subjects presenting with high CD8+ expression, low Foxp3+ expression, and high tumor grade was estimated at 96.98%.
CONCLUSION: The combination of high expression of CD8+ T lymphocyte, low expression of Foxp3+ T lymphocyte and high tumor grade might be useful to predict good response to NAC in stage III breast cancer.
KEYWORDS: CD8+ T lymphocyte, Foxp3+ T lymphocyte, neoadjuvant chemotherapy, breast cancer
Full Text:
PDFReferences
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,
https://doi.org/10.18585/inabj.v13i4.1674">CrossRef.
Shang C, Xu D. Epidemiology of breast cancer. Oncologie. 2022; 24(4): 649-63,
https://doi.org/10.32604/oncologie.2022.027640">CrossRef.
Widiana IK, Irawan H. Clinical and subtypes of breast cancer in Indonesia. Asian Pac J Cancer Care. 2020; 5(4): 281-5,
https://doi.org/10.31557/apjcc.2020.5.4.281-285">CrossRef.
Narisuari IDAPM, Manuaba IBTW. Prevalensi dan gambaran karakteristik penderita kanker payudara di poliklinik bedah onkologi RSUP Sanglah, Bali, Indonesia tahun 2016. Intisari Sains Medis. 2020; 11(1): 183-9,
https://doi.org/10.15562/ism.v11i1.526">CrossRef.
Cuniolo L, Gipponi M, Murelli F, Depaoli F, Cornacchia C, Franchelli S, et al. Multidisciplinary and tailored treatment of locally advanced breast cancer in progression during neoadjuvant chemotherapy: Case report. Curr Oncol. 2024; 31(5): 2856-66,
https://doi.org/10.3390/curroncol31050217">CrossRef.
Giani M, Tavella K, Renda I, Tartarotti E, Nori J, Vanzi E, et al. Prognostic role of tumor size reduction >50% after neoadjuvant chemotherapy for breast cancer. J Cancer Sci Clin Ther. 2022; 6(4): 1-9,
https://doi.org/10.26502/jcsct.5079174">CrossRef.
Tauber N, Cirkel C, Claussen A, Fick F, Kontomanolis E, Krawczyk N, et al. HER2-positive early breast cancer: time for ultimate de-escalation? Cancers. 2024; 16(6): 1121,
https://doi.org/10.3390/cancers16061121">CrossRef.
Panigoro SS, Kurniawan A, Ramadhan R, Sukartini N, Herqutanto H, Paramita RI, et al. Amino acid profile of luminal A and B subtypes breast cancer. Indones Biomed J. 2023; 15(3): 269-76,
https://doi.org/10.18585/inabj.v15i3.2109">CrossRef.
Naji O, Ghouzlani A, Rafii S, Sadiqi R, Kone A, Harmak Z, et al. Investigating tumor immunogenicity in breast cancer: deciphering the tumor immune response to enhance therapeutic approaches. Front Immunol. 2024; 15: 1399754,
https://doi.org/10.3389/fimmu.2024.1399754">CrossRef.
Bai Y, Xu H, Guo M, Xia L, Deng S. Extensive infiltration of CD8⁺ T cells and M1 macrophages is beneficial for multiple cancer patients undergoing chemotherapy. MedComm Oncol. 2024; 3(3): 1-14,
https://doi.org/10.1002/mog2.89">CrossRef.
Yin C, Okugawa Y, Yamamoto A, Kitajima T, Shimura T, Kawamura M, et al. Prognostic significance of CD8⁺ tumor-infiltrating lymphocytes and CD66b⁺ tumor-associated neutrophils in the invasive margins of stages I-III colorectal cancer. Oncol Lett. 2022; 24(1): 212,
https://doi.org/10.3892/ol.2022.13333">CrossRef.
Baxevanis CN, Fortis SP, Perez SA. The balance between breast cancer and the immune system: challenges for prognosis and clinical benefit from immunotherapies. Semin Cancer Biol. 2021; 72: 76-89,
https://doi.org/10.1016/j.semcancer.2019.12.018">CrossRef.
Ahmed H, Mahmud AR, Siddiquee MF-R, Shahriar A, Biswas P, Shimul MEK, et al. Role of T cells in cancer immunotherapy: opportunities and challenges. Cancer Pathog Ther. 2023; 1(2): 116-26,
https://doi.org/10.1016/j.cpt.2022.12.002">CrossRef.
Rustamadji P, Wiyarta E, Pramono M, Maulanisa SC. Differential effects of anthracycline-based neoadjuvant chemotherapy on stromal and intratumoral FOXP3⁺ tumor-infiltrating lymphocytes in invasive breast cancer of no special type. Indones Biomed J. 2024; 16(2): 135-43,
https://doi.org/10.18585/inabj.v16i2.2828">CrossRef.
Raskov H, Orhan A, Christensen JP, Gögenur I. Cytotoxic CD8⁺ T cells in cancer and cancer immunotherapy. Br J Cancer. 2021; 124(2): 359-67,
https://doi.org/10.1038/s41416-020-01048-4">CrossRef.
Elsharkawy SS, Elrheem MA, Elrheem SA. The tumor infiltrating lymphocytes (TILs): Did we find the missed piece of the huge puzzle? Open J Obstet Gynecol. 2021; 11(2): 146-61,
https://doi.org/10.4236/ojog.2021.112017">CrossRef.
Xiang YJ, Feng M, Liu LY, Wang F, Yu LX, Zhou F, et al. The role of FOXP3 of interstitial tissue in the pathogenesis of breast cancer. Transl Breast Cancer Res. 2021; 2: 11,
https://doi.org/10.21037/tbcr-21-1">CrossRef.
Wang W, Ding M, Wang Q, Song Y, Huo K, Chen X, et al. Advances in FOXP3⁺ regulatory T cells (FOXP3⁺ Treg) and key factors in digestive malignancies. Front Immunol. 2024; 15: 1404974, CrossRef.
Jin Y, Jia Z, Xia X, Gordon NB, Ludwig JA, Somaiah N, et al. Anti-CD137 agonist antibody-independent and clinically feasible preparation of tumor-infiltrating lymphocytes from soft tissue sarcoma and osteosarcoma. Front Immunol. 2025; 16: 1557006,
https://doi.org/10.3389/fimmu.2025.1557006">CrossRef.
Cunha D, Neves M, Silva D, Silvestre AR, Nunes PB, Arrobas F, et al. Tumor-infiltrating T cells in skin basal cell carcinomas and squamous cell carcinomas: Global Th1 preponderance with Th17 enrichment-A cross-sectional study. Cells. 2024; 13(11): 964,
https://doi.org/10.3390/cells13110964">CrossRef.
Łukasiewicz S, Czeczelewski M, Forma A, Baj J, Sitarz R, Stanisławek A. Breast cancer-epidemiology, risk factors, classification, prognostic markers, and current treatment strategies-An updated review. Cancers. 2021; 13(17): 4287,
https://doi.org/10.3390/cancers13174287">CrossRef.
McPhail S, Swann R, Johnson SA, Barclay ME, Abd Elkader H, Alvi R, et al. Risk factors and prognostic implications of diagnosis of cancer within 30 days after an emergency hospital admission (emergency presentation): An International Cancer Benchmarking Partnership (ICBP) population-based study. Lancet Oncol. 2022; 23(5): 587-600,
https://doi.org/10.1016/S1470-2045(22)00127-9">CrossRef.
Xu H, Xu B. Breast cancer: Epidemiology, risk factors and screening. Chin J Cancer Res. 2023; 35(6): 565-83,
https://doi.org/10.21147/j.issn.1000-9604.2023.06.02">CrossRef.
Ahir BK, Engelhard HH, Lakka SS. Tumor development and angiogenesis in adult brain tumor: glioblastoma. Mol Neurobiol. 2020; 57(5): 2461-78,
https://doi.org/10.1007/s12035-020-01892-8">CrossRef.
Orrantia-Borunda E, Anchondo-Nuñez P, Acuña-Aguilar LE, Gómez-Valles FO, Ramírez-Valdespino CA. Subtypes of breast cancer. In: Breast Cancer. Brisbane: Exon Publications; 2022. p. 31-42,
https://doi.org/10.36255/exon-publications-breast-cancer-subtypes">CrossRef.
Hurvitz SA, McAndrew NP, Bardia A, Press MF, Pegram M, Crown JP, et al. A careful reassessment of anthracycline use in curable breast cancer. NPJ Breast Cancer. 2021; 7(1): 134,
https://doi.org/10.1038/s41523-021-00342-5">CrossRef.
Liu B, Zhou H, Tan L, Siu KTH, Guan X-Y. Exploring treatment options in cancer: Tumor treatment strategies. Signal Transduct Target Ther. 2024; 9(1): 175,
https://doi.org/10.1038/s41392-024-01856-7">CrossRef.
Chen W, Li FX, Lu DL, Jiang J, Li J. Differences between the efficacy of HER2(2⁺)/FISH-positive and HER2(3⁺) in breast cancer during dual-target neoadjuvant therapy. Breast. 2023; 71: 69-73,
https://doi.org/10.1016/j.breast.2023.07.008">CrossRef.
Olfatbakhsh A, Tafazzoli-Harandi H, Najafi S, Hashemi EAS, Sari F, Mokhtari Hesari P, et al. Factors impacting pathologic complete response after neoadjuvant chemotherapy in breast cancer: a single-center study. Int J Cancer Manag. 2018;11(5): e60098,
https://doi.org/10.5812/ijcm.60098">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.
Spagnol G, Ghisoni E, Morotti M, De Tommasi O, Marchetti M, Bigardi S, et al. The impact of neoadjuvant chemotherapy on ovarian cancer tumor microenvironment: A systematic review of the literature. Int J Mol Sci. 2024; 25(13): 7070, CrossRef.
Behranvand N, Nasri F, Zolfaghari Emameh R, Khani P, Hosseini A, Garssen J, et al. Chemotherapy: A double-edged sword in cancer treatment. Cancer Immunol Immunother. 2022; 71(3): 507-26, CrossRef.
Miskad UA, Rifai RA, Masadah R, Nelwan B, Ahmad D, Cangara H, et al. The value of tumor-infiltrating lymphocytes and CD8 expression as a predictor of response to anthracycline-based neoadjuvant chemotherapy in invasive breast carcinoma of no special type. Breast Dis. 2021; 40(s1): S9-14, CrossRef.
Ng T, Phey XY, Yeo HL, Shwe M, Gan YX, Ng R, et al. Impact of adjuvant anthracycline-based and taxane-based chemotherapy on plasma VEGF levels and cognitive function in breast cancer patients: A longitudinal study. Clin Breast Cancer. 2018; 18(5): e927-37, CrossRef.
Shi X, Wang X, Yao W, Shi D, Shao X, Lu Z, et al. Mechanism insights and therapeutic intervention of tumor metastasis: Latest developments and perspectives. Signal Transduct Target Ther. 2024; 9(1): 192, CrossRef.
Saleh R, Elkord E. FoxP3⁺ T regulatory cells in cancer: Prognostic biomarkers and therapeutic targets. Cancer Lett. 2020; 490: 174-85, CrossRef.
Rustamadji P, Wiyarta E, Pramono M, Maulanisa S. Response to neoadjuvant chemotherapy in invasive breast cancer predicted by CD4⁺, CD8⁺, and FOXP3⁺ tumor-infiltrating lymphocytes. Asian Pac J Cancer Prev. 2024; 25(5): 1607-13, CrossRef.
Lejeune M, Reverté L, Sauras E, Gallardo N, Bosch R, Roso A, et al. Prognostic implications of the residual tumor microenvironment after neoadjuvant chemotherapy in triple-negative breast cancer patients without pathological complete response. Cancers. 2023; 15(3): 597, CrossRef.
Liu Z, Wang C, Chen X, Zhu J, Sun X, Xia Q, et al. Pathological response and predictive role of tumour-infiltrating lymphocytes in HER2-positive early breast cancer treated with neoadjuvant pyrotinib plus trastuzumab and chemotherapy (Panphila): A multicentre phase 2 trial. Eur J Cancer. 2022; 165: 157-68, CrossRef.
Leary A, Genestie C, Blanc-Durand F, Gouy S, Dunant A, Maulard A, et al. Neoadjuvant chemotherapy alters the balance of effector to suppressor immune cells in advanced ovarian cancer. Cancer Immunol Immunother. 2021; 70(2): 519-31, CrossRef.
DOI: https://doi.org/10.18585/inabj.v17i3.3680
Copyright (c) 2025 The Prodia Education and Research Institute
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
Indexed by:
The Prodia Education and Research Institute
