Summary
The transforming growth factor β1 (TGF-β1) and CD8-positive T cells are two important immune factors that function at opposite directions. The purpose of this study was to verify the relationship between the two factors and their associations with long-term effects of adjuvant chemotherapy or endocrine therapy in breast cancer. Expression of TGF-β1 precursor and CD8 was immunohistochemically detected on surgically-obtained tumor samples of 130 (stage I–III) invasive breast carcinomas from Chinese subjects, who were followed up for a mean time of 112 months. Interstitial CD8-positive cells and TGF-β1 precursor-positive cells adjacent to tumor nests were counted. Infiltration of CD8-positive lymphocytes into tumor nests and TGF-β1 precursor expression in tumor cells were observed and survival analysis was performed. Our results showed that density of interstitial CD8-positive lymphocytes was an independent adverse prognostic factor for distant disease-free survival (DDFS) (HR=8.416, 95% CI=1.636–43.292, P=0.011) in hormone receptor-positive patients who were on adjuvant endocrine therapy. For breast cancer patients who did not receive adjuvant chemotherapy, those without infiltration of CD8-positive cells into tumor nests had a shorter overall survival (OS) than their counterparts with CD8-positive cell infiltration into tumor nests (Log-Rank, P=0.003). But OS of patients without infiltration of CD8-positive cells into tumor nests was significantly prolonged by adjuvant chemotherapy (Log-Rank, P=0.013) and paralleled that of patients with CD8-positive cell infiltration. Although OS was shorter in the tumor cell TGF-β1 precursor (t-TGF-β1-pre)-positive patients than in the negative patients in patients without recieiving chemotherapy (P=0.053), OS of t-TGF-β1-pre-positive patients was significantly prolonged by adjuvant chemotherapy (P=0.035) and was longer than that of t-TGF-β1-pre-negative patients. Analysis showed that t-TGF-β1-pre was an independent positive prognostic factor for DDFS (HR=0.392 95% CI=0.157–0.978, P=0.045) in patients who received adjuvant chemotherapy. This study suggested that density of interstitial CD8-positive lymphocytes was of prognostic value in hormone receptor-positive patients who received adjuvant endocrine therapy. Our study verified that adverse immunologic signatures consisting of absence of CD8-positive cells in tumor nests or expression of TGF-β1 precursor in tumor cells in breast cancer were associated with worse prognosis and significantly improved long-term survival with adjuvant chemotherapy, respectively.
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Chen ML, Pittet MJ, Gorelik L, et al. Regulatory T cells suppress tumor-specific CD8 T cell cytotoxicity through TGF-beta signals in vivo. Proc Natl Acad Sci USA, 2005, 102(2):419–424
Olkhanud PB, Damdinsuren B, Bodogai M, et al. Tumor-evoked regulatory B cells promote breast cancer metastasis by converting resting CD4.T cells to T-regulatory cells. Cancer Res, 2011,71(10):3505–3515
Xu L, Xu W, Wen Z, et al. In situ prior proliferation of CD4+ CCR6+ regulatory T cells facilitated by TGF-β secreting DCs is crucial for their enrichment and suppression in tumor immunity. PLoS One, 2011,6(5):e20282
Yu J, Wei M, Becknell B, et al. Pro- and antiinflammatory cytokine signaling: reciprocal antagonism regulates interferon-gamma production by human natural killer cells. Immunity, 2006,24(5):575–590
Yang L, Huang J, Ren X, et al. Abrogation of TGF beta signaling in mammary carcinomas recruits Gr-1+CD11b+ myeloid cells that promote metastasis. Cancer Cell, 2008, 13(1):23–35
Laoui D, Movahedi K, Van Overmeire E, et al. Tumor-associated macrophages in breast cancer: distinct subsets, distinct functions. Int J Dev Biol, 2011,55(7–9): 861–867
Hung SP, Yang MH, Tseng KF, et al. Hypoxia-induced secretion of TGF-beta 1 in mesenchymal stem cell promotes breast cancer cell progression. Cell Transplant, 2013,22(10):1869–1882
Filaci G, Suciu-Foca N. CD8+ T suppressor cells are back to the game: are they players in autoimmunity? Autoimmun Rev, 2002,1(5):279–283
Murri AM, Hilmy M, Bell J, et al. The relationship between the systemic inflammatory response, tumour proliferative activity, T-lymphocytic and macrophage infiltration, microvessel density and survival in patients with primary operable breast cancer. Br J Cancer, 2008, 99(7):1013–1019
Lee AH, Happerfield LC, Bobrow LG, et al. Angiogenesis and inflammation in ductal carcinoma in situ of the breast. J Pathol, 1997,181(2):200–206
Rody A, Karn T, Liedtke C, et al. A clinically relevant gene signature in triple negative and basal-like breast cancer. Breast Cancer Res, 2011,13(5):R97
Finak G, Bertos N, Pepin F, et al. Stromal gene expression predicts clinical outcome in breast cancer. Nat Med, 2008, 14(5):518–527
Mahmoud SM, Paish EC, Powe DG, et al. Tumor-infiltrating CD8+ lymphocytes predict clinical outcome in breast cancer. J Clin Oncol, 2011,29(15): 1949–1955
Liu S, Lachapelle J, Leung S, et al. CD8+ lymphocyte infiltration is an independent favorable prognostic indicator in basal-like breast cancer. Breast Cancer Res, 2012,14(2):R48
DeNardo DG, Brennan DJ, Rexhepaj E. Leukocyte complexity predicts breast cancer survival and functionally regulates response to chemotherapy. Cancer Discov, 2011,(1):54–67
West NR, Milne K, Truong PT, et al. Tumor-infiltrating lymphocytes predict response to anthracycline-based chemotherapy in estrogen receptor-negative breast cancer. Breast Cancer Res, 2011,13(6):R126
Ladoire S, Arnould L, Apetoh L, et al. Pathologic complete response to neoadjuvant chemotherapy of breast carcinoma is associated with the disappearance of tumor-infiltrating foxp3+ regulatory T cells. Clin Cancer Res, 2008,14(8):2413–2420
Rody A, Holtrich U, Pusztai L, et al. T-cell metagene predicts a favorable prognosis in estrogen receptor-negative and HER2-positive breast cancers. Breast Cancer Res, 2009,11(2):R15
Emens LA. Chemoimmunotherapy. Cancer J, 2010,16(4): 295–303
Padua D, Zhang XH, Wang Q, et al. TGFbeta primes breast tumors for lung metastasis seeding through angiopoietin-like 4. Cell, 2008,133(1):66–77
Arteaga CL, Hurd SD, Winnier AR, et al. Anti-transforming growth factor (TGF)-beta antibodies inhibit breast cancer cell tumorigenicity and increase mouse spleen natural killer cell activity. Implications for a possible role of tumor cell/host TGF-beta interactions in human breast cancer progression. J Clin Invest, 1993, 92(6):2569–2576
Bluff JE, Menakuru SR, Cross SS, et al. Angiogenesis is associated with the onset of hyperplasia in human ductal breast disease. Br J Cancer, 2009,18;101(4):666–672
Imai K, Minamiya Y, Koyota S, et al. Inhibition of dendritic cell migration by transforming growth factor-β1 increases tumor-draining lymph node metastasis. J Exp Clin Cancer Res, 2012,31:3
Lee GT, Hong JH, Kwak C, et al. Effect of dominant negative transforming growth factor-beta receptor type II on cytotoxic activity of RAW 264.7, a murine macrophage cell line. Cancer Res, 2007,67(14):6717–6724
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The two authors contributed equally to the project.
This project was supported by the Wu Jieping Medical Foundation (No. 320.6752.1230).
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Yu, Hm., Yang, Jl., Jiao, Sc. et al. TGF-β1 precursor and CD8 are potential prognostic and predictive markers in operated breast cancer. J. Huazhong Univ. Sci. Technol. [Med. Sci.] 34, 51–58 (2014). https://doi.org/10.1007/s11596-014-1231-2
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DOI: https://doi.org/10.1007/s11596-014-1231-2