T regulatory cell markers in oral squamous cell carcinoma: Relationship with survival and tumor aggressiveness

Moreira,Geane; Fulgêncio,Lívia B.; De Mendonça,Elismauro F.; Leles,Cláudio R.; Batista,Aline C.; Da Silva,Tarcília A.

doi:10.3892/ol_00000023

T regulatory cell markers in oral squamous cell carcinoma: Relationship with survival and tumor aggressiveness

Authors:
- Geane Moreira
- Lívia B. Fulgêncio
- Elismauro F. De Mendonça
- Cláudio R. Leles
- Aline C. Batista
- Tarcília A. Da Silva
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Affiliations: Department of Oral Surgery and Pathology, Dental School, Federal University of Minas Gerais, Belo Horizonte, Brazil
Published online on: January 1, 2010 https://doi.org/10.3892/ol_00000023
Pages: 127-132

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Abstract

Tumor-infiltrating lymphocytes (TILs) are a heterogeneous cell family which plays an important role in tumor-associated immune response. Of these, T regulatory (Treg) cells have also been shown to inhibit anti-tumor response. We aimed to evaluate the expression of T regulatory cell markers (CD4, CD25, CTLA-4 and FoxP3) in samples of oral cavity squamous cell carcinoma (OCSCC) and lip SCC (LSCC) by immunohistochemistry. The relationship of Treg markers with survival data and the proliferative index were also evaluated. We observed similar numbers of CD4−, CD25− and FoxP3+ cells in OCSCC and LSCC. On the other hand, numbers of CTLA-4+ cells were significantly lower in OCSCC than in LSCC. OCSCC samples with high numbers of CD4 exhibited a high proliferative index, while samples with high CTLA-4 counts demonstrated a low tumoral proliferative index. A log-rank test showed that patients with OCSCC that presented high counts of CD4 showed a significantly decreased survival compared with patients with low cell counts. In contrast, high CD25+ cell counts were associated with increased survival. Our results suggest an association of CD4 with poor prognosis, while CD25 expression is related with favorable prognosis. These findings result from the heterogeneity of TIL subsets that display an antagonistic role in tumor immune cell response.

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1	Hanahan D, Lanzavecchia A and Mihich E: Fourteenth Annual Pezcoller Symposium: the novel dichotomy of immune interactions with tumors. Cancer Res. 63:3005–3008. 2003.PubMed/NCBI
2	Oliveira-Neto HH, Leite AF, Costa NL, et al: Decrease in mast cells in oral squamous cell carcinoma: possible failure in the migration of these cells. Oral Oncol. 43:484–490. 2007. View Article : Google Scholar : PubMed/NCBI
3	Akbar AN, Taams LS, Salmon M and Vukmanovic-Stejic M: The peripheral generation of CD4⁺ CD25⁺ regulatory T cells. Immunology. 109:319–325. 2003. View Article : Google Scholar : PubMed/NCBI
4	Wang HY, Lee DA, Peng G, et al: Tumor-specific human CD4+ regulatory T cells and their ligands: implications for immunotherapy. Immunity. 20:107–118. 2004.
5	Wei WZ, Morris GP and Kong YC: Anti-tumor immunity and autoimmunity: a balancing act of regulatory T cells. Cancer Immunol Immunother. 53:73–78. 2004. View Article : Google Scholar : PubMed/NCBI
6	Wang RF: Regulatory T cells and innate immune regulation in tumor immunity. Springer Semin Immunopathol. 28:17–23. 2006. View Article : Google Scholar : PubMed/NCBI
7	Yamaguchi T and Sakaguchi S: Regulatory T cells in immune surveillance and treatment of cancer. Semin Cancer Biol. 16:115–123. 2006. View Article : Google Scholar : PubMed/NCBI
8	Chen L: Co-inhibitory molecules of the B7-CD28 family in the control of T-cell immunity. Nat Rev Immunol. 4:336–347. 2004. View Article : Google Scholar : PubMed/NCBI
9	Chen W, Jen W, Hardegen N, et al: Conversion of peripheral CD4⁺ CD25 naive T cells to CD4⁺ CD25⁺ regulatory T cells by TGF-β induction of transcription factor FoxP3. J Exp Med. 198:1875–1886. 2003.
10	Hurwitz AA, Yu TF, Leach DR and Allison JP: CTLA-4 blockade synergizes with tumor-derived granulocyte-macrophage colony-stimulating factor for treatment of an experimental mammary carcinoma. Proc Natl Acad Sci USA. 95:10067–10071. 1998. View Article : Google Scholar
11	Hurwitz AA, Foster BA, Kwon ED, et al: Combination immunotherapy of primary prostate cancer in a transgenic mouse model using CTLA-4 blockade. Cancer Res. 60:2444–2448. 2000.PubMed/NCBI
12	Tartour E, Mosseri V, Jouffroy T, et al: Serum soluble interleukin-2 receptor concentrations as an independent prognostic marker in head and neck cancer. Lancet. 357:1263–1264. 2001. View Article : Google Scholar : PubMed/NCBI
13	Jones E, Dahm-Vicker M, Simon AK, et al: Depletion of CD25⁺ regulatory cells results in suppression of melanoma growth and induction of autoreactivity in mice. Cancer Immun. 2:1–12. 2002.
14	Phan GQ, Yang JC, Sherry RM, et al: Cancer regression and autoimmunity induced by cytotoxic T lymphocyte-associated antigen 4 blockade in patients with metastatic melanoma. Proc Natl Acad Sci USA. 100:8372–8377. 2003. View Article : Google Scholar : PubMed/NCBI
15	Curiel TJ, Coukos G, Zou L, et al: Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat Med. 10:942–949. 2004. View Article : Google Scholar : PubMed/NCBI
16	Ghaderi A, Yeganeh F, Kalantari T, et al: Cytotoxic T lymphocyte antigen-4 gene in breast cancer. Breast Cancer Res Treat. 86:1–7. 2004. View Article : Google Scholar : PubMed/NCBI
17	Wolf D, Wolf AM, Rumpold H, et al: The expression of the regulatory T cell-specific forkhead box transcription factor FoxP3 is associated with poor prognosis in ovarian cancer. Clin Cancer Res. 11:8326–8331. 2005. View Article : Google Scholar : PubMed/NCBI
18	Hiraoka N, Onozato K, Kosuge T and Hirohashi S: Prevalence of FoxP3⁺ regulatory T cells increases during the progression of pancreatic ductal adenocarcinoma and its premalignant lesions. Clin Cancer Res. 12:5423–5434. 2006.
19	Larkin J, Tangney M, Collins C, et al: Oral immune tolerance mediated by suppressor T cells may be responsible for the poorer prognosis of foregut cancers. Med Hypotheses. 66:541–544. 2006. View Article : Google Scholar : PubMed/NCBI
20	Downey SG, Klapper JA, Smith FO, et al: Prognostic factors related to clinical response in patients with metastatic melanoma treated by CTL-associated antigen-4 blockade. Clin Cancer Res. 13:6681–6688. 2007. View Article : Google Scholar : PubMed/NCBI
21	Fecci PE, Ochiai H, Mitchell DA, et al: Systemic CTLA-4 blockade ameliorates glioma-induced changes to the CD4⁺ T cell compartment without affecting regulatory T-cell function. Clin Cancer Res. 13:2158–2167. 2007. View Article : Google Scholar : PubMed/NCBI
22	Fu J, Xu D, Liu Z, et al: Increased regulatory T cells correlate with CD8 T-cell impairment and poor survival in hepatocellular carcinoma patients. Gastroenterology. 132:2328–2339. 2007. View Article : Google Scholar : PubMed/NCBI
23	Miracco C, Mourmouras V, Biagioli M, et al: Utility of tumour-infiltrating CD25⁺ FoxP3⁺ regulatory T cell evaluation in predicting local recurrence in vertical growth phase cutaneous melanoma. Oncol Rep. 18:1115–1122. 2007.PubMed/NCBI
24	Strauss L, Bergmann C and Whiteside TL: Functional and phenotypic characteristics of D4⁺ CD25-high FoxP3⁺ Treg clones obtained from peripheral blood of patients with cancer. Int J Cancer. 121:2473–2483. 2007.PubMed/NCBI
25	Chikamatsu K, Sakakura K, Whiteside TL and Furuya N: Relationships between regulatory T cells and CD8⁺ effector populations in patients with squamous cell carcinoma of the head and neck. Head Neck. 29:120–127. 2007.PubMed/NCBI
26	Loose D, Signore A, Bonanno E, et al: Prognostic value of CD25 expression on lymphocytes and tumor cells in squamous-cell carcinoma of the head and neck. Cancer Biother Radiopharm. 23:25–33. 2008. View Article : Google Scholar : PubMed/NCBI
27	Bai XF, Liu J, May KF Jr, Guo Y, Zheng P and Liu Y: B7-CTLA4 interaction promotes cognate destruction of tumor cells by cytotoxic T lymphocytes in vivo. Blood. 99:2880–2889. 2002. View Article : Google Scholar : PubMed/NCBI
28	Wang J, Ioan-Facsinay A, van der Voort EI, Huizinga TW and Toes RE: Transient expression of FoxP3 in human activated nonregulatory CD4⁺ T cells. Eur J Immunol. 37:129–138. 2007. View Article : Google Scholar : PubMed/NCBI
29	Zheng Y and Rudensky AY: Foxp3 in control of the regulatory T cell lineage. Nat Immunol. 8:457–462. 2007. View Article : Google Scholar : PubMed/NCBI
30	Badoual C, Hans S, Rodriguez J, et al: Prognostic value of tumor-infiltrating CD4⁺ T-cell subpopulations in head and neck cancers. Clin Cancer Res. 12:465–472. 2006. View Article : Google Scholar : PubMed/NCBI
31	Böheim K, Denz H, Böheim C, Glassl H and Huber H: An immunohistologic study of the distribution and status of activation of head and neck tumor infiltrating leukocytes. Arch Otorhinolaryngol. 244:127–132. 1987.PubMed/NCBI
32	Antunes JLF, Biazevic MGH, de Araujo ME, Tomita NE, Chinellato LEM and Narvai PC: Trends and spatial distribution of oral cancer mortality in São Paulo, Brazil, 1980–1998. Oral Oncol. 37:345–350. 2001.
33	Vartanian JG, Carvalho AL, Filho MJA, Júnior MH, Magrin J and Kowalski LP: Predictive factors and distribution of lymph node metastasis in lip cancer patients and their implications on the treatment of the neck. Oral Oncol. 40:223–227. 2004. View Article : Google Scholar : PubMed/NCBI
34	Wong YK, Chang KW, Cheng CY and Liu CJ: Association of CTLA-4 gene polymorphism with oral squamous cell carcinoma. J Oral Pathol Med. 35:51–54. 2006. View Article : Google Scholar : PubMed/NCBI
35	Ke X, Wang J, Li L, Chen IH, Wang H and Yang XF: Roles of CD4⁺xCD25(high) FoxP3⁺ Tregs in lymphomas and tumors are complex. Front Biosci. 13:3986–4001. 2008.
36	Schwarz S, Butz M, Morsczeck C, Reichert TE and Driemel O: Increased number of CD25 FoxP3 regulatory T cells in oral squamous cell carcinomas detected by chromogenic immunohistochemical double staining. J Oral Pathol Med. 37:485–489. 2008. View Article : Google Scholar : PubMed/NCBI
37	Cho Y, Miyamoto M, Kato K, et al: CD4⁺ and CD8⁺ T cells cooperate to improve prognosis of patients with esophageal squamous cell carcinoma. Cancer Res. 63:1555–1559. 2003.
38	Bromwich EJ, McArdle PA, Canna K, et al: The relationship between T-lymphocyte infiltration, stage, tumour grade and survival in patients undergoing curative surgery for renal cell cancer. Br J Cancer. 89:1906–1908. 2003. View Article : Google Scholar
39	Agarwal A, Rani M, Saha GK, et al: Disregulated expression of the Th2 cytokine gene in patients with intraoral squamous cell carcinoma. Immunol Invest. 32:17–30. 2003. View Article : Google Scholar : PubMed/NCBI
40	Ebert LM, Tan BS, Browning J, et al: The regulatory T cell-associated transcription factor FoxP3 is expressed by tumor cells. Cancer Res. 68:3001–3009. 2008. View Article : Google Scholar : PubMed/NCBI
41	Karanikas V, Speletas M, Zamanakou M, et al: FoxP3 expression in human cancer cells. J Transl Med. 6:19–24. 2008. View Article : Google Scholar : PubMed/NCBI