Skip to main content
Top
Published in: Journal of Cancer Research and Clinical Oncology 10/2010

01-10-2010 | Original Paper

Higher intratumoral infiltrated Foxp3+ Treg numbers and Foxp3+/CD8+ ratio are associated with adverse prognosis in resectable gastric cancer

Authors: Zhengbin Shen, Shuang Zhou, Yanna Wang, Ri-lun Li, Cuiping Zhong, Chunmin Liang, Yihong Sun

Published in: Journal of Cancer Research and Clinical Oncology | Issue 10/2010

Login to get access

Abstract

Purpose

The aim of the present study was to investigate the prognostic value of tumor-infiltrated lymphocytes (TILs), especially the prognostic value of Foxp3+ regulatory T cells (Tregs), CD8+ CTLs and Tregs/CD8+ ratios in gastric cancer patients after R0 resection.

Patients and methods

From 133 patients, CD4+, CD8+ and Foxp3+ TILs were assessed by immunohistochemistry in tissue microarrays and N1 regional lymph nodes sections containing gastric cancer. The prognostic effects of low- or high-density TIL subsets were evaluated by Cox regression and Kaplan–Meier analysis using median values as cutoff, while the effects of Foxp3+/CD8+ ratios were evaluated using the value determined by ROC cure analysis as cutoff.

Results

It was found that CD4+ and CD8+ TILs were not associated with overall survival (OS). In the tumor sites, higher Foxp3+ Tregs/CD8+ ratio was an independent factor for worse OS (multivariate analysis HR = 2.827, P = 0.037). The 1-year, 2-year and 3-year OS rates were 90, 77.5 and 70% for the group with intratumoral high Tregs/CD8+ ratio, compared with 100, 94.3 and 90.5% for the group with intratumoral low ratio. At the same time, the presence of intratumoral high Foxp3+ Tregs was also associated with worse OS (log rank test, P = 0.025); however, it was not an independent predictor and correlated with intratumoral Foxp3+ Tregs/CD8+ ratio (χ 2 test, P < 0.001). Although the infiltration of Foxp3+ Tregs in N1 regional lymph nodes was associated with lymph node metastasis (P = 0.028), it was not associated with prognosis (P = 0.458).

Conclusions

Intratumoral high Foxp3+ Tregs/CD8+ ratio was an independent predictor for the prognosis of gastric cancer. It can be inferred that a combination of deletion of Tregs and stimulation of CD8+ effector T cells may be an effective immunotherapy to prolong survival after surgery.
Appendix
Available only for authorised users
Literature
go back to reference Alvaro T, Lejeune M, Salvado MT et al (2005) Outcome in Hodgkin’s lymphoma can be predicted from the presence of accompanying cytotoxic and regulatory T cells. Clin Cancer Res 11:1467–1473CrossRefPubMed Alvaro T, Lejeune M, Salvado MT et al (2005) Outcome in Hodgkin’s lymphoma can be predicted from the presence of accompanying cytotoxic and regulatory T cells. Clin Cancer Res 11:1467–1473CrossRefPubMed
go back to reference Amy B, Heimberger, Mohamed AG et al (2008) Incidence and prognostic impact of Foxp3+ regulatory T cells in human gliomas. Clin Cancer Res 14:5166–5172CrossRef Amy B, Heimberger, Mohamed AG et al (2008) Incidence and prognostic impact of Foxp3+ regulatory T cells in human gliomas. Clin Cancer Res 14:5166–5172CrossRef
go back to reference Badoual C, Hans S, Rodriguez J et al (2006) Prognostic value of tumor-infiltrating CD4+ T-cell subpopulations in head and neck cancers. Clin Cancer Res 12:465–472CrossRefPubMed Badoual C, Hans S, Rodriguez J et al (2006) Prognostic value of tumor-infiltrating CD4+ T-cell subpopulations in head and neck cancers. Clin Cancer Res 12:465–472CrossRefPubMed
go back to reference Bates GJ, Fox SB, Han C et al (2006) Quantification of regulatory T cells enables the identification of high-risk breast cancer patients and those at risk of late relapse. J Clin Oncol 24:5373–5380CrossRefPubMed Bates GJ, Fox SB, Han C et al (2006) Quantification of regulatory T cells enables the identification of high-risk breast cancer patients and those at risk of late relapse. J Clin Oncol 24:5373–5380CrossRefPubMed
go back to reference Chiou SH, Sheu BC, Chang WC et al (2005) Current concepts of tumor-infiltrating lymphocytes in human malignancies. J Reprod Immunol 67:35–50CrossRefPubMed Chiou SH, Sheu BC, Chang WC et al (2005) Current concepts of tumor-infiltrating lymphocytes in human malignancies. J Reprod Immunol 67:35–50CrossRefPubMed
go back to reference Curiel TJ, Coukos G, Zou L et al (2004) Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat Med 10:942–949CrossRefPubMed Curiel TJ, Coukos G, Zou L et al (2004) Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat Med 10:942–949CrossRefPubMed
go back to reference Dieckmann D, Bruett CH, Ploettner H, Lutz MB, Schuler G (2002) Human CD41CD251 regulatory, contact-dependent T cells, induce interleukin 10-producing, contact-independent type 1-like regulatory T cells. J Exp Med 196:247–253CrossRefPubMed Dieckmann D, Bruett CH, Ploettner H, Lutz MB, Schuler G (2002) Human CD41CD251 regulatory, contact-dependent T cells, induce interleukin 10-producing, contact-independent type 1-like regulatory T cells. J Exp Med 196:247–253CrossRefPubMed
go back to reference Earle KE, Tang Q, Zhou X, Liu W, Zhu S, Bonyhadi ML, Bluestone JA (2005) In vitro expanded human CD41CD251 regulatory T cells suppress effector T cell proliferation. Clin Immunol 115:3–9CrossRefPubMed Earle KE, Tang Q, Zhou X, Liu W, Zhu S, Bonyhadi ML, Bluestone JA (2005) In vitro expanded human CD41CD251 regulatory T cells suppress effector T cell proliferation. Clin Immunol 115:3–9CrossRefPubMed
go back to reference Fu J, Xu D, Liu Z et al (2007) Increased regulatory T cells correlate with CD8 T-cell impairment and poor survival in hepatocellular carcinoma patients. Gastroenterology 132:2328–2339CrossRefPubMed Fu J, Xu D, Liu Z et al (2007) Increased regulatory T cells correlate with CD8 T-cell impairment and poor survival in hepatocellular carcinoma patients. Gastroenterology 132:2328–2339CrossRefPubMed
go back to reference Galon J, Costes A, Sanchez-Cabo F et al (2006) Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science 313:1960–1964CrossRefPubMed Galon J, Costes A, Sanchez-Cabo F et al (2006) Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science 313:1960–1964CrossRefPubMed
go back to reference Gao Q, Qiu SJ, Fan J et al (2007) Intratumoral balance of regulatory and cytotoxic T cells is associated with prognosis of hepatocellular carcinoma after resection. J Clin Oncol 25:2586–2593CrossRefPubMed Gao Q, Qiu SJ, Fan J et al (2007) Intratumoral balance of regulatory and cytotoxic T cells is associated with prognosis of hepatocellular carcinoma after resection. J Clin Oncol 25:2586–2593CrossRefPubMed
go back to reference Giuseppe P, Pier AR, Vincenzo C et al (2008) Intratumoural Foxp3+ Regulatory T cells are associated with adverse prognosis in radically resected gastric cancer. Eur J Cancer 44:1875–1882CrossRef Giuseppe P, Pier AR, Vincenzo C et al (2008) Intratumoural Foxp3+ Regulatory T cells are associated with adverse prognosis in radically resected gastric cancer. Eur J Cancer 44:1875–1882CrossRef
go back to reference Grabenbauer GG, Lahmer G, Distel L et al (2006) Tumor-infiltrating cytotoxic T cells but not regulatory T cells predict outcome in anal squamous cell carcinoma. Clin Cancer Res 12:3355–3360CrossRefPubMed Grabenbauer GG, Lahmer G, Distel L et al (2006) Tumor-infiltrating cytotoxic T cells but not regulatory T cells predict outcome in anal squamous cell carcinoma. Clin Cancer Res 12:3355–3360CrossRefPubMed
go back to reference Griffiths RW, Elkord E, Gilham DE et al (2007) Frequency of regulatory T cells in renal cell carcinoma patients and investigation of correlation with survival. Cancer Immunol Immunother 56:1743–1753CrossRefPubMed Griffiths RW, Elkord E, Gilham DE et al (2007) Frequency of regulatory T cells in renal cell carcinoma patients and investigation of correlation with survival. Cancer Immunol Immunother 56:1743–1753CrossRefPubMed
go back to reference Hiraoka N, Onozato K, Kosuge T, Hirohashi S (2006) Prevalence of FOXP3+ regulatory T cells increases during the progression of pancreatic ductal adenocarcinoma and its premalignant lesions. Clin Cancer Res 12:5423–5434CrossRefPubMed Hiraoka N, Onozato K, Kosuge T, Hirohashi S (2006) Prevalence of FOXP3+ regulatory T cells increases during the progression of pancreatic ductal adenocarcinoma and its premalignant lesions. Clin Cancer Res 12:5423–5434CrossRefPubMed
go back to reference Hori S, Sakaguchi S (2004) Foxp3: a critical regulator of the development and function of regulatory T cells. Microbes Infect 6:745–751CrossRefPubMed Hori S, Sakaguchi S (2004) Foxp3: a critical regulator of the development and function of regulatory T cells. Microbes Infect 6:745–751CrossRefPubMed
go back to reference Ichihara F, Kono K, Takahashi A, Kawaida H et al (2003) Increased populations of regulatory T cells in peripheral blood and tumor-infiltrating lymphocytes in patient with gastric and esophageal cancers. Clin Cancer Res 9:4404–4408PubMed Ichihara F, Kono K, Takahashi A, Kawaida H et al (2003) Increased populations of regulatory T cells in peripheral blood and tumor-infiltrating lymphocytes in patient with gastric and esophageal cancers. Clin Cancer Res 9:4404–4408PubMed
go back to reference Japanese Gastric Cancer Association (1998) Japanese classification of gastric carcinoma–2nd English edition. Gastric Cancer 1:10–24CrossRefPubMed Japanese Gastric Cancer Association (1998) Japanese classification of gastric carcinoma–2nd English edition. Gastric Cancer 1:10–24CrossRefPubMed
go back to reference Kamangar F, Dores GM, Anderson WF (2006) Patterns of cancer incidence, mortality, and prevalence across five continents: defining priorities to reduce cancer disparities in different geographic regions of the world. J Clin Oncol 24(14):2137–2150CrossRefPubMed Kamangar F, Dores GM, Anderson WF (2006) Patterns of cancer incidence, mortality, and prevalence across five continents: defining priorities to reduce cancer disparities in different geographic regions of the world. J Clin Oncol 24(14):2137–2150CrossRefPubMed
go back to reference Kawaida H, Kono K, Takahashi A et al (2005) Distribution of CD4+ CD25high regulatory T-cells in tumor-draining lymph nodes in patients with gastric cancer. J Surg Res 124:151–157CrossRefPubMed Kawaida H, Kono K, Takahashi A et al (2005) Distribution of CD4+ CD25high regulatory T-cells in tumor-draining lymph nodes in patients with gastric cancer. J Surg Res 124:151–157CrossRefPubMed
go back to reference Kononen J, Bubendorf L, Kallioniemi A et al (1998) Tissue microarrays for high throughput molecular profiling of tumor specimens. Nat Med 4:844–847CrossRefPubMed Kononen J, Bubendorf L, Kallioniemi A et al (1998) Tissue microarrays for high throughput molecular profiling of tumor specimens. Nat Med 4:844–847CrossRefPubMed
go back to reference Lee AM, Clear AJ, Calaminici M et al (2006) Number of CD4+ cells and location of forkhead box protein P3-positive cells in diagnostic follicular lymphoma tissue microarrays correlates with outcome. J Clin Oncol 24:5052–5059CrossRefPubMed Lee AM, Clear AJ, Calaminici M et al (2006) Number of CD4+ cells and location of forkhead box protein P3-positive cells in diagnostic follicular lymphoma tissue microarrays correlates with outcome. J Clin Oncol 24:5052–5059CrossRefPubMed
go back to reference Li JF, Chu YW, Wang GM et al (2008) The prognostic value of peritumoral regulatory T cells and its correction with intratumoral cyclooxygenase-2 expression in clear cell renal cell carcinoma. BJU Int 103:399–405CrossRefPubMed Li JF, Chu YW, Wang GM et al (2008) The prognostic value of peritumoral regulatory T cells and its correction with intratumoral cyclooxygenase-2 expression in clear cell renal cell carcinoma. BJU Int 103:399–405CrossRefPubMed
go back to reference Longhi MS, Hussain MJ, Mitry RR et al (2006) Functional study of CD41CD251 regulatory T cells in health and autoimmune hepatitis. J Immunol 176:4484–4491PubMed Longhi MS, Hussain MJ, Mitry RR et al (2006) Functional study of CD41CD251 regulatory T cells in health and autoimmune hepatitis. J Immunol 176:4484–4491PubMed
go back to reference Mizukami Y, Kono K, Kawaguchi Y et al (2008) Localisation pattern of Foxp3+ regulatory T cell is associated with clinical behavior in gastric cancer. Br J Cancer 98:148–153CrossRefPubMed Mizukami Y, Kono K, Kawaguchi Y et al (2008) Localisation pattern of Foxp3+ regulatory T cell is associated with clinical behavior in gastric cancer. Br J Cancer 98:148–153CrossRefPubMed
go back to reference Nakano O, Sato M, Naito Y et al (2001) Proliferative activity of intratumoral CD8+ T-lymphocytes as a prognostic factor in human renal cell carcinoma: Clinicopathologic demonstration of antitumor immunity. Cancer Res 61:5132–5136PubMed Nakano O, Sato M, Naito Y et al (2001) Proliferative activity of intratumoral CD8+ T-lymphocytes as a prognostic factor in human renal cell carcinoma: Clinicopathologic demonstration of antitumor immunity. Cancer Res 61:5132–5136PubMed
go back to reference Petersen RP, Campa MJ, Sperlazza J et al (2006) Tumor-infiltrating Foxp3+ regulatory T-cells are associated with recurrence in pathologic stage I NSCLC patients. Cancer 107:2866–2872CrossRefPubMed Petersen RP, Campa MJ, Sperlazza J et al (2006) Tumor-infiltrating Foxp3+ regulatory T-cells are associated with recurrence in pathologic stage I NSCLC patients. Cancer 107:2866–2872CrossRefPubMed
go back to reference Piccirillo CA, Thornton AM (2004) Cornerstone of peripheral tolerance: naturally occurring CD4+ CD25+ regulatory T cells. Trends Immunol 25:374–380CrossRefPubMed Piccirillo CA, Thornton AM (2004) Cornerstone of peripheral tolerance: naturally occurring CD4+ CD25+ regulatory T cells. Trends Immunol 25:374–380CrossRefPubMed
go back to reference Salama P, Phillips M, Grieu F et al (2008) Tumor-infiltrating FOXP3+ T regulatory cells show strong prognostic significance in colorectal cancer. J Clin Oncol 27:186–192CrossRefPubMed Salama P, Phillips M, Grieu F et al (2008) Tumor-infiltrating FOXP3+ T regulatory cells show strong prognostic significance in colorectal cancer. J Clin Oncol 27:186–192CrossRefPubMed
go back to reference Sato E, Olson SH, Ahn J et al (2005) Intraepithelial CD8+ tumor-infiltrating lymphocytes and a high CD8+/regulatory T cell ratio are associated with favorable prognosis in ovarian cancer. Proc Natl Acad Sci USA 102:18538–18543CrossRefPubMed Sato E, Olson SH, Ahn J et al (2005) Intraepithelial CD8+ tumor-infiltrating lymphocytes and a high CD8+/regulatory T cell ratio are associated with favorable prognosis in ovarian cancer. Proc Natl Acad Sci USA 102:18538–18543CrossRefPubMed
go back to reference Schumacher K, Haensch W, Roefzaad C et al (2001) Prognostic significance of activated CD8+ T cell infiltrations within esophageal carcinomas. Cancer Res 61:3932–3936PubMed Schumacher K, Haensch W, Roefzaad C et al (2001) Prognostic significance of activated CD8+ T cell infiltrations within esophageal carcinomas. Cancer Res 61:3932–3936PubMed
go back to reference Yuan XL, Chen L, Li MX et al (2009) Elevated expression of Foxp3 in tumor-infiltrating Treg cells suppresses T-cell proliferation and contributes to gastric cancer progression in a COX-2- dependent manner. Clin Immunol. 7 Nov 2009 [Epub ahead of print] Yuan XL, Chen L, Li MX et al (2009) Elevated expression of Foxp3 in tumor-infiltrating Treg cells suppresses T-cell proliferation and contributes to gastric cancer progression in a COX-2- dependent manner. Clin Immunol. 7 Nov 2009 [Epub ahead of print]
Metadata
Title
Higher intratumoral infiltrated Foxp3+ Treg numbers and Foxp3+/CD8+ ratio are associated with adverse prognosis in resectable gastric cancer
Authors
Zhengbin Shen
Shuang Zhou
Yanna Wang
Ri-lun Li
Cuiping Zhong
Chunmin Liang
Yihong Sun
Publication date
01-10-2010
Publisher
Springer-Verlag
Published in
Journal of Cancer Research and Clinical Oncology / Issue 10/2010
Print ISSN: 0171-5216
Electronic ISSN: 1432-1335
DOI
https://doi.org/10.1007/s00432-010-0816-9

Other articles of this Issue 10/2010

Journal of Cancer Research and Clinical Oncology 10/2010 Go to the issue