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

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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.

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Acknowledgments

This work was supported by grants from the National Science Foundation of China (grants 30500280 and 30871312).

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Authors and Affiliations

  1. The General Surgery Department of Zhongshan Hospital, Fudan University, Shanghai, China

    Zhengbin Shen, Yanna Wang & Yihong Sun

  2. The Department of Anatomy and Histology and Embryology, Shanghai Medical College, Fudan University, Shanghai, China

    Shuang Zhou, Ri-lun Li, Cuiping Zhong & Chunmin Liang

  3. The Liver Cancer Institue of Zhongshan Hospital, Fudan University, Shanghai, China

    Chunmin Liang

Authors
  1. Zhengbin Shen
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  2. Shuang Zhou
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  3. Yanna Wang
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  4. Ri-lun Li
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  5. Cuiping Zhong
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  6. Chunmin Liang
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  7. Yihong Sun
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Corresponding authors

Correspondence to Chunmin Liang or Yihong Sun.

Appendix

Appendix

See Fig. 4.

Fig. 4
figure 4

K–M analysis for the direct correlation between the infiltration of TILs and clinical overall survival (OS) after surgery. a, b The correlation of introtumor infiltrated CD4+, CD8+ T cells with OS. c, d The correlation of infiltrated CD4+, CD8+ T cells in L.N with OS. e, f The correlation of infiltrated Foxp3+ Treg cells with OS

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See Tables 6, 7 and 8.

Table 6 Multiple analysis of factors associated with overall survival
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Table 7 Correlation between CD4+ TILs and clinical characteristics
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Table 8 Correlation between CD8+ TILs and clinical characteristics
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Shen, Z., Zhou, S., Wang, Y. et al. Higher intratumoral infiltrated Foxp3+ Treg numbers and Foxp3+/CD8+ ratio are associated with adverse prognosis in resectable gastric cancer. J Cancer Res Clin Oncol 136, 1585–1595 (2010). https://doi.org/10.1007/s00432-010-0816-9

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  • DOI: https://doi.org/10.1007/s00432-010-0816-9

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