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Annals of Surgical Oncology

, Volume 21, Supplement 3, pp 414–421 | Cite as

CD8+ and FOXP3+ Tumor-Infiltrating T Cells Before and After Chemoradiotherapy for Rectal Cancer

  • Eiji ShintoEmail author
  • Kazuo Hase
  • Yojiro Hashiguchi
  • Akinori Sekizawa
  • Hideki Ueno
  • Atsushi Shikina
  • Yoshiki Kajiwara
  • Hirotoshi Kobayashi
  • Megumi Ishiguro
  • Junji Yamamoto
Colorectal Cancer

Abstract

Background

CD8+ cytotoxic T cells and forkhead box P3 (FOXP3)+ regulatory T cells are major players in tumor immunity. Increased CD8+ tumor-infiltrating lymphocytes (TILs) and high CD8/FOXP3 TIL ratios are associated with improved survival. Neoadjuvant chemoradiotherapy (CRT) can result in tumor regression; however, immunomodulation during CRT for rectal cancer has not been thoroughly assessed. We investigated whether neoadjuvant CRT altered the in situ immune cell population and clinical implications of TIL accumulation before and after CRT.

Methods

We recruited 93 rectal cancer patients who underwent neoadjuvant CRT and radical resection. Pretreatment biopsy and post-CRT resected specimens were immunostained for CD8 and FOXP3, and the densities of stromal (STL) and intraepithelial (IEL) immunopositive TILs were determined separately. In addition, 54 patients with resections but without neoadjuvant CRT were enrolled for comparison.

Results

CD8+ STL density doubled after CRT (average counts: 92 vs. 230 per microscopic field using a 20 × objective lens; P < 0.0001), whereas FOXP3+ STL counts remained stable (109 vs. 109). Compared with non-CRT cases, CRT increased CD8+ STL density. Multivariate analyses demonstrated that high post-CRT CD8 + STL density was associated with better prognosis (5-year recurrence-free survival: 87.5 vs. 57.8 %; P = 0.0058) and that a high pretreatment CD8/FOXP3 IEL ratio was a predictor of favorable tumor regression (P = 0.0029).

Conclusions

Favorable anticancer immunity occurred after CRT for rectal cancer by altering TIL subsets. A high CD8/FOXP3 IEL ratio before CRT and a high CD8+ STL density after CRT were associated with a favorable clinical outcome.

Keywords

Rectal Cancer Resected Specimen Total Mesorectal Excision Rectal Cancer Patient Lower Rectal Cancer 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgment

This work was supported in part by the National Cancer Center Research and Development Fund (23-A-11 and 23-A-26) and by Japan Society for the Promotion of Science KAKENHI (23501302 and 25462074). We certify that we do not have any commercial associations that may pose a conflict of interest in connection with this article.

References

  1. 1.
    Galon J, Costes A, Sanchez-Cabo F, et al. Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science. 2006;313:1960–4.PubMedCrossRefGoogle Scholar
  2. 2.
    Gao Q, Qiu SJ, Fan J, et al. Intratumoral balance of regulatory and cytotoxic T cells is associated with prognosis of hepatocellular carcinoma after resection. J Clin Oncol. 2007;25:2586–93.PubMedCrossRefGoogle Scholar
  3. 3.
    Ladoire S, Martin F, Ghiringhelli F. Prognostic role of FOXP3+ regulatory T cells infiltrating human carcinomas: the paradox of colorectal cancer. Cancer Immunol Immunother. 2011;60:909–18.PubMedCrossRefGoogle Scholar
  4. 4.
    Naito Y, Saito K, Shiiba K, et al. CD8 + T cells infiltrated within cancer cell nests as a prognostic factor in human colorectal cancer. Cancer Res. 1998;58:3491–4.PubMedGoogle Scholar
  5. 5.
    Colorectal Cancer Collaborative Group. Adjuvant radiotherapy for rectal cancer: a systematic overview of 8,507 patients from 22 randomised trials. Lancet. 2001;358:1291–304.CrossRefGoogle Scholar
  6. 6.
    Folkesson J, Birgisson H, Pahlman L, Cedermark B, Glimelius B, Gunnarsson U. Swedish rectal cancer trial: long lasting benefits from radiotherapy on survival and local recurrence rate. J Clin Oncol. 2005;23:5644–50.PubMedCrossRefGoogle Scholar
  7. 7.
    Hoff PM, Pazdur R, Benner SE, et al. UFT and leucovorin: a review of its clinical development and therapeutic potential in the oral treatment of cancer. Anticancer Drugs. 1998;9:479–90.PubMedGoogle Scholar
  8. 8.
    Hirata K, Sasaki K, Yamamitsu S, et al. A comparison of 5-fluorouracil concentration of 5-fluorouracil drip infusion versus oral UFT in plasma of same patients (in Japanese). Gan To Kagaku Ryoho (Jpn J Cancer Chemother). 1993;20:1409–11.Google Scholar
  9. 9.
    Ho DH, Pazdur R, Covington W, et al. Comparison of 5-fluorouracil pharmacokinetics in patients receiving continuous infusion and oral uracil plus N1-(29-tetrahydrofuryl)-5-fluorouracil. Clin Cancer Res. 1998;4:2085–8.PubMedGoogle Scholar
  10. 10.
    Cellier P, Leduc B, Martin L, et al. Phase II study of preoperative radiation plus concurrent daily tegafur-uracil (UFT) with leucovorin for locally advanced rectal cancer. BMC Cancer. 2011;11:98.PubMedCentralPubMedCrossRefGoogle Scholar
  11. 11.
    Stewart CC, Perez CA. Effect of irradiation on immune responses. Radiology. 1976;118:201–10.PubMedGoogle Scholar
  12. 12.
    Kitayama J, Yasuda K, Kawai K, Sunami E, Nagawa H. Circulating lymphocyte number has a positive association with tumor response in neoadjuvant chemoradiotherapy for advanced rectal cancer. Radiat Oncol. 2010;5:47.PubMedCentralPubMedCrossRefGoogle Scholar
  13. 13.
    Wilkins RC, Kutzner BC, Truong M, McLean JR. The effect of the ratio of CD4+ to CD8+ T-cells on radiation-induced apoptosis in human lymphocyte subpopulations. Int J Radiat Biol. 2002;78:681–8.PubMedCrossRefGoogle Scholar
  14. 14.
    Wilkins RC, Wilkinson D, Maharaj HP, Bellier PV, Cybulski MB, McLean JR. Differential apoptotic response to ionizing radiation in subpopulations of human white blood cells. Mutat Res. 2002;513:27–36.PubMedCrossRefGoogle Scholar
  15. 15.
    Kachikwu EL, Iwamoto KS, Liao YP, et al. Radiation enhances regulatory T cell representation. Int J Radiat Oncol Biol Phys. 2011;81:1128–35.PubMedCentralPubMedCrossRefGoogle Scholar
  16. 16.
    Apetoh L, Ghiringhelli F, Tesniere A, et al. Toll-like receptor 4-dependent contribution of the immune system to anticancer chemotherapy and radiotherapy. Nat Med. 2007;13:1050–9.PubMedCrossRefGoogle Scholar
  17. 17.
    Qinfeng S, Depu W, Xiaofeng Y, Shah W, Hongwei C, Yili W. In situ observation of the effects of local irradiation on cytotoxic and regulatory T lymphocytes in cervical cancer tissue. Radiat Res. 2013;179:584–9.PubMedCrossRefGoogle Scholar
  18. 18.
    Tabachnyk M, Distel LV, Büttner M, et al. Radiochemotherapy induces a favourable tumour infiltrating inflammatory cell profile in head and neck cancer. Oral Oncol. 2012;48:594–601.PubMedCrossRefGoogle Scholar
  19. 19.
    Tsuchikawa T, Hirano S, Tanaka E, et al. Novel aspects of preoperative chemoradiation therapy improving anti-tumor immunity in pancreatic cancer. Cancer Sci. 2013;104:531–5.PubMedCrossRefGoogle Scholar
  20. 20.
    Yasuda K, Nirei T, Sunami E, Nagawa H, Kitayama J. Density of CD4(+) and CD8(+) T lymphocytes in biopsy samples can be a predictor of pathological response to chemoradiotherapy (CRT) for rectal cancer. Radiat Oncol. 2011;6:49.PubMedCentralPubMedCrossRefGoogle Scholar
  21. 21.
    Yasuda K, Nirei T, Tsuno NH, Nagawa H, Kitayama J. Intratumoral injection of interleukin-2 augments the local and abscopal effects of radiotherapy in murine rectal cancer. Cancer Sci. 2011;102:1257–63.PubMedCrossRefGoogle Scholar
  22. 22.
    Prall F, Wöhlke M, Klautke G, Schiffmann L, Fietkau R, Barten M. Tumour regression and mesorectal lymph node changes after intensified neoadjuvant chemoradiation for carcinoma of the rectum. APMIS. 2006;114:201–10.PubMedCrossRefGoogle Scholar
  23. 23.
    Dworak O, Keilholz L, Hoffmann A. Pathological features of rectal cancer after preoperative radiochemotherapy. Int J Colorectal Dis. 1997;12:19–23.PubMedCrossRefGoogle Scholar
  24. 24.
    Shinto E, Hashiguchi Y, Ueno H, et al. Pretreatment CD133 and cyclooxygenase-2 expression as the predictive markers of the pathological effect of chemoradiotherapy in rectal cancer patients. Dis Colon Rectum. 2011;54:1098–106.PubMedCrossRefGoogle Scholar
  25. 25.
    Fleiss JL. Measuring nominal scale agreement among many raters. Psychol Bull. 1971;76:378–82.CrossRefGoogle Scholar
  26. 26.
    Landis JR, Koch GG. The measurement of observer agreement for categorical data. Biometrics. 1977;33:159–74.PubMedCrossRefGoogle Scholar
  27. 27.
    Lugade AA, Sorensen EW, Gerber SA, Moran JP, Frelinger JG, Lord EM. Radiation-induced IFN-gamma production within the tumor microenvironment influences antitumor immunity. J Immunol. 2008;180:3132–9.PubMedCrossRefGoogle Scholar
  28. 28.
    Plotnikov A, Niego B, Ophir R, Korenstein R, Keisari Y. Effective treatment of mouse metastatic prostate cancer by low electric field enhanced chemotherapy. Prostate. 2006;66:1620–30.PubMedCrossRefGoogle Scholar
  29. 29.
    Rödel C, Martus P, Papadoupolos T, et al. Prognostic significance of tumor regression after preoperative chemoradiotherapy for rectal cancer. J Clin Oncol. 2005;23:8688–96.PubMedCrossRefGoogle Scholar
  30. 30.
    Suzuki T, Sadahiro S, Tanaka A, et al. Biopsy specimens obtained 7 days after starting chemoradiotherapy (CRT) provide reliable predictors of response to CRT for rectal cancer. Int J Radiat Oncol Biol Phys. 2013;85:1232–8.PubMedCrossRefGoogle Scholar

Copyright information

© Society of Surgical Oncology 2014

Authors and Affiliations

  • Eiji Shinto
    • 1
    Email author
  • Kazuo Hase
    • 1
  • Yojiro Hashiguchi
    • 2
  • Akinori Sekizawa
    • 1
  • Hideki Ueno
    • 1
  • Atsushi Shikina
    • 1
  • Yoshiki Kajiwara
    • 1
  • Hirotoshi Kobayashi
    • 3
  • Megumi Ishiguro
    • 3
  • Junji Yamamoto
    • 1
  1. 1.Department of SurgeryNational Defense Medical CollegeSaitamaJapan
  2. 2.Department of SurgeryTeikyo UniversityTokyoJapan
  3. 3.Department of Surgical Oncology, Graduate SchoolTokyo Medical and Dental UniversityTokyoJapan

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