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Cancer Immunology, Immunotherapy

, Volume 61, Issue 10, pp 1849–1856 | Cite as

Tumor-infiltrating lymphocytes predict response to chemotherapy in patients with advance non-small cell lung cancer

  • Hui Liu
  • Tiantuo ZhangEmail author
  • Jin Ye
  • Hongtao Li
  • Jing Huang
  • Xiaodong Li
  • Benquan Wu
  • Xubing Huang
  • Jinghui Hou
Original article

Abstract

Accumulating preclinical evidence suggests that anticancer immune responses contribute to the success of chemotherapy. The predictive significance of tumor-infiltrating lymphocytes (TILs) for response to neoadjuvant chemotherapy in non-small cell lung cancer (NSCLC) remains unknown. The aim of this study was to investigate the prognostic and predictive value of TIL subtypes in patients with advanced NSCLC treated with platinum-based chemotherapy. In total, 159 patients with stage III and IV NSCLC were retrospectively enrolled. The prevalence of CD3+, CD4+, CD8+ and Foxp3+ TILs was assessed by immunohistochemistry in tumor tissue obtained before chemotherapy. The density of TILs subgroups was treated as dichotomous variables using the median values as cutoff. Survival curves were estimated by the Kaplan–Meier method, and differences in overall survival between groups were determined using the Log-rank test. Prognostic effects of TIL subsets density were evaluated by Cox regression analysis. The presence of CD3+, CD4+, CD8+, and FOXP3+ TILs was not correlated with any clinicopathological features. Neither the prevalence of TILs nor combined analysis displayed obvious prognostic performances for overall survival in Cox regression model. Instead, higher FOXP3+/CD8+ ratio in tumor sites was an independent factor for poor response to platinum-based chemotherapy in overall cohort. These findings suggest that immunological CD8+ and FOXP3+Tregs cell infiltrate within tumor environment is predictive of response to platinum-based neoadjuvant chemotherapy in advanced NSCLC patients. The understanding of the clinical relevance of the microenvironmental immunological milieu might provide an important clue for the design of novel strategies in cancer immunotherapy.

Keywords

Chemotherapy Cytotoxic T lymphocytes Immunity Prognostic factor Non-small cell lung cancer Tumor-infiltrating lymphocytes 

Abbreviations

BC

Breast cancer

CRC

Colorectal cancer

CTL

Cytotoxic T lymphocytes

FOXP3

Forkhead box P3

HPF

High power field

IHC

Immunohistochemistry

NSCLC

Non-small cell lung cancer

OC

Ovarian cancer

OS

Overall survival

TIL

Tumor-infiltrating lymphocytes

Treg

Regulatory T lymphocytes

Notes

Acknowledgments

This work was supported by grants from the National Science Foundation of China (grants 81000986).

Conflict of interest

All other authors indicated no potential conflict of interest.

References

  1. 1.
    Schreiber RD, Old LJ, Smyth MJ (2011) Cancer immunoediting: integrating immunity’s roles in cancer suppression and promotion. Science 331:1565–1570PubMedCrossRefGoogle Scholar
  2. 2.
    Pages F, Galon J, Dieu-Nosjean MC et al (2010) Immune infiltration in human tumors: a prognostic factor that should not be ignored. Oncogene 29:1093–1102PubMedCrossRefGoogle Scholar
  3. 3.
    Zitvogel L, Kepp O, Kroemer G (2011) Immune parameters affecting the efficacy of chemotherapeutic regimens. Nat Rev Clin Oncol 8:151–160PubMedCrossRefGoogle Scholar
  4. 4.
    Liu H, Zhang T, Li X et al (2008) Predictive value of MMP-7 expression for response to chemotherapy and survival in patients with non-small cell lung cancer. Cancer Sci 99:2185–2192PubMedCrossRefGoogle Scholar
  5. 5.
    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 313:1960–1964PubMedCrossRefGoogle Scholar
  6. 6.
    Fridman WH, Galon J, Pagès F et al (2011) Prognostic and predictive impact of intra- and peritumoral immune infiltrates. Cancer Res 71:5601–5605PubMedCrossRefGoogle Scholar
  7. 7.
    Tosolini M, Kirilovsky A, Mlecnik B et al (2011) Clinical impact of different classes of infiltrating T cytotoxic and helper cells (Th1, th2, treg, th17) in patients with colorectal cancer. Cancer Res 71:1263–1271PubMedCrossRefGoogle Scholar
  8. 8.
    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 102:18538–18543PubMedCrossRefGoogle Scholar
  9. 9.
    Sheu BC, Chang WC, Lin HH et al (2007) Immune concept of human papillomaviruses and related antigens in local cancer milieu of human cervical neoplasia. J Obstet Gynaecol Res 33:103–113PubMedCrossRefGoogle Scholar
  10. 10.
    Liu F, Lang R, Zhao J et al (2011) CD8+ cytotoxic T cell and FOXP3+ regulatory T cell infiltration in relation to breast cancer survival and molecular subtypes. Breast Cancer Res Treat 130:645–655PubMedCrossRefGoogle Scholar
  11. 11.
    Al-Shibli KI, Donnem T, Al-Saad S et al (2008) Prognostic effect of epithelial and stromal lymphocyte infiltration in non-small cell lung cancer. Clin Cancer Res 14:5220–5227PubMedCrossRefGoogle Scholar
  12. 12.
    Hiraoka K, Miyamoto M, Cho Y et al (2006) Concurrent infiltration by CD8+ T cells and CD4+ T cells is a favourable prognostic factor in non-small-cell lung carcinoma. Br J Cancer 94:275–280PubMedCrossRefGoogle Scholar
  13. 13.
    Ladoire S, Martin F, Ghiringhelli F (2011) Prognostic role of FOXP3+ regulatory T cells infiltrating human carcinomas: the paradox of colorectal cancer. Cancer Immunol Immunother 60:909–918PubMedCrossRefGoogle Scholar
  14. 14.
    Piersma SJ, Welters MJ, van der Burg SH (2008) Tumor-specific regulatory T cells in cancer patients. Hum Immunol 69:241–249PubMedCrossRefGoogle Scholar
  15. 15.
    Elkord E, Alcantar-Orozco EM, Dovedi SJ et al (2010) T regulatory cells in cancer: recent advances and therapeutic potential. Expert Opin Biol Ther 10:1573–1586PubMedCrossRefGoogle Scholar
  16. 16.
    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 107:2866–2872PubMedCrossRefGoogle Scholar
  17. 17.
    Shimizu K, Nakata M, Hirami Y et al (2010) Tumor-infiltrating Foxp3+ regulatory T cells are correlated with cyclooxygenase-2 expression and are associated with recurrence in resected non-small cell lung cancer. J Thorac Oncol 5:585–590PubMedGoogle Scholar
  18. 18.
    Ishibashi Y, Tanaka S, Tajima K et al (2006) Expression of Foxp3 in non-small cell lung cancer patients is significantly higher in tumor tissues than in normal tissues, especially in tumors smaller than 30 mm. Oncol Rep 15:1315–1319PubMedGoogle Scholar
  19. 19.
    Demaria S, Volm MD, Shapiro RL et al (2001) Development of tumor-infiltrating lymphocytes in breast cancer after neoadjuvant paclitaxel chemotherapy. Clin Cancer Res 7:3025–3030PubMedGoogle Scholar
  20. 20.
    Halama N, Michel S, Kloor M et al (2009) The localization and density of immune cells in primary tumors of human metastatic colorectal cancer shows an association with response to chemotherapy. Cancer Immun 9:1–6PubMedGoogle Scholar
  21. 21.
    Halama N, Michel S, Kloor M et al (2011) Localization and density of immune cells in the invasive margin of human colorectal cancer liver metastases are prognostic for response to chemotherapy. Cancer Res 71:5670–5677PubMedCrossRefGoogle Scholar
  22. 22.
    de Kruijf EM, van Nes JG, Sajet A et al (2010) The predictive value of HLA class I tumor cell expression and presence of intratumoral Tregs for chemotherapy in patients with early breast cancer. Clin Cancer Res 16:1272–1280PubMedCrossRefGoogle Scholar
  23. 23.
    Ladoire S, Mignot G, Dabakuyo S et al (2011) In situ immune response after neoadjuvant chemotherapy for breast cancer predicts survival. J Pathol 224:389–400PubMedCrossRefGoogle Scholar
  24. 24.
    Bösmüller H, Haitchi-Petnehazy S, Webersinke G et al (2011) Intratumoral lymphocyte density in serous ovarian carcinoma is superior to ERCC1 expression for predicting response to platinum-based therapy. Virchows Arch 459:183–191PubMedCrossRefGoogle Scholar
  25. 25.
    Nagai H, Miyaki D, Matsui T et al (2008) Th1/Th2 balance: an important indicator of efficacy for intra-arterial chemotherapy. Cancer Chemother Pharmacol 62:959–963PubMedCrossRefGoogle Scholar
  26. 26.
    Bamias A, Tsiatas ML, Kafantari E et al (2007) Significant differences of lymphocytes isolated from ascites of patients with ovarian cancer compared to blood and tumor lymphocytes. Association of CD3+ CD56+ cells with platinum resistance. Gynecol Oncol 106:75–81PubMedCrossRefGoogle Scholar
  27. 27.
    Suzuki H, Chikazawa N, Tasaka T et al (2010) Intratumoral CD8(+) T/FOXP3 (+) cell ratio is a predictive marker for survival in patients with colorectal cancer. Cancer Immunol Immunother 59:653–661PubMedCrossRefGoogle Scholar
  28. 28.
    Ohkura N, Hamaguchi M, Sakaguchi S et al (2011) FOXP3+ regulatory T cells: control of FOXP3 expression by pharmacological agents. Trends Pharmacol Sci 32:158–166PubMedCrossRefGoogle Scholar
  29. 29.
    Andersen MH, Sørensen RB, Schrama D et al (2008) Cancer treatment: the combination of vaccination with other therapies. Cancer Immunol Immunother 57:1735–1743PubMedCrossRefGoogle Scholar
  30. 30.
    Denkert C, Loibl S, Noske A et al (2010) Tumor-associated lymphocytes as an independent predictor of response to neoadjuvant chemotherapy in breast cancer. J Clin Oncol 28:105–113PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  • Hui Liu
    • 1
  • Tiantuo Zhang
    • 1
    Email author
  • Jin Ye
    • 2
  • Hongtao Li
    • 1
  • Jing Huang
    • 1
  • Xiaodong Li
    • 3
  • Benquan Wu
    • 1
  • Xubing Huang
    • 4
  • Jinghui Hou
    • 5
  1. 1.Institute of Respiratory Diseases of Sun Yat-Sen University, Division of Pulmonary and Critical Care, Department of Internal MedicineThe Third Affiliated Hospital of Sun Yat-Sen UniversityGuangzhouChina
  2. 2.Department of Otolaryngology, Head and Neck SurgeryThe Third Affiliated Hospital of Sun Yat-Sen UniversityGuangzhouChina
  3. 3.Department of Thoracic Surgery, Cancer CenterSun Yat-Sen UniversityGuangzhouChina
  4. 4.Division of Pulmonary and Critical Care, Department of Internal MedicineThe First Affiliated Hospital of Sun Yat-Sen UniversityGuangzhouChina
  5. 5.Department of Pathology, Cancer CenterSun Yat-Sen UniversityGuangzhouChina

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