Laboratory Research

Annals of Surgical Oncology

, 15:2310

First online:

Detection and Functional Analysis of Tumor Infiltrating T-Lymphocytes (TIL) in Liver Metastases from Colorectal Cancer

  • Philipp WagnerAffiliated withDepartment of Surgery, University of Heidelberg
  • , Moritz KochAffiliated withDepartment of Surgery, University of Heidelberg
  • , Daniel NummerAffiliated withDivision of Cellular Immunology, Tumor Immunology Program, German Cancer Research Center
  • , Sylvia PalmAffiliated withDepartment of Surgery, University of Heidelberg
  • , Luis GalindoAffiliated withDepartment of Surgery, University of Heidelberg
  • , Daniel AutenriethAffiliated withDepartment of Surgery, University of Heidelberg
  • , Friedrich H. Schmitz-WinnenthalAffiliated withDepartment of Surgery, University of Heidelberg
  • , Volker SchirrmacherAffiliated withDivision of Cellular Immunology, Tumor Immunology Program, German Cancer Research Center
  • , Markus W. BüchlerAffiliated withDepartment of Surgery, University of Heidelberg
    • , Philipp BeckhoveAffiliated withDivision of Cellular Immunology, Tumor Immunology Program, German Cancer Research Center
    • , Jürgen WeitzAffiliated withDepartment of Surgery, University of Heidelberg Email author 

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Abstract

Background

Tumor-infiltrating T lymphocytes (TIL) play an important role in primary colorectal cancer, but their activity in liver metastases has not yet been investigated. The aim of this study was to examine whether tumor-selective infiltration, activation, and cytotoxic activity of TIL can be demonstrated in situ in colorectal liver metastases.

Methods

TIL were obtained from liver metastases and corresponding normal liver tissue of 16 patients with colorectal liver metastases. Characterization of TIL in situ was performed by multicolor flowcytometric analysis. Presence of tumor antigen-reactive T cells was evaluated by interferon gamma Elispot analysis.

Results

TIL in colorectal liver metastases responding against tumor antigens were present in most patients. Although the proportions of CD3+ T cells were comparable in liver metastasis and normal liver tissue, metastases contained significantly enhanced proportions of CD4+ cells (49% vs. 22%, P < .001). Among all CD4+ T helper cells, the proportion of activated (CD4+CD25+) effector cells was significantly increased in liver metastases (15.0% vs. 7.8%, P = .003). Metastases showed significantly higher proportions of activated (CD69+ [70.1% vs. 49.8%, P = .02] and CD25+ [4.1% vs. .6%, P = .06]) and cytotoxically active (CD107a+) CD8+ TIL (3.2% vs. 1.3%, P = .03). Importantly, the presence of activated T helper cells correlated with the frequencies of cytotoxic T lymphocytes that exerted cytotoxic activity in situ (P = .02).

Conclusion

CD4+ and CD8+ TIL are selectively activated in liver metastases, and cytotoxic T lymphocytes exert tumor-selective cytotoxic activity in situ in the presence of activated T helper cells, suggesting the requirement of in-situ-activated T helper cells for efficient cytotoxic T lymphocytes effector function.

Keywords

Liver metastasis Colorectal cancer Tumor-infiltrating lymphocytes Anti-tumor immune response Regulatory T cells