The cytokine microenvironment of human colon carcinoma. Lymphocyte expression of tumor necrosis factor-alpha and interleukin-4 predicts improved survival

Cancer. 1996 Sep 15;78(6):1168-78. doi: 10.1002/(SICI)1097-0142(19960915)78:6<1168::AID-CNCR2>3.0.CO;2-6.


Background: The functional significance of cytokines expressed in situ by tumor cells and tumor infiltrating lymphocytes (TIL) in human colon carcinomas is largely unknown.

Methods: We assessed TIL expression of interleukin-2 (IL-2), IL-4, tumor necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma), granulocyte-macrophage colony stimulating factor (GM-CSF), IL-10, and transforming growth factor-beta (TGF-beta), and tumor cell expression of IL-10 and TGF-beta in situ in 49 primary colon carcinomas and 20 metastases using immunohistochemistry.

Results: The percentage of primary colon carcinoma samples in which > 20% of TIL expressed each cytokine was as follows: IL-4: 47%; TNF-alpha: 22%; TGF-beta: 10%; IFN-gamma: 6%; IL-2:2%; IL-10: 0%; and GM-CSF: 0%. Lymphocytes more commonly infiltrated colon carcinoma primaries than metastases, and TIL expression of IL-4 and TNF-alpha was more common in primary than metastastatic carcinomas. Expression of TNF-alpha by even a small proportion (> or = 3%) of the TIL in a colon carcinoma specimen was associated with better overall survival (P = 0.01) when compared with patients with little or no TIL TNF-alpha expression (5-year survival 82% vs. 47%). Expression of IL-4 by > or = 20% of colon carcinoma TIL was also associated with improved survival (P = 0.01; 5-year survival 87% vs. 50%). The expression of IL-10 or TGF-beta by colon carcinoma TIL or colon tumor cells themselves was not associated with impaired survival. Benign epithelial cells stained positively for IL-10 and TGF-beta more frequently than tumor cells (P < 0.001).

Conclusions: There are differences between the immune microenvironment of primary tumors and metastases. Although IL-10 is expressed by colon carcinoma cells and TIL, it is unlikely that it plays an important immunosuppressive role. TNF-alpha and IL-4 are commonly expressed by colon carcinoma TIL and both are associated with improved survival.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carcinoma / immunology*
  • Carcinoma / secondary
  • Colonic Neoplasms / immunology*
  • Cytokines / biosynthesis*
  • Cytokines / genetics
  • Epithelium / immunology
  • Epithelium / pathology
  • Follow-Up Studies
  • Forecasting
  • Gene Expression Regulation, Neoplastic
  • Granulocyte-Macrophage Colony-Stimulating Factor / biosynthesis
  • Granulocyte-Macrophage Colony-Stimulating Factor / genetics
  • Humans
  • Immunohistochemistry
  • Immunosuppressive Agents / pharmacology
  • Interferon-gamma / biosynthesis
  • Interferon-gamma / genetics
  • Interleukin-10 / biosynthesis
  • Interleukin-10 / genetics
  • Interleukin-10 / physiology
  • Interleukin-2 / biosynthesis
  • Interleukin-2 / genetics
  • Interleukin-4 / biosynthesis*
  • Interleukin-4 / genetics
  • Lymphocytes, Tumor-Infiltrating / immunology*
  • Lymphotoxin-alpha / biosynthesis
  • Lymphotoxin-alpha / genetics
  • Survival Rate
  • Tumor Necrosis Factor-alpha / biosynthesis*
  • Tumor Necrosis Factor-alpha / genetics


  • Cytokines
  • Immunosuppressive Agents
  • Interleukin-2
  • Lymphotoxin-alpha
  • Tumor Necrosis Factor-alpha
  • Interleukin-10
  • Interleukin-4
  • Interferon-gamma
  • Granulocyte-Macrophage Colony-Stimulating Factor