Activated but not resting regulatory T cells accumulated in tumor microenvironment and correlated with tumor progression in patients with colorectal cancer

• Published in: International journal of cancer Vol. 132; no. 6; pp. 1341 - 1350
• Main Authors: Lin, Yung‐Chang, Mahalingam, Jayashri, Chiang, Jy‐Ming, Su, Po‐Jung, Chu, Yu‐Yi, Lai, Hsin‐Yi, Fang, Jian‐He, Huang, Ching‐Tai, Chiu, Cheng‐Tang, Lin, Chun‐Yen
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 15.03.2013; Wiley-Blackwell; Wiley Subscription Services, Inc
• Subjects: Adult; Aged; Aged, 80 and over; Biological and medical sciences; Cancer; CC chemokine receptors; Colorectal cancer; Colorectal Neoplasms - immunology; CTLA-4 Antigen - analysis; Disease Progression; effector memory T cells; Female; Gastroenterology. Liver. Pancreas. Abdomen; Humans; Immunologic Memory; Immunotherapy; Leukocyte Common Antigens - analysis; Lymphocyte Activation; Lymphocytes, Tumor-Infiltrating - immunology; Male; Medical research; Medical sciences; Middle Aged; Receptors, Tumor Necrosis Factor, Type II - analysis; regulatory T cell; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus; T cell receptors; T-Lymphocytes, Regulatory - immunology; tumor infiltrating lymphocyte; Tumor Microenvironment; Tumors; Activated state; Human; Effectory cell; Rectal disease; Treg cell; Colorectal cancer; Cell microenvironment; effector memory T cells; Cellular immunity; Tumor infiltrating lymphocyte; Malignant tumor; Metastasis; regulatory T cell; Carcinogenesis; Memory lymphocyte; Colonic disease; Cancerology; Tumor progression; Digestive diseases; Intestinal disease; Cancer
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.27784

Activated T regulatory (Treg) cells are potent suppressors that mediate immune tolerance. We investigated the relationship between activated Treg cells and the progression of human colon cancer. We designed a cross‐sectional study of CD4+Foxp3+ T cells from peripheral blood, primary tumor and nontumor colon tissue of 42 patients with colon cancer and correlated the percentages of different subgroups of Treg cells with colon cancer stage. The phenotypes, cytokine‐release patterns and suppression ability of these Treg cells were analyzed. We found that Treg cells increased significantly in both peripheral blood and cancer tissue. In addition, the Treg cells expressed significantly lower levels of CCR7, CD62L and CD45RA in comparison to normal volunteers. Further dividing Treg cells into subgroups based on Foxp3 and CD45RA expression revealed that both activated Treg cells (Foxp3hiCD45RA−) and nonsuppressive Treg cells (Foxp3loCD45RA−), but not resting Treg cells (Foxp3lowCD45RA+), increased in the peripheral blood and cancer tissue of patients with colon cancer. Only the activated Treg cells expressed significantly higher levels of tumor necrosis factor receptor 2 and cytotoxic T‐cell antigen‐4. Activated Treg cells, however, secreted significantly lower levels of effector cytokines (interleukin‐2, tumor necrosis factor‐α and interferon‐γ) than did resting Treg cells and nonsuppressive cells upon ex vivo stimulation. Activated, but not resting, Treg cells in cancer tissue correlated with tumor metastases. In summary, we confirmed that activated Treg cells are a distinct subgroup with effector memory phenotype and fully functional regulatory activity against human colorectal cancer immunity. What's new? Activated T regulatory (Treg) cells suppress the immune response, and can interfere with immunological attacks on cancer cells. This study examined levels of Treg cells in human colorectal cancer, and found that cancer tissue and peripheral blood contained more activated Treg cells than healthy tissue. Also, the presence of activated Treg cells correlated with tumor metastases, suggesting these cells might be an important key to improving immune therapeutic strategies.