Analysis of the T-Cell Receptor Repertoires of Tumor-Infiltrating Conventional and Regulatory T Cells Reveals No Evidence for Conversion in Carcinogen-Induced Tumors

• Published in: Cancer research (Chicago, Ill.) Vol. 71; no. 3; pp. 736 - 746
• Main Authors: HINDLEY, James P, FERREIRA, Cristina, DYSON, Julian, GALLIMORE, Awen, JONES, Emma, LAUDER, Sarah N, LADELL, Kristin, WYNN, Katherine K, BETTS, Gareth J, SINGH, Yogesh, PRICE, David A, GODKIN, Andrew J
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01-02-2011
• Subjects: Animals; Antineoplastic agents; Antitumor activity; Biological and medical sciences; Cancer; Carcinogens; Carcinoma; CD4 antigen; Forkhead Transcription Factors - genetics; Forkhead Transcription Factors - immunology; Foxp3 protein; Immunoregulation; Lymph nodes; Lymphocytes T; Lymphocytes, Tumor-Infiltrating - immunology; Medical sciences; Methylcholanthrene; Mice; Mice, Transgenic; Microenvironments; Neoplasms, Experimental - chemically induced; Neoplasms, Experimental - genetics; Neoplasms, Experimental - immunology; Pharmacology. Drug treatments; Receptors, Antigen, T-Cell - immunology; T-cell receptor; T-Lymphocytes, Regulatory - immunology; Therapeutic applications; Tumor-infiltrating lymphocytes; Tumors; Carcinogen; T cell receptor; Toxicity; Analysis; T-Lymphocyte; Immunologic repertoire; Infiltrating tumor; Malignant tumor; Conversion; Regulatory cell; Cancer
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-10-1797

A significant enrichment of CD4(+)Foxp3(+) T cells (regulatory T cells, Treg) is frequently observed in murine and human carcinomas. As Tregs can limit effective antitumor immune responses, thereby promoting tumor progression, it is important that the mechanisms underpinning intratumoral accumulation of Tregs are identified. Because of evidence gathered mostly in vitro, the conversion of conventional T cells (Tconv) into Tregs has been proposed as one such mechanism. We assessed the contribution of conversion in vivo by analyzing the TCR (T-cell receptor) repertoires of Tconvs and Tregs in carcinogen-induced tumors in mice. Our results indicate that the TCR repertoires of Tregs and Tconvs within tumor-infiltrating lymphocytes (TIL) are largely distinct. Indeed, the cell population with the greatest degree of repertoire similarity with tumor-infiltrating Tregs was the Treg population from the tumor-draining lymph node. These findings demonstrate that conversion of Tconvs does not contribute significantly to the accumulation of tumor-infiltrating Tregs; rather, Tconvs and Tregs arise from different populations with unique TCR repertoires. Enrichment of Tregs within TILs most likely, therefore, reflects differences in the way that Tregs and Tconvs are influenced by the tumor microenvironment. Elucidating the nature of these influences may indicate how the balance between tumor-infiltrating Tregs and Tconvs can be manipulated for therapeutic purposes.