The Journal of Experimental Medicine
StemCell Technologies
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Published online 28 May 2002 doi:10.1084/jem.20020141
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© Rockefeller University Press, 0022-1007/2002/6/1397/ $5.00
The Journal of Experimental Medicine, Volume 195, Number 11, June 3, 2002 1397-1406
Identification of a Mutated Fibronectin As a Tumor Antigen Recognized by CD4+ T Cells : Its Role in Extracellular Matrix Formation and Tumor Metastasis



Helen Y. Wang1, Juhua Zhou1, Kuichun Zhu1, Adam I. Riker2, Francesco M. Marincola3 and Rong-Fu Wang1

1 The Center for Cell and Gene Therapy and Department of Immunology, Baylor College of Medicine, Houston, TX 77030
2 Department of Surgery, Loyola University Chicago, Maywood, IL 60153
3 Immunogenetics Laboratory, Department of Transfusion Medicine, Clinical Center, National Institutes of Health, Bethesda, MD 20852

Address correspondence to Rong-Fu Wang, The Center for Cell and Gene Therapy and Department of Immunology, Baylor College of Medicine, ALKEK Building N1120, One Baylor Plaza, Houston, TX 77030. Phone: 713-798-1244; Fax: 713-798-1263; E-mail: rongfuw{at}bcm.tmc.edu

CD4+ T cells play an important role in orchestrating host immune responses against cancer, particularly by providing critical help for priming and extending the survival of CD8+ T cells. However, relatively little is known about major histocompatibility complex class II–restricted human tumor antigens capable of activating CD4+ T cells. Here, we describe the identification of a mutated fibronectin (FN) as a tumor antigen recognized by human histocompatibility leukocyte antigen-DR2–restricted CD4+ T cells. Deoxyribonucleic acid (DNA) sequencing analysis indicated that this gene contains a mutation that results in the substitution of lysine for glutamic acid and gives rise to a new T cell epitope recognized by CD4+ T cells. Tumor cells harboring the mutant FN resulted in the loss of FN matrix formation and the gain of metastatic potential based on the migration pattern compared with that of tumor cells that express wild-type FN. Additional experiments using cell lines stably expressing the mutated FN cDNA demonstrated that the point mutation in FN was responsible for the loss of FN staining in extracellular matrices and the enhancement of tumor cell migration. These findings represent the first demonstration that a mutated gene product recognized by CD4+ T cells is directly involved in tumor metastasis, which indicates the importance of CD4+ T cells in controlling the spread of tumor cells to distant anatomic sites.

Key Words: cancer vaccines • cancer biology • CD4+ T cells • antitumor immunity • immunotherapy


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