Identification of a Mutated Fibronectin As a Tumor Antigen Recognized by CD4+T Cells

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.

[1]  S. Elledge,et al.  Expression profiling of medulloblastoma: PDGFRA and the RAS/MAPK pathway as therapeutic targets for metastatic disease , 2003, Nature Genetics.

[2]  Rong Wang,et al.  The role of MHC class II-restricted tumor antigens and CD4+ T cells in antitumor immunity. , 2001, Trends in immunology.

[3]  A. Houghton,et al.  Immunity against cancer: lessons learned from melanoma. , 2001, Current opinion in immunology.

[4]  P. Srivastava,et al.  The immunoprotective MHC II epitope of a chemically induced tumor harbors a unique mutation in a ribosomal protein , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[5]  S. Rosenberg,et al.  CD4+ T cell recognition of MHC class II-restricted epitopes from NY-ESO-1 presented by a prevalent HLA DP4 allele: Association with NY-ESO-1 antibody production , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[6]  Eric S. Lander,et al.  Genomic analysis of metastasis reveals an essential role for RhoC , 2000, Nature.

[7]  S. Rosenberg,et al.  Identification of CD4+ T Cell Epitopes from NY-ESO-1 Presented by HLA-DR Molecules , 2000, The Journal of Immunology.

[8]  Steven A. Rosenberg,et al.  Identification of a MHC Class II-Restricted Human gp100 Epitope Using DR4-IE Transgenic Mice , 2000, The Journal of Immunology.

[9]  D. Jäger,et al.  Identification of Ny-Eso-1 Epitopes Presented by Human Histocompatibility Antigen (Hla)-Drb4*0101–0103 and Recognized by Cd4+T Lymphocytes of Patients with Ny-Eso-1–Expressing Melanoma , 2000, The Journal of experimental medicine.

[10]  V. Brusic,et al.  Melan-A/MART-151–73 represents an immunogenic HLA-DR4-restricted epitope recognized by melanoma-reactive CD4+ T cells , 2000 .

[11]  V. Brusic,et al.  Melan-A/MART-1(51-73) represents an immunogenic HLA-DR4-restricted epitope recognized by melanoma-reactive CD4(+) T cells. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[12]  P. Meltzer,et al.  Vascular channel formation by human melanoma cells in vivo and in vitro: vasculogenic mimicry. , 1999, The American journal of pathology.

[13]  S. Rosenberg,et al.  Human tumor antigens for cancer vaccine development , 1999, Immunological reviews.

[14]  R. Schreiber,et al.  CD4+ T cells eliminate MHC class II-negative cancer cells in vivo by indirect effects of IFN-γ , 1999 .

[15]  S. Rosenberg,et al.  Cloning genes encoding MHC class II-restricted antigens: mutated CDC27 as a tumor antigen. , 1999, Science.

[16]  S. Rosenberg,et al.  Identification of a Novel Major Histocompatibility Complex Class II–restricted Tumor Antigen Resulting from a Chromosomal Rearrangement Recognized by CD4+ T Cells , 1999, The Journal of experimental medicine.

[17]  Ferry Ossendorp,et al.  CD4 T Cells and Their Role in Antitumor Immune Responses , 1999, The Journal of experimental medicine.

[18]  Matteo Bellone,et al.  Melanoma Cells Present a MAGE-3 Epitope to CD4+ Cytotoxic T Cells in Association with Histocompatibility Leukocyte Antigen DR11 , 1999, The Journal of experimental medicine.

[19]  A. Eggermont,et al.  Identification of MAGE-3 Epitopes Presented by HLA-DR Molecules to CD4+ T Lymphocytes , 1999, The Journal of experimental medicine.

[20]  J. Shabanowitz,et al.  Biochemical Identification of a Mutated Human Melanoma Antigen Recognized by CD4+ T Cells , 1999, The Journal of experimental medicine.

[21]  R. Schreiber,et al.  CD4(+) T cells eliminate MHC class II-negative cancer cells in vivo by indirect effects of IFN-gamma. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[22]  C. Lowenstein,et al.  The Central Role of CD4+ T Cells in the Antitumor Immune Response , 1998, The Journal of experimental medicine.

[23]  Spyros A. Kalams,et al.  The Critical Need for CD4 Help in Maintaining Effective Cytotoxic T Lymphocyte Responses , 1998, The Journal of experimental medicine.

[24]  S. Tonegawa,et al.  CD4+ T Cells Prevent Spontaneous Experimental Autoimmune Encephalomyelitis in Anti–Myelin Basic Protein T Cell Receptor Transgenic Mice , 1998, The Journal of experimental medicine.

[25]  S. Rosenberg,et al.  A breast and melanoma-shared tumor antigen: T cell responses to antigenic peptides translated from different open reading frames. , 1998, Journal of immunology.

[26]  C. Melief,et al.  Specific T Helper Cell Requirement for Optimal Induction of Cytotoxic T Lymphocytes against Major Histocompatibility Complex Class II Negative Tumors , 1998, The Journal of experimental medicine.

[27]  S. Kimura,et al.  CD4+ T cells from peripheral blood of a melanoma patient recognize peptides derived from nonmutated tyrosinase. , 1998, Cancer research.

[28]  F. Brasseur,et al.  A CASP-8 Mutation Recognized by Cytolytic T Lymphocytes on a Human Head and Neck Carcinoma , 1997, The Journal of experimental medicine.

[29]  E. Appella,et al.  Identification of TRP-2 as a Human Tumor Antigen Recognized by Cytotoxic T Lymphocytes , 1996, The Journal of experimental medicine.

[30]  K. Sekiguchi,et al.  Suppression of transformed phenotypes of human fibrosarcoma cells by overexpression of recombinant fibronectin. , 1996, Cancer research.

[31]  A Sette,et al.  Melanoma-specific CD4+ T cells recognize nonmutated HLA-DR-restricted tyrosinase epitopes , 1996, The Journal of experimental medicine.

[32]  E. Appella,et al.  A mutated beta-catenin gene encodes a melanoma-specific antigen recognized by tumor infiltrating lymphocytes , 1996, The Journal of experimental medicine.

[33]  E. Appella,et al.  A Mutated f3-Catenin Gene Encodes a Melanoma-specifi c Antigen Recognized by Tumor Infiltrating Lymphocytes By Paul F. tLobbins,* Mona E1-Gamil,* Yong F. Li,* , 1996 .

[34]  M. Serrano,et al.  A p16INK4a-insensitive CDK4 mutant targeted by cytolytic T lymphocytes in a human melanoma , 1995, Science.

[35]  A. Houghton,et al.  Reactivity of autologous CD4+ T lymphocytes against human melanoma. Evidence for a shared melanoma antigen presented by HLA-DR15. , 1995, Journal of immunology.

[36]  P. Monach,et al.  A unique tumor antigen produced by a single amino acid substitution. , 1995, Immunity.

[37]  P. Bruggen,et al.  Tumor antigens recognized by T lymphocytes. , 1994, Annual review of immunology.

[38]  R. Hynes,et al.  Defects in mesoderm, neural tube and vascular development in mouse embryos lacking fibronectin. , 1993, Development.

[39]  F. Giancotti,et al.  Elevated levels of the α 5 β 1 fibronectin receptor suppress the transformed phenotype of Chinese hamster ovary cells , 1990, Cell.

[40]  E. Ruoslahti,et al.  Elevated levels of the alpha 5 beta 1 fibronectin receptor suppress the transformed phenotype of Chinese hamster ovary cells. , 1990, Cell.

[41]  W. Carter,et al.  The fibronectin receptor is organized by extracellular matrix fibronectin: implications for oncogenic transformation and for cell recognition of fibronectin matrices , 1989, The Journal of cell biology.

[42]  A. Kornblihtt,et al.  Identification of a third region of cell-specific alternative splicing in human fibronectin mRNA. , 1987, Proceedings of the National Academy of Sciences of the United States of America.

[43]  A. Kornblihtt,et al.  Isolation and characterization of cDNA clones for human and bovine fibronectins. , 1983, Proceedings of the National Academy of Sciences of the United States of America.

[44]  R. Hynes,et al.  A LARGE GLYCOPROTEIN LOST FROM THE SURFACES OF TRANSFORMED CELLS * , 1978, Annals of the New York Academy of Sciences.