Crisscross CTL Induction by SYT-SSX Junction Peptide and Its HLA-A*2402 Anchor Substitute1

To investigate the effects of anchor substitutions in SYT-SSX junction peptide, an HLA-A24 anchor residue (position 9) of the SYT-SSX B peptide (GYDQIMPKK) was substituted to more favorable residues according to the HLA-A24-binding motif. Among four substitutes constructed, a substitute with isoleucine (termed K9I peptide) most apparently enhanced the affinity for HLA-A24 molecule. Subsequent in vitro CTL induction analysis using PBMCs of 15 HLA-A24+ synovial sarcoma patients revealed that the original B peptide allowed to induce synovial sarcoma-specific CTLs from 7 patients (47%), whereas such CTLs were inducible from 12 patients (80%) with K9I peptide. Moreover, the extent of cytotoxicity against HLA-A24+ synovial sarcoma cell lines was higher in K9I peptide-induced CTLs than B peptide-induced CTLs. Influence of anchor substitution on peptide/TCR interaction was evaluated by cytotoxicity assays against autologous cells and tetramer analysis. CTLs induced from a synovial sarcoma patient using K9I peptide did not lyse autologous PHA blasts or EBV-infected B cells. In vitro stimulations of PBMCs from 5 HLA-A24+ synovial sarcoma patients with K9I peptide increased the frequency of T cells reacting with both HLA-A24/K9I peptide tetramer and HLA-A24/B peptide tetramer. In contrast, the frequency of T cells reacting with HLA/HIV-derived peptide tetramer remained low. These findings support the validity in design of anchor residue substitution in SYT-SSX fusion gene-derived peptide, and provide a potential clue to the current stagnation in vaccination trials of fusion gene-derived natural junction peptides.

[1]  T. Yamashita,et al.  Recognition by cellular and humoral autologous immunity in a human osteosarcoma cell line , 2003, Journal of orthopaedic science : official journal of the Japanese Orthopaedic Association.

[2]  T. Rabbitts,et al.  Chromosomal translocation products engender new intracellular therapeutic technologies , 2003, Nature Medicine.

[3]  D. Speiser,et al.  Activation of human melanoma reactive CD8+ T cells by vaccination with an immunogenic peptide analog derived from Melan-A/melanoma antigen recognized by T cells-1. , 2003, Clinical cancer research : an official journal of the American Association for Cancer Research.

[4]  G. Pawelec,et al.  The abl/bcr gene product as a novel leukemia-specific antigen: peptides spanning the fusion region of abl/bcr can be recognized by both CD4+ and CD8+ T lymphocytes , 2003, Cancer Immunology, Immunotherapy.

[5]  T. Yamashita,et al.  Improved generation of HLA class I/peptide tetramers. , 2002, Journal of immunological methods.

[6]  I. L. Le Poole,et al.  Emerging strategies in tumor vaccines. , 2002, Current opinion in oncology.

[7]  E. Klechevsky,et al.  Modification of a Tumor-Derived Peptide at an HLA-A2 Anchor Residue Can Alter the Conformation of the MHC-Peptide Complex: Probing with TCR-Like Recombinant Antibodies1 , 2002, The Journal of Immunology.

[8]  D. Speiser,et al.  Antigenicity and immunogenicity of Melan‐A/MART‐1 derived peptides as targets for tumor reactive CTL in human melanoma , 2002, Immunological reviews.

[9]  A. Necker,et al.  Cytotoxic T-lymphocyte responses in melanoma through in vitro stimulation with the Melan-A peptide analogue A27L: a qualitative analysis , 2002, Melanoma research.

[10]  T. Yamashita,et al.  Detection and Induction of CTLs Specific for SYT-SSX-Derived Peptides in HLA-A24+ Patients with Synovial Sarcoma1 , 2002, The Journal of Immunology.

[11]  F. Barr,et al.  Chromosomal translocations and sarcomas , 2002, Current Opinion in Oncology.

[12]  J. Berzofsky,et al.  Pilot trial of tumor-specific peptide vaccination and continuous infusion interleukin-2 in patients with recurrent Ewing sarcoma and alveolar rhabdomyosarcoma: an inter-institute NIH study. , 2002, Medical and pediatric oncology.

[13]  T. Eberlein,et al.  Modification of the HER2/NEU‐derived tumor antigen GP2 improves induction of GP2‐reactive cytotoxic T lymphocytes , 2001, International journal of cancer.

[14]  T. Tsurumi,et al.  Efficient identification of HLA-A*2402-restricted cytomegalovirus-specific CD8(+) T-cell epitopes by a computer algorithm and an enzyme-linked immunospot assay. , 2001, Blood.

[15]  F. Marincola,et al.  Antigenicity of fusion proteins from sarcoma-associated chromosomal translocations. , 2001, Cancer research.

[16]  R. Maki,et al.  Soft tissue sarcoma as a model disease to examine cancer immunotherapy. , 2001, Current opinion in oncology.

[17]  R. Tisch,et al.  Class I Major Histocompatibility Complex Anchor Substitutions Alter the Conformation of T Cell Receptor Contacts* , 2001, The Journal of Biological Chemistry.

[18]  D. Speiser,et al.  CD8+ T-cell response to NY-ESO-1: relative antigenicity and in vitro immunogenicity of natural and analogue sequences. , 2001, Clinical cancer research : an official journal of the American Association for Cancer Research.

[19]  V. Cerundolo,et al.  Identification of NY-ESO-1 Peptide Analogues Capable of Improved Stimulation of Tumor-Reactive CTL1 , 2000, The Journal of Immunology.

[20]  S. Soignet,et al.  Vaccination of patients with chronic myelogenous leukemia with bcr-abl oncogene breakpoint fusion peptides generates specific immune responses. , 2000, Blood.

[21]  H. Fujita,et al.  Identification of a Gene Coding for a New Squamous Cell Carcinoma Antigen Recognized by the CTL1 , 2000, The Journal of Immunology.

[22]  B. Tirosh,et al.  Induction of antitumor immunity by proteasome‐inhibited syngeneic fibroblasts pulsed with a modified TAA peptide , 2000, International journal of cancer.

[23]  Shuqin Yan,et al.  Poor Binding of a HER-2/neu Epitope (GP2) to HLA-A2.1 Is due to a Lack of Interactions with the Center of the Peptide* , 1999, The Journal of Biological Chemistry.

[24]  Parkhurst,et al.  Changes in the fine specificity of gp100(209-217)-reactive T cells in patients following vaccination with a peptide modified at an HLA-A2.1 anchor residue. , 1999, Journal of immunology.

[25]  B. Moss,et al.  gp100/pmel 17 Is a Murine Tumor Rejection Antigen: Induction of “Self”-reactive, Tumoricidal T Cells Using High-affinity, Altered Peptide Ligand , 1998, The Journal of experimental medicine.

[26]  F. Lemonnier,et al.  Cytotoxic T cell response against the chimeric p210 BCR-ABL protein in patients with chronic myelogenous leukemia. , 1998, The Journal of clinical investigation.

[27]  F. Marincola,et al.  Immunologic and therapeutic evaluation of a synthetic peptide vaccine for the treatment of patients with metastatic melanoma , 1998, Nature Medicine.

[28]  J. Schlom,et al.  Development of a murine mutant Ras CD8+ CTL peptide epitope variant that possesses enhanced MHC class I binding and immunogenic properties. , 1998, Journal of immunology.

[29]  A. Rickinson,et al.  Conserved CTL epitopes within EBV latent membrane protein 2: a potential target for CTL-based tumor therapy. , 1997, Journal of immunology.

[30]  P. Coulie,et al.  Characterization of an antigen that is recognized on a melanoma showing partial HLA loss by CTL expressing an NK inhibitory receptor. , 1997, Immunity.

[31]  A Sette,et al.  Improved induction of melanoma-reactive CTL with peptides from the melanoma antigen gp100 modified at HLA-A*0201-binding residues. , 1996, Journal of immunology.

[32]  M F del Guercio,et al.  Prominent roles of secondary anchor residues in peptide binding to HLA-A24 human class I molecules. , 1995, Journal of immunology.

[33]  A Sette,et al.  Definition of specific peptide motifs for four major HLA-A alleles. , 1994, Journal of immunology.

[34]  K. Shibata,et al.  Vesicular stomatitis virus antigenic octapeptide N52-59 is anchored into the groove of the H-2Kb molecule by the side chains of three amino acids and the main-chain atoms of the amino terminus. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[35]  T. Matsuno,et al.  Morphological and Cytogenetic Studies of a Human Synovial Sarcoma Xenotransplanted into Nude Mice , 1990, Acta pathologica japonica.

[36]  P. Cresswell,et al.  Genes regulating HLA class I antigen expression in T-B lymphoblast hybrids , 2004, Immunogenetics.

[37]  P. Allen,et al.  Altered peptide ligand-induced partial T cell activation: molecular mechanisms and role in T cell biology. , 1996, Annual review of immunology.

[38]  M. Furihata,et al.  Establishment and characterization of a new human synovial sarcoma cell line, HS-SY-II. , 1992, Laboratory investigation; a journal of technical methods and pathology.