Enhanced antigen-specific antitumor immunity with altered peptide ligands that stabilize the MHC-peptide-TCR complex.

T cell responsiveness to an epitope is affected both by its affinity for the presenting MHC molecule and the affinity of the MHC-peptide complex for TCR. One limitation of cancer immunotherapy is that natural tumor antigens elicit relatively weak T cell responses, in part because high-affinity T cells are rendered tolerant to these antigens. We report here that amino acid substitutions in a natural MHC class I-restricted tumor antigen that increase the stability of the MHC-peptide-TCR complex are significantly more potent as tumor vaccines. The improved immunity results from enhanced in vivo expansion of T cells specific for the natural tumor epitope. These results indicate peptides that stabilize the MHC-peptide-TCR complex may provide superior antitumor immunity through enhanced stimulation of specific T cells.

[1]  T. Greten,et al.  Monitoring antigen-specific T cells using MHC-Ig dimers. , 2001, Current protocols in immunology.

[2]  E. Margoliash,et al.  T-lymphocyte response to cytochrome c. I. Demonstration of a T-cell heteroclitic proliferative response and identification of a topographic antigenic determinant on pigeon cytochrome c whose immune recognition requires two complementing major histocompatibility complex-linked immune response genes , 1979, The Journal of experimental medicine.

[3]  D. Margulies,et al.  A three-domain T cell receptor is biologically active and specifically stains cell surface MHC/peptide complexes. , 1997, Journal of immunology.

[4]  S. Rosenberg,et al.  IL-2 enhances the function of recombinant poxvirus-based vaccines in the treatment of established pulmonary metastases. , 1995, Journal of immunology.

[5]  M. Shields,et al.  Characterization of the interactions between MHC class I subunits: a systematic approach for the engineering of higher affinity variants of beta 2-microglobulin. , 1998, Journal of immunology.

[6]  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.

[7]  T. Boon,et al.  Structure of the gene of tum− transplantation antigen P91A: The mutated exon encodes a peptide recognized with Ld by cytolytic T cells , 1989, Cell.

[8]  S. Kozlowski,et al.  Naive alloreactive CD8 T cells are activated by purified major histocompatibility complex class I and antigenic peptide , 1997, European journal of immunology.

[9]  W. Gillanders,et al.  Definition of TCR recognition sites on Ld-tum- complexes. , 1994, International immunology.

[10]  D. Margulies,et al.  Lack of strict correlation of functional sensitization with the apparent affinity of MHC/peptide complexes for the TCR. , 1995, Journal of immunology.

[11]  Yutaka Kawakami,et al.  Human tumor antigens recognized by T-cells , 1997, Immunologic research.

[12]  J. Sacchettini,et al.  Crystal structure of the major histocompatibility complex class I H-2Kb molecule containing a single viral peptide: implications for peptide binding and T-cell receptor recognition. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[13]  S. Jameson,et al.  T-cell-receptor affinity and thymocyte positive selection , 1996, Nature.

[14]  Methods : A Companion to Methods in Enzymology , 2022 .

[15]  J. Altman,et al.  Counting antigen-specific CD8 T cells: a reevaluation of bystander activation during viral infection. , 1998, Immunity.

[16]  M. Davis,et al.  A kinetic basis for T cell receptor repertoire selection during an immune response. , 1999, Immunity.

[17]  A. George,et al.  A bacterially expressed single-chain Fv construct from the 2B4 T-cell receptor. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[18]  L. Zitvogel,et al.  Bone marrow-derived dendritic cells pulsed with synthetic tumour peptides elicit protective and therapeutic antitumour immunity , 1995, Nature Medicine.

[19]  Willett W. Breast.  This work was supported in part by a Faculty Research Award (to B. E. H.) from the American Cancer Society and an unrestricted grant from Dupontâ€"Merck Pharmaceutical Co. (Billerica, MA). , 1997 .

[20]  D. Margulies,et al.  Studying interactions involving the T-cell antigen receptor by surface plasmon resonance. , 1996, Current opinion in immunology.

[21]  Jonathan J. Lewis,et al.  Heteroclitic Immunization Induces Tumor Immunity , 1998, The Journal of experimental medicine.

[22]  P. Marrack,et al.  The Bacterial and Mouse Mammary Tumor Virus Superantigens; Two Different Families of Proteins with the Same Functions , 1993, Immunological reviews.

[23]  D. Margulies,et al.  Solution binding of an antigenic peptide to a major histocompatibility complex class I molecule and the role of beta 2-microglobulin. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[24]  Philip J. R. Goulder,et al.  Phenotypic Analysis of Antigen-Specific T Lymphocytes , 1996, Science.

[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]  J. Berzofsky,et al.  The importance of dominant negative effects of amino acid side chain substitution in peptide-MHC molecule interactions and T cell recognition. , 1993, Journal of immunology.

[27]  D. Margulies,et al.  Three-dimensional structure of H-2Dd complexed with an immunodominant peptide from human immunodeficiency virus envelope glycoprotein 120. , 1998, Journal of molecular biology.

[28]  U. Utz,et al.  Analysis of the Expression of Peptide–Major Histocompatibility Complexes Using High Affinity Soluble Divalent T Cell Receptors , 1997, The Journal of experimental medicine.

[29]  E. Padlan,et al.  Endogenous peptides of a soluble major histocompatibility complex class I molecule, H-2Lds: sequence motif, quantitative binding, and molecular modeling of the complex , 1992, The Journal of experimental medicine.

[30]  Z Reich,et al.  Ligand recognition by alpha beta T cell receptors. , 1998, Annual review of immunology.

[31]  Mark M. Davis,et al.  LIGAND RECOGNITION BY T CELL RECEPTORS , 1998 .

[32]  P. Robbins,et al.  Human tumor antigens recognized by T cells. , 1996, Current opinion in immunology.

[33]  Mario Roederer,et al.  Characterization of circulating T cells specific for tumor-associated antigens in melanoma patients , 1999, Nature Medicine.

[34]  K. Parker,et al.  Scheme for ranking potential HLA-A2 binding peptides based on independent binding of individual peptide side-chains. , 1994, Journal of immunology.

[35]  S. H. van der Burg,et al.  Analogues of CTL epitopes with improved MHC class‐I binding capacity elicit anti‐melanoma CTL recognizing the wild‐type epitope , 1997, International journal of cancer.

[36]  E. Jaffee,et al.  Direct visualization of antigen-specific T cells: HTLV-1 Tax11-19- specific CD8(+) T cells are activated in peripheral blood and accumulate in cerebrospinal fluid from HAM/TSP patients. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[37]  P. Coulie,et al.  Tumor antigens recognized by T cells. , 1997, Immunology today.

[38]  D. Marguet,et al.  Soluble, high-affinity dimers of T-cell receptors and class II major histocompatibility complexes: biochemical probes for analysis and modulation of immune responses. , 1999, Cellular immunology.

[39]  D. Margulies,et al.  Measuring interactions of MHC class I molecules using surface plasmon resonance. , 1995, Journal of immunological methods.

[40]  F. Jotereau,et al.  Suboptimal activation of melanoma infiltrating lymphocytes (TIL) due to low avidity of TCR/MHC-tumor peptide interactions , 1996, The Journal of experimental medicine.

[41]  J. Sacchettini,et al.  The three-dimensional structure of an H-2Ld-peptide complex explains the unique interaction of Ld with beta-2 microglobulin and peptide. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[42]  D. Cheresh,et al.  Human tumor antigens. , 1987, Advances in immunology.

[43]  P. A. Peterson,et al.  Structural basis of 2C TCR allorecognition of H-2Ld peptide complexes. , 1998, Immunity.

[44]  J. H. Parish.  ISOLATION AND FRACTIONATION OF RNA , 1972 .

[45]  J. Renauld,et al.  Identification of genes coding for tumor antigens recognized by cytolytic T lymphocytes. , 1997, Methods.

[46]  T. Corbett,et al.  A colon tumor model for anticancer agent evaluation , 1975, Cancer.

[47]  R. Steinman,et al.  Dendritic cells and the control of immunity , 1998, Nature.

[48]  D. Margulies,et al.  Direct detection of major histocompatibility complex class I binding to antigenic peptides using surface plasmon resonance. Peptide immobilization and characterization of binding specificity. , 1993, The Journal of biological chemistry.

[49]  T. Ezaki,et al.  Isolation of dendritic cells in the rat liver lymph. , 1995, Transplantation.

[50]  D. Margulies,et al.  MHC Class I/peptide interactions: Binding specificity and kinetics , 1993, Journal of molecular recognition : JMR.

[51]  D. Tuveson,et al.  A soluble divalent class I major histocompatibility complex molecule inhibits alloreactive T cells at nanomolar concentrations. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[52]  D. R. Lee,et al.  Studies of tum- peptide analogs define an alternative anchor that can be utilized by Ld ligands lacking the consensus P2 anchor. , 1996, Journal of immunology.

[53]  D. Margulies,et al.  Determinant selection of major histocompatibility complex class I- restricted antigenic peptides is explained by class I-peptide affinity and is strongly influenced by nondominant anchor residues , 1994, The Journal of experimental medicine.

[54]  L. Chen.  Mimotopes of cytolytic T lymphocytes in cancer immunotherapy. , 1999, Current opinion in immunology.

[55]  D. Kranz,et al.  Binding energetics of T-cell receptors: correlation with immunological consequences. , 1999, Immunology today.

[56]  E. Jaffee,et al.  Murine tumor antigens: is it worth the search? , 1996, Current opinion in immunology.

[57]  D. Speiser,et al.  Optimal activation of tumor-reactive T cells by selected antigenic peptide analogues. , 1999, International immunology.

[58]  R. Henderson,et al.  Identification of a peptide recognized by five melanoma-specific human cytotoxic T cell lines. , 1994, Science.

[59]  D. Pardoll.  Therapeutic vaccination for cancer. , 2000, Clinical immunology.

[60]  E. Jaffee,et al.  The immunodominant major histocompatibility complex class I-restricted antigen of a murine colon tumor derives from an endogenous retroviral gene product. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[61]  D. Margulies,et al.  T cell receptor-MHC class I peptide interactions: affinity, kinetics, and specificity. , 1994, Science.

[62]  E. Gilboa.  The makings of a tumor rejection antigen. , 1999, Immunity.

[63]  E. Coligan.  Current protocols in immunology , 1991 .

[64]  Tumor antigens. , 1981, The New England journal of medicine.

[65]  D. Hafler,et al.  Functional three-domain single-chain T-cell receptors. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

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

[67]  D. Pardoll,et al.  Activation of low avidity CTL specific for a self epitope results in tumor rejection but not autoimmunity. , 1998, Journal of immunology.