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1 Factoring in Antigen Processing in Designing Antitumor T-Cell Vaccines Frédéric Lévy, Sara Colombetti, Jozef Janda, Laurence Chapatte, Pedro Alves, Javier Garcia Casado, Nicole Lévy, and Anne-Lise Peitrequin INTRODUCTION Ludwig Institute for Cancer Research, Lausanne Branch, University of Lausanne, Epalinges, Switzerland Cytolytic CD8 þ T cells are critical mediators of tumor cell lysis. Their stimulation and/or inhibition are regulated by CD4 þ Tcells.CD8 þ and CD4 þ T cells recognize peptides presented at the surface of antigen-presenting cells (APCs) by MHC class I and class II molecules, respectively. These peptides are the products of antigen processing. In the context of this chapter, the term “antigen processing” defines the ensemble of biochemical pathways involved in the production of peptides associated with MHC class I and class II molecules. Even though the transport of peptides across the endoplasmic reticulum membrane by transporters associated with antigen processing (TAP) is frequently included as part of the MHC class I–restricted antigen-processing pathway, it will not be discussed here. It is commonly assumed that antigen processing produces antigenic peptides, i.e., peptides recognized by specific T cells. This notion stems from the fact that T cells are used as readouts in experiments addressing antigen processing. However, it should be noted that the pool of antigenic peptides presented by MHC This work was supported in part by grants from the Swiss National Funds, the Cancer Research Institute, the NCCR, the Leenaards Foundation and the Hans Altschüler Stiftung. 1
2 Lévy et al. molecules constitutes only a small fraction of all cellular peptides binding to MHC molecules (1,2). The majority of those MHC-associated peptides are immunologically silent in that they are either ignored by T cells or unable to stimulate T cells because of tolerance. Some of them might nevertheless become targets of autoreactive T cells in the context of autoimmune diseases. Similarly, many tumorassociated peptides, which are derived from self-proteins, are not immunogenic (i.e., they do not induce T cells) but are nevertheless antigenic (i.e., they can be recognized by T cells), provided that specific CD8 þ T cells can be efficiently stimulated. The goal of anticancer T-cell vaccines is to activate cytolytic CD8 þ T cells capable of recognizing tumor-associated peptide antigens presented at the surface of tumor cells. In this chapter, the major components involved in the processing of peptide antigens by tumor cells will be summarized and the impact of antigen processing on the design of antitumor T-cell vaccines will be discussed. THE ANTIGEN-PROCESSING MACHINERY Because peptides are mostly produced in the course of protein degradation, the main components of the antigen-processing pathway are proteases (generally referring to enzymes degrading proteins) and peptidases (enzymes degrading peptides). The processing of antigens presented in the context of MHC class I molecules is thought to occur predominantly in the cytosol and the endoplasmic reticulum, while the processing of MHC class II–restricted antigens takes place primarily within the endo/lysosomal compartment. Processing of MHC Class I–Restricted Peptide Antigens 20 S Proteasomes MHC class I molecules generally bind peptides of 8 to 10 amino acids in length and present them to CD8 þ T cells; however, longer peptides have also been found (3). The vast majority of these peptide antigens derive from proteins degraded by the proteasomes, a multicatalytic protease complex of the cytosol and nucleus. The core unit of the proteasome, the 20 S proteasome, is composed of 2 pairs of 14 different subunits arranged in 4 heptameric rings. Each of the two outer rings contains seven a subunits (a1–a7) and each of the two inner rings contains seven b subunits (b1–b7). The catalytic activities of the proteasome are confined to the inner cavity formed by the two b rings and are associated with three pairs of particular b subunits. There are at least four types of 20 S proteasomes: the standard proteasome, the immunoproteasome, the intermediate proteasome, and the thymoproteasome (4–6). Each type differs from the others by the composition of their catalytic subunits. The standard proteasome contains the catalytic subunits b1, b2, and b5; the immunoproteasome contains the subunits b1i/LMP2, b2i/MECL1, and b5i/LMP7; the intermediate proteasome contains the subunits b1i/LMP2, b2, b5i/LMP7 or b1, b2, and b5i/LMP7; and the thymoproteasome contains the subunits b1i/LMP2, b2i/MECL1, and b5t
Page 1 and 2: Translational Medicine Series 6 Can
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Page 8 and 9: Preface Throughout the last 20 year
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Page 14 and 15: Contributors Pedro Alves Ludwig Ins
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Preclinical Models and Clinical Sit
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56 Srinivasan disease agents. Garda
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62 Srinivasan (69). In another stud
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66 Srinivasan 33. Salgia R, Lynch T
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68 Srinivasan 67. Werness BA, Levin
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70 Teofilovici and Wentworth In 190
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84 Luptrawan et al. Dendritic cells
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86 Luptrawan et al. of cancer cells
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88 Luptrawan et al. NK cells can ki
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Table 1 Summary of results of phase
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104 Luptrawan et al. antigens (84,8
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106 Luptrawan et al. 30. Ranges GE,
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108 Luptrawan et al. 66. Dunn GP, B
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110 Schroter and Minev proteins (2,
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7 Multimodality Immunization Approa
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Multimodality Immunization Approach
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Figure 5.1 Immunohistochemical char
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8 Bidirectional Bedside Lab Bench P
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Development of Novel Immunotherapeu
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Diagnostic Approaches to Maximize T
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206 Index Antigenic peptides degrad
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208 Index Chromogens, enzymatic act
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210 Index Freund’s adjuvants. See
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212 Index Langerhans cells, 133, 13
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214 Index [Peptide vaccines] invest
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216 Index TCRL. See TCR-like immuno
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Oncology and Immunology about the b
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