2016Basic SciencesLife Sciences (Molecular Biology, Cell Biology, Neurobiology)
Tasuku Honjo photo

Tasuku Honjo

  • Japan / January 27, 1942
  • Medical Scientist
  • Professor, Kyoto University

Discovery of the Mechanism Responsible for the Functional Diversification of Antibodies, Immunoregulatory Molecules and Clinical Applications of PD-1

Dr. Honjo has elucidated the mechanism for the functional diversification of antibodies by clarifying Class Switch Recombination and its responsible enzyme, AID. He also identified several important immunoregulatory molecules, including PD-1, whose function has led to the development of effective cancer immunotherapy. His discoveries and their clinical applications have significantly influenced research in the life sciences and medicine, resulting in eminent contributions to human welfare.

Profile

Brief Biography

1942
Born in Kyoto City, Japan
1966
M.D. Faculty of Medicine, Kyoto University
1975
Ph.D. in Medical Chemistry, Kyoto University
1971-1973
Fellow, Department of Embryology, Carnegie Institution of Washington
1973-1974
Visiting Fellow and Associate, National Institute of Child Health and Human Development, National Institutes of Health
1974-1979
Assistant Professor, Faculty of Medicine, The University of Tokyo
1979-1984
Professor, Graduate School of Medicine, Osaka University
1984-
Professor, Graduate School of Medicine, Kyoto University
1989-1997
Professor, School of Medicine, Hirosaki University
2005
Professor Emeritus, Kyoto University
2012-
Chairman of the Board, Shizuoka Prefectural University Corporation
2015-
President, Foundation for Biomedical Research and Innovation

Selected Awards and Honors

1981
Noguchi Hideyo-Memorial Award for Medicine
1985
Erwin von Balz Prize, Boehringer Ingelheim
1988
Takeda Medical Prize
1993
Uehara Prize
1996
The Imperial Prize and the Japan Academy Prize
2012
Robert-Koch-Preis
2013
Order of Culture, Government of Japan
2014
Tang Prize
2014
William B. Coley Award for Distinguished Research in Basic and Tumor Immunology, Cancer Research Institute
2015
Richard V. Smalley, MD Memorial Award, Society for Immunotherapy of Cancer
Members:
Leopoldina, National Academy of Sciences, The American Association of Immunologists, The Japan Academy

Citation

Discovery of the Mechanism Responsible for the Functional Diversification of Antibodies, Immunoregulatory Molecules and Clinical Applications of PD-1

Antibodies, a major component of the immune system, are produced by B cells. The rearrangements of variable gene fragments of immunoglobulin (Ig) genes during the development of B cells in bone marrow provides antibodies binding activity to a vast variety of potential antigens. Upon activation by exposure to antigens and associated cytokine milieu in the secondary lymphoid tissues, B cells then produce antibodies of different classes such as IgM, IgA, IgG and IgE, which are different in biological functions and distribution on the body. Exposure to antigens also evokes somatic hypermutations (SHM) in the variable region, which confers higher binding affinity to particular antigens. However, how different classes of antibodies are produced and how SHM occurs remained long unknown.
In 1978, Dr. Tasuku Honjo proposed a class switch recombination (CSR) model of antibody class production, which he corroborated in subsequent works. According to this model, antibody class is determined by deleting a part of the immunoglobulin heavy chain gene and joining the region coding the corresponding class segment. He then established an in vitro model that recapitulates CSR using cultured B cells activated with interleukin (IL)-4, and cloned activation-induced cytidine deaminase (AID). Subsequent studies by his group proved that AID is not only responsible for CSR but also essential for SHM. Dr. Honjo thus identified the molecular mechanism underlying the generation of functionally divergent antibodies, thereby elucidating one of the basic principles of immunology.
In parallel with this study, Dr. Honjo cloned a variety of molecules that play important roles in immune responses. These include IL-4 and IL-5, which activate B cells and induce CSR; RBP-J kappa, which is a key mediator of Notch signaling in cell fate determination; and a chemokine SDF-1, which is important in hematopoietic niche formation in the bone marrow.
One of the molecules cloned by Dr. Honjo is PD-1, which negatively regulates the self-tolerance of the immune system, as evidenced by the development of various autoimmune diseases after deletion of this gene as well as suppression of T cell activation by binding to its specific ligand PD-L1. Based on these findings, Dr. Honjo and his colleagues administered anti-PD-L1 antibodies in mice bearing PD-L1-expressing tumors and found that blocking the PD-1-PD-L1 binding significantly inhibited tumor growth and prolonged survival. This milestone discovery by Dr. Honjo stimulated the development of anti-PD-1 and anti-PD-L1 antibodies as anti-cancer immunotherapeutic agents. Subsequent large-scale clinical trials using the humanized anti-PD-1 antibody demonstrated marked efficacy against various cancers in humans and the antibody drug is now in clinical use in Japan, the U.S., and Europe.
Dr. Honjo has thus contributed to basic science by clarifying the mechanism responsible for the functional diversification of antibodies, one of the basic principles of immunology, and by identifying several important immunoregulatory molecules. His identification of PD-1/PD-L1 and their function has led to the development of effective cancer immunotherapy contributing significantly to human health and welfare.
For these reasons, the Inamori Foundation is pleased to present the 2016 Kyoto Prize in Basic Sciences to Dr. Tasuku Honjo.

Lecture

Abstract of the Lecture

Serendipities of Acquired Immunity

In this lecture, I want to talk about several fortuitous developments that I have experienced during my time as a researcher. In the 1950s, Frank M. Burnet published the clonal selection theory, which motivated numerous researchers to explore how the cells of the immune system work to produce enormous antibody diversity. I came across this topic in the early 1970s, during my stay in the United States, where, as luck would have it, a new technology in molecular biology had just begun to be developed. After returning to the University of Tokyo in 1974, our group accidentally identified a deletion of antibody genes and proposed a hypothesis on the genetic principle for class switch recombination. We succeeded in proving that hypothesis on a molecular level after moving to Osaka University. Then, in 2000, whilst working at Kyoto University, we found that a single gene encoding activation-induced cytidine deaminase (AID) has a dual role in class switch recombination and somatic mutation, two separate, mysterious phenomena.

In 1992, we started working on PD-1 and found that this acts as a brake in the immune system. Then, in 2002, we discovered that PD-1 inhibition could be effective in treating cancer in animal models. After 22 years of study, this idea has borne fruit in a new, breakthrough immunotherapy that is being hailed as a ‘penicillin moment’ in cancer treatment. I believe that, just as a number of antibiotics developed in the wake of the discovery of penicillin now protect humans against threats of infectious diseases, this discovery will play a leading role in advancement of cancer immunotherapy so that in the future the fear of dying from cancer will cease to exist.

Through evolution, vertebrate animals have developed immunity against infection by microorganisms. In the process, they incidentally acquired a sophisticated system for diversifying genomic information by combining gene fragments. It was doubly fortunate that the success in cancer treatment via PD-1 inhibition brought the realization that immunity, a “weapon” against infectious diseases, could also serve as a “shield” against cancer. It has been said that, whereas humankind’s greatest enemies in the 20th century were infectious diseases, cancer is the major foe in the 21st century. It is a pleasant surprise to discover that the acquired immunity system holds the keys to overcoming both of these difficult medical challenges.

Workshop

Workshop

From the Molecular Immunity to the Suppression of Cancer

date
Saturday, November 12, 2016
palce
Clock Tower Centennial Hall, Kyoto University
Coordinator and Chair
Nagahiro Minato (Executive Vice President, Kyoto University)
Organized by
Inamori Foundation and Kyoto University
Supported by
Kyoto Prefectural Government, Kyoto City Government, NHK
With the cooperation of
Japanese Cancer Association, Japanese Society for Immunology, The Japanese Biochemical Society, The Molecular Biology Society of Japan

Program

13:30
Opening Address and Introduction of Laureate Nagahiro Minato
13:40
Laureate’s Lecture Tasuku Honjo (the Laureate in Basic Sciences)
“Revival of Immunology”
14:30
Intermission
14:40
Lecture Masamichi Muramatsu (Professor, Kanazawa University)
“Antiviral Activity of the AID/APOBEC Family of Cytidine Deaminases”
15:10
Lecture Kenji Chamoto (Assistant Professor, Kyoto University)
“Mitochondria Activation Chemicals Synergize with PD-1 Checkpoint Blockade for T Cell-Dependent Anti-Tumor Activity”
15:40
Intermission
15:55
Lecture Seishi Ogawa (Professor, Kyoto University)
“Cancer Immune Evasion via the Disruption of PD-L1 3’-UTR”
16:25
Lecture Robert A. Anders (Associate Professor, Johns Hopkins University)
“Translating the Power of PD-L1 into Clinical Success”
16:55
Lecture Sidonia Fagarasan (Team Leader, RIKEN)
“Involvement of PD-1 in Antibody Diversification and Body Homeostasis”
17:25
Closing Address Nagahiro Minato
17:30
Closing
PAGETOP