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.
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.
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.