Tasuku Honjo, M.D., Ph.D.Professor
We have been studying molecular mechanisms controlling development and function of lymphocytes. Currently we are addressing important questions:
1) How antibody diversity is controlled by AID, a putative RNA-editing enzyme required for class switch recombination (CSR) and somatic hypermutation (SHM)? We found that AID reduces the amount of Topoisomerase 1, generating non-B DNA and inducing irreversible cleavage by Topoisomearse 1.
2) How PD-1 deficiency leads to development of autoimmune diseases? Why a fraction of cancer patients are not sensitive to the PD-1 blockade cancer immunotherapy.
Research and EducationWe proved that class switch is mediated by recombination with dynamic excision of genomic fragments. In 2000, we discovered activation-induced cytidine deaminase (AID), which is responsible for DNA cleavage to initiate both CSR and SHM. Surprisingly, AID mutates not only the antibody gene, but also protooncogenes. We have found that topoisomerase 1 (Top1) is the enzyme that initiates CSR and SHM by cleaving S and V region, respectively. Furthermore, the transcription coupled nucleosomal reassembly is critical for this Top1-mediated DNA cleavage during CSR and SHM.
Recently, clinical trials of humanized anti-PD-1 antibody against melanoma, renal cancer and lung cancer demonstrated that PD-1 blockade can cure cancer mediated by tumor-reactive T cell activation. Although anti-human PD-1 antibody (Nivolumab) has been approved for the above cancers, more than half patients were still unresponsive. PD-1 blockade leads not only anti-cancer immunity, but slso autoimmunity. The aim of our research is to elucidate how PD-1 control the anti-tumor or auto-immunity and to regulate the sensitivity for the PD-1 blockade cancer immunotherapy.
Blockade of PD-1 pathway provides an effective immunotherapy for cancer
- Muramatsu, M., Kinoshita, K., Fagarasan, S., Yamada, S., Shinkai, Y. and Honjo, T. “Class switch recombination and hypermutation require activation-induced cytidine deaminase (AID), a potential RNA editing enzyme.”Cell (2000) 102(5):553-63.
- Kobayashi, M., Aida, M., Nagaoka, H., Begum, N. A., Kitawaki, Y., Nakata, M., Stanlie, A., Doi, T., Kato, L., Okazaki, I., Shinkura R., Muramatsu, M., Kinoshita, K. and Honjo, T. “AID-induced decrease in topoisomerase 1 induces DNA structural alteration and DNA cleavage for class switch recombination.” Proc. Natl. Acad. Sci. USA (2009) 106:22375-80.
- Stanlie, A., Aida, M., Muramatsu, M., Honjo, T. and Begum, N. A. “Histone3 lysine4 trimethylation regulated by the facilitates chromatin transcription complex is critical for DNA cleavage in class switch recombination.” Proc. Natl. Acad. Sci. USA (2010) 107: 22190-5.
- OkazakiT, Chikuma S, Iwai Y, Fagarasan S, Honjo T. “A rheostat for immune responses: the unique properties of PD-1 and their advantages for clinical application.” Nat Immunol. (2013) 14:1212-8. Review.
- Chamoto K, Chowdhury PS, Kumar A, Sonomura K, Matsuda F, Fagarasan S, Honjo T. “Mitochondrial activation chemicals synergize with surface receptor PD-1 blockade for T cell-dependent antitumor activity.” Proc Natl Acad Sci U S A. (2017) 114:E761-E770.
Immunology and Genomic MedicineProfessor：Tasuku Honjo
Associate Professor：Nasim Begum, Maki Kobayashi
Assistant Professor：Kenji Chamoto